Annex I - âDescription of Workâ - European Society for Molecular ...

SIXTH FRAMEWORK PROGRAMME 

PRIORITY FP6-2003-LIFESCIHEALTH-I 

LSH-2003-1.2.2-2 

Contract for: 

NETWORK OF EXCELLENCE 

Annex I - “Description of Work” 

Project acronym: 

Project full title: 

DiMI 

Diagnostic Molecular Imaging: 

A Network of Excellence for Identification of new 

molecular imaging markers for diagnostic purposes 

Proposal/Contract no.: 512146 

Related to other Contract no.: (to be completed by Commission) 

Date of preparation of Annex I: 15 th November 2004 

Start date of contract: 

(to be completed by Commission)

LSH-2003-1.2.2-2 DiMI-Diagnostic Molecular Imaging 2/412 

Contents 

1. Project summary ..................................................................................................................................... 3 

2. Project objective(s) ..................................................................................................................................4 

3. Participant list ........................................................................................................................................ 11 

4. Relevance to the objectives of the specific programme and / or thematic ........................................13 

5. Potential Impact .....................................................................................................................................16 

5.1 Contributions to standards, if appropriate ..........................................................................18 

6. Outline joint programme of activities (JPA) - for the full duration of the project ..........................19 

6.A Activities .................................................................................................................................22 

6.1 Integrating activities ..................................................................................................22 

6.2 Programme for jointly executed research activities ...............................................26 

6.3 Spreading of excellence activities .............................................................................57 

6.4 Management of the Consortium activities ...............................................................61 

6.B Plans ........................................................................................................................................65 

6.5 Plan for using and disseminating knowledge ..........................................................65 

6.6 Gender Action Plan ...................................................................................................65 

6.7 Raising public participation and awareness ............................................................67 

6.C Milestones ...............................................................................................................................68 

6.8 Major Milestones over full duration of the action ..................................................68 

7. Quality of integration and performance indicators ............................................................................77 

8. Project organisation, management and governance structure ..........................................................81 

9. Detailed joint programme of activities (JPA) – first 18 months ........................................................89 

9.1 Introduction - general description and milestones ..............................................................89 

9.2 Planning and timetable and 9.3 Graphical presentation of work packages .................... 107 

9.4 Work package list /overview ................................................................................................142 

9.5 Deliverables list ..................................................................................................................... 144 

9.6 Work package descriptions .................................................................................................152 

10. Project resources and estimation of incurred eligible costs ............................................................... 215 

10.1 Indicative Efforts full duration ......................................................................................... 215 

10.2 Indicative Efforts first 18 months .................................................................................... 216 

10.3 EC contribution full duration............................................................................................. 242 

10.4 Project management level description of resources and grant ....................................... 246 

11. Ethical Issues ...................................................................................................................................... 249 

Appendix A - Consortium description ................................................................................................... 263 

A.1 Participants and Consortium ............................................................................................. 267 

Researchers and Doctoral Students .......................................................................................... 353


1. Project Summary 

The goal of this proposal (DiMI) is the creation of a network of excellence to integrate multidisciplinary 

research for the development of new probes and multimodal non-invasive imaging technology for early 

diagnosis, assessment of disease progression and treatment evaluation. The general objectives of DiMI 

are: 

• To coordinate and efficiently integrate more than 45 research groups from various disciplines to 

study non-invasively gene expression and function in major diseases such as neurodegeneration, 

stroke, heart failure, atherosclerosis and autoimmune diseases. 

• To advance molecular imaging for diagnostic purposes to a high scientific, technical and 

economical status and to form synergistic partnerships with other EU-funded networks and 

projects to translate fundamental research discoveries into medical applications, health benefit and 

value for European society. 

• To stimulate strong technological developments inspired by the specific research projects by the 

implementation of Technology and Training Platforms (DiMI-TTPs). 

Because of the multi-disciplinary nature of molecular imaging technology the instrument for our goals is 

a Network of Excellence bringing together genome-oriented scientists with the various actors of imaging 

science and clinicians dedicated to formulate novel diagnostic methods based on imaging. 

The Joint Programme of Activities comprises 

1. Integrating Activities (sharing facilities, exchange of personnel, integration of SMEs) 

2. Three horizontal and 3 vertical research activities in the JPRA serving integration and crossfertilization: 

• Horizontal activities comprising technological aspects: 

1. multimodal imaging technology, 

2. library of diagnostic and smart probes, 

3. library of animal models for image validation. 

• Vertical research activities comprising major applications in 

1. neuroscience, 

2. cardiovascular research, 

3. inflammation & regeneration. 

3. Activities for Dissemination with special respect to training, education, communication and 

management of common knowledge and intellectual property rights. 

The strengths of this proposal are that it will coordinate research and training related to molecular 

imaging for diagnostic purposes with special emphasis on “bench-to-bedside” (translational) 

applications. With its intellectual excellence and critical mass the DiMI-consortium will reach a durable 

integration into the European Research Area and gain European leadership in the creation of common 

data platforms and relevant standards and guidelines in terms of molecular imaging for diagnostic 

purposes.


2. Project Objectives 

The main objective of “Diagnostic Molecular Imaging” (DiMI) is the creation of a network of excellence to 

integrate multidisciplinary research aiming towards the development of new probes and multimodal noninvasive 

imaging technology for early diagnosis, assessment of disease progression and treatment evaluation 

of various human diseases. DiMI will 

• further advance the exciting and rapidly emerging technology of molecular imaging; 

• coordinate research and research training related to molecular imaging for diagnostic purposes; 

• develop and implement a program that cross trains research scientists in the biological and 

quantitative sciences; 

• aim towards a durable integration of the partners activities to act as a world force in molecular 

imaging; 

• form synergistic partnerships with other EU-funded networks and projects to translate fundamental 

research discoveries into medical applications; 

• coordinate and collaborate with academia and industry to translate fundamental crosscutting 

discoveries and developments in imaging and engineering into biomedical applications; 

• aim towards the European leadership role in the creation of common data platforms and relevant 

standards and guidelines in terms of molecular imaging for diagnostic purposes. 

The great potential of molecular imaging technology especially in translational research (“from bench to 

bedside”) has been recognized since 2000 by the National Institute of Health (NIH) and the National Cancer 

Institute (NCI) of the United States and also by the European Commission, which is funding an IP on 

Molecular Imaging for Phenotyping (MI; LSH-2002-1.1.3-2) as well as an NoE on Molecular Imaging for 

Early Detection and Therapy Evaluation of Cancer (EMIL; LSH-2002-2.2.0-5). The overall aim of this 

proposal is the further extension and complementation of EMIL with its already existing platforms for 

molecular imaging in various applications in cancer research towards the establishment of a NoE for new 

molecular imaging probes and diagnostic tests with its specific imaging acquisition methods and technology 

for 

‣ early diagnosis of other major diseases: 

1. neurological, 

2. cardiovascular, 

3. inflammation and regeneration; 

‣ monitoring disease progression, and 

‣ validation and interpretation of molecular imaging markers obtained in vivo to enable an improved 

monitoring of the effectiveness of individual therapies. 

In general, the potential of molecular imaging is a non-invasive assessment, visualization, characterization 

and quantification of gene and protein function, protein-protein interaction, and profiling of signal 

transduction pathways in animal models of human disease and even in patients (Jacobs et al. 2001) to get 

further insight into the molecular pathology of a specific disease. The novelty of molecular imaging is that 

the cellular and molecular pathways and in vivo mechanisms of disease can be directly assessed in the 

physiologically authentic environment on a dynamic and repeated basis (Jacobs et al. 2003; Massoud & 

Gambhir 2003). Moreover, the knowledge of an underlying genetic defect and the understanding of related 

pathophysiological alterations in, for example, neuronal degeneration, atherosclerotic plaque formation, 

migration of inflammatory cells, signal transduction, and others are the first steps towards the development of 

new drug-, gene- or cell-based and, most importantly, patient-tailored therapies (Rudin & Weissleder 2003).


Molecular imaging employs probes which are specific for a certain molecular event, which provides the basis 

for understanding of integrative biology, earlier detection and characterization of disease, and therapy 

evaluation, all in the same, living, but diseased subject. Molecular imaging enables the optimization of drug 

and gene therapy by imaging of drug effects at the molecular and cellular level as well as by the assessment 

of disease progression with and without therapy. Most importantly, molecular imaging can be performed in a 

relatively rapid, reproducible, and quantitative manner, which enables the monitoring of time-dependent 

experimental, developmental, environmental, and therapeutic influences on gene and protein function in the 

same animal or patient. The multidisciplinary research within the proposed DiMI uses the tools of molecular 

imaging which are based on existing imaging technology such as positron emission tomography (PET), single 

photon emission computed tomography (SPECT), magnetic resonance imaging and spectroscopy (MRI; 

MRS) and optical imaging (OI). Each of these imaging modalities has certain advantages and disadvantages, 

and the overall goal of DiMI is to make use of and integrate the individual advantages of the single imaging 

modalities. 

The present initiative is taken to capitalize on the extraordinary opportunity for studying non-invasively gene 

expression and function in major diseases such as neurodegeneration, stroke, heart failure, atherosclerosis 

and autoimmune diseases due to recent advances in molecular imaging modalities. Because molecular 

imaging is fundamentally multi-disciplinary by nature, featuring applications in biology, cell biology, 

biochemistry, genetics, bioinformatics, pharmacology, instrumentation physics, etc. the instrument for this 

goal is a Network of Excellence bringing together genome-oriented scientists with the various actors of 

imaging science and clinicians dedicated to formulate novel diagnostic methods based on imaging. 

The four goals and objectives of DiMI are 

1. to create a NoE for six integrating research activities with three horizontal and three vertical research 

activities, the integration of SMEs, and a program for training and dissemination; 

2. to integrate and coordinate the individual research activities for Diagnostic Molecular Imaging in 

Europe; 

3. to achieve sufficient strengthening of Molecular Imaging research activities on the European level in 

comparison to the ongoing activities in the United States; 

4. to stimulate new technological developments based on the strong interaction of various disciplines 

each having specific needs from the perspective of translational research (“from bench to bedside”). 

1. Creating a NoE for research activities of DiMI integrating SMEs, training and dissemination 

Six main scientific goals will be the focus of DiMI, three of them comprising (horizontal) technical aspects 

serving the basis of three further goals concerning (vertical) experimental and clinical imaging applications 

(Fig.1). 

The horizontal goals comprise 

‣ the optimization of technology for integration of multimodal radiotracer, magnetic resonance and 

optical imaging methods. This requires the co-registration of molecular information acquired by each 

of these imaging modalities on a voxel-by-voxel basis. The specific technological requirements for 

neurological and cardiovascular diseases and inflammation and regeneration processes have to be 

taken into account (e.g. movement of the heart, migration of single cells). 

‣ the development of new diagnostic and smart imaging probes which are specific for a given 

molecular process and which can be detected and localized by at least one imaging modality. 

‣ the use and further development of mouse models of human neurological, cardiovascular and 

autoimmune diseases to directly study alteration of gene expression, transcriptional regulation and 

molecular events leading e.g. to neurodegeneration and plaque formation in vivo over an extended


period of time in the same animal. These animal models shall serve for adequate validation of in vivo 

molecular imaging markers with other known molecular markers as assessed by “invasive” 

technologies in cellular and molecular biology (e.g. PCR, Southern-, Northern-, Western-blot, 

immunohistochemistry, etc.). 

The vertical goals aim towards 

‣ the non-invasive characterization (“phenotyping”) of animal models and patients for early diagnosis 

of neurodegenerative, cardiovascular and autoimmune diseases; 

‣ imaging of key regulators of atherosclerotic plaque formation, cardiac dysfunction and inflammation; 

‣ imaging disease progression and assessment of the effects of molecular targeted therapies; 

‣ imaging the dynamics within neural networks after gene and stem cell-based therapies for e.g. 

ischemic stroke; 

‣ imaging the effects of molecular targeted therapies and stem cell replacement after myocardial 

infarction. 

The six main scientific goals of the proposed DiMI incorporate 

‣ the integration of related SMEs and 

‣ a specific workpackage aiming on training and dissemination. A major objective of DiMI is to 

provide support for pre- and post-doctoral cross-disciplinary training programs in the field of in vivo 

diagnostic molecular imaging. The training program of DiMI will be based on the implementation 

of training platforms and designed for the training of young scientists providing the necessary 

technical know-how to the European Research Area in the field of diagnostic molecular imaging. 

Figure 1. Creation of a NoE for horizontal and vertical research activities 

4. 

TRAINING 

& 

DISSEMI- 

NATION 

Bertrand 

Tavitian 

3. 

INTE- 

GRATION 

OF 

SMEs 

Marie 

Meynadier 

2.1 

NEUROSCIENCE 

Phenotyping of animal 

models and patients for 

early diagnosis and imaging 

disease progression 

Gitte Knudsen 

Annemie van der Linden 

Karl Herholz 

2.2 

CARDIOVASCULAR 

Early detection of 

atherosclerosis / cardiac 

dysfunction and imaging 


Frank Bengel 

Chrit Moonen 

2.3 

INFLAMMATION / 

REGENERATION 

In vivo detection of 

transcriptional regulation and 

migration of inflammatory 

and stem cells 

Harald Carlson 

Andreas Jacobs 

1.3 

Animal Models 

“Animal Imaging Library” for validation of molecular markers in vitro and in vivo 

Anna Planas, Adriana Maggi, Harald Carlson 

1.2 

Diagnostic Molecular Imaging Probes 

Development of improved “smart” diagnostic imaging agents 

Denis Guilloteau, Silvio Aime 

1.1 

Diagnostic Molecular Imaging Technology 

Integrating multimodal imaging technology (MRI, PET, SPECT, OI) 

John Clark, Marie Meynadier


2. Integrate and coordinate the individual research activities for Diagnostic Molecular Imaging 

The great potential of molecular imaging technology has been recognized by the European Commission in 

funding an IP on Molecular Imaging for Phenotyping (MI; LSH-2002-1.1.3-2) as well as an NoE on 

Molecular Imaging for Combating Cancer (EMIL; LSH-2002-2.2.0-5). However, both of these activities 

focus on a single molecular imaging technology (MI for phenotyping by optical imaging only) or a single 

molecular imaging application (EMIL for combating cancer only). Therefore, the basic goal of the DiMI- 

NoE is to structure and integrate the highly interdisciplinary scientific field acting with various imaging 

methods (radionuclide, magnetic resonance, optical) in various other major diseases (neurology, 

cardiovascular, autoimmune) bridging together these previously separate and partly unrelated disciplines. 

Over 50 groups from universities, research centres and SMEs, with unparalleled experience in initiating 

projects as well as in developing and operating structures similar to a NoE, will join forces and resources in 

the DiMI-NoE. Already identified as key players in their respective field of excellence, they have been 

selected for the complementarities of their competence, their multidisciplinarity (biology, cell biology, 

chemistry, biochemistry, radiochemistry, bioinformatics, instrumentation physics, engineering science, 

medical science) and their strong intention to establish a framework for longer-term cooperation. 

Within 5 years, DiMI will develop into a virtual European Institute for Diagnostic Molecular Imaging. This 

Institute embodies the most efficient and durable way to shape European research activities defining a 

common strategy and policy for the most advanced institutes and organisations coming from 11 european 

countries, and it is designed to facilitate intellectual cross-fertilization among other groups of investigators. 

Most importantly, the activities of DiMI will stimulate collaboration and exchanges with other related 

European IPs and NoEs such as specific programs in neuroscience and cardiovascular disease, gene and stem 

cell-based therapy, Imaging for Phenotyping and for Combating Cancer, etc. 

Mesureables for a successful implementation, integration and coordination of DiMI will be the amount and 

quality of 

‣ publications arisen within the DiMI NoE; 

‣ early and experienced researchers involved in the Joint Research Program; 

‣ patents obtained from networking DiMI laboratories; 

‣ new research tools developed and marketed by related SMEs; and most importantly 

‣ new diagnostic tools which will be implemented into routine clinical application. 

3. Strengthening the Diagnostic Molecular Imaging research activities on the European level 

With the advances in genomics and proteomics, the type and state of a disease will be more and more based 

on a molecular diagnosis. Molecular imaging uses the same key molecular events for early diagnosis, early 

intervention and investigation of the efficiency of therapy. Its non-invasive, harmless nature and its 

repeatability enables the implementation of key molecular imaging markers which can be non-invasively 

assessed in vivo for targeted management of patients. Especially with the implementation of new molecular 

therapies including gene and cell-based therapies the amount of animals to be studied can be significantly 

reduced by having the read-out of the effectiveness directly in the same animal. At the same time this allows 

the design and implementation of patient-tailored, targeted therapies which are controlled by imaging.


Various European teams hold a leading international position in the field of molecular imaging. However, in 

contrast to the United States where the field of molecular imaging has been fully recognized as one of the 

main important technologies for advancing the understanding of disease and for the development of better 

treatment strategies for patients by the implementation of 

‣ the National Institute for BioImaging and BioEngineering (NIBIB; Budget in 2003: $121.378.000); 

‣ three large molecular imaging centres (MIC) in Boston, New York and Los Angeles funded by the 

NIH and NCI with a budget of over 2.000.000 $ per year; 

‣ foundation of the Society for Molecular Imaging (SMI) and the Academy for Molecular Imaging 

(AMI) with over 1000 active members mostly from the US; 

little efforts have been made in Europe to attain the critical mass of molecular imaging technology necessary 

to reap the benefits for improvement of human health and insemination of biotech and pharmaceutical 

industries. DiMI brings together top scientists to establish Europe as a world force in molecular imaging for 

diagnostic purposes. Its Joint Program of Activities including research, education, dissemination and 

management, creates a sustainable framework for one of the most promising and exciting new technologies 

in the European Research and Health Care Area. It is the networking of individual elements of excellence, 

previously scattered, that will provide a leading edge for European research, health care and economy in 

their competition against similar initiatives outside Europe. 

Promoting Molecular Imaging will directly 

‣ support science; 

‣ improve health care; and 

‣ result into high economic benefits. The Medical Isotopes Market will show tremendous growth 

potential with an annual growth rate of 9.6 % for the next 20 years (Frost & Sullivan 1997: FFTF 

Medical Isotopes Market Study). The diagnostic radiopharmaceutical market will grow from $ 2.7 

billion to $ 18.7 billion in the next five years (annual growth rate 7-16 %/year), and the therapeutic 

radiopharmaceutical market will grow from $244 million to $ 1.11 billion (Philips Medical Systems 

2001: molecular imaging and diagnostics positioning paper; DOE expert panel 1999: forecast future 

demand for medical isotopes). By integrating RTD-intensive SMEs, DiMI will directly contribute to 

the transformation of its world-leading research into economic benefits. Moreover, DiMI will 

benefit large pharmaceutical companies which needs to reduce costs of drug development. A recent 

study of drug development estimates that costs per drug average $ 802 million and concluded that 

using modern pre-clinical screens, such as pre-clinical molecular imaging, to boost success rates, 

could reduce costs per drug by $341 million (Tufts Center for the Study of Drug development 2002). 

Measureables for the achievement of sufficient strengthening of European Molecular imaging research for 

diagnostic purpose are 

‣ the amount of additional funds raised for diagnostic molecular imaging research using DiMI as a 

platform of excellence; 

‣ a sustained Joint Research and Training program of highest quality extending the 5-year period; 

‣ patents obtained from networking DiMI laboratories; 

‣ new research tools and diagnostic tests which will be commercialized and implemented in 

experimental research and clinical application. 

4. Stimulate new technological developments and training 

Ambitious objectives can only be based on excellent infrastructures, and one of the major goals of DiMI will 

be to establish strong hardware-oriented core facilities linked to a network of institutions involved in basic 

research, clinical application, and commercial applications. The first 18 months objective will be to establish


a limited number (12) of core multidisciplinary DiMI Technology and Training Platforms (DiMI-TTPs) with 

the required critical mass of technological and human resources necessary to drive ambitious priority 

research projects. These training platforms will give scientists from a variety of fields (imaging, including 

the physics of nuclear, optics and magnetic imaging, chemistry including radiopharmacy, cellular and 

molecular biology, biochemistry, pharmacology, computer science for image analysis, biomedical 

engineering, neuro- and cardiovascular sciences) the means of conducting multidisciplinary research in a 

highly collaborative atmosphere and extend their research outside of their own discipline to establish 

creative, productive interactions. DiMI shall then provide extensive support including funding for feasibility 

testing of new projects. It is expected that the range of research programs supported by DiMI will by 

extremely dynamic not only restricted to those identified in this initial proposal. A high priority will be the 

identification and support of new pilot projects that will take advantage of emerging research opportunities. 

The DiMI-TTPs will provide specialized resource facilities and services in order to break through the barrier 

to productive scientific interaction due to the lack of available facilities for cross-disciplinary experiments. 

The involvement of SMEs is of particularly interest in the field of molecular imaging. Many demands on 

equipment and reagents that are not presently satisfied prohibit ready access to investigators interested in 

expanding their studies into new areas of research, including Small and Medium Enterprises (SMEs). SMEs 

serve already as providers for instrumentation or as biotech start-ups in the development of molecular probes 

and potentially diagnostic or therapeutic molecules. In both cases, SMEs need for their development access 

to imaging technology platforms and the associated technical know-how. Instrumentation providers greatly 

benefit from early, strong coupling with biologists for the design, evolution and validation of their 

prototypes. Biotech companies do not have the financial capacity to purchase high-end imaging equipment 

that is needed for their development. DiMI will couple specific SMEs to the DiMI technology and training 

platforms facilitating early stage tests of new prototypes provided by SMEs thereby helping the translation 

into further commercialization. 

To educate scientists, clinicians and society about the potential impact of diagnostic molecular imaging and 

to ensure responsible development of devices, materials and services according to European and 

international social and ethical standards, DiMI will implement 

‣ joined training and education courses with a strong program of practical training in selected topics 

(e.g. probe development, radiopharmacy, stem cell labelling, multimodality imaging by PET, MRI, 

OI). This training will be open to local students of the university, students involved in the Marie 

Curie programs and to other students or scientists inside or outside the network. Thus, DiMI will 

offer access to various laboratories in the European Research Arena to a concentrated pool of 

expertise in a wide range of disciplines devoted to in vivo diagnostic molecular imaging. 

‣ formation of a European Society of Molecular Imaging (ESMI; together with the consortia of 

Molecular Imaging for Phenotyping and Cancer, respectively). Therefore, DiMI will function as a 

pacemaker in promoting molecular imaging technology for diagnostic and other purposes. 

‣ web-based communication and dissemination ensuring that the activities of DiMI and ESMI with 

respect to research, training, funding, and annual research meetings will be transparent and open to 

public attention. 

Measureables for successful stimulation of new technological developments and training are 

‣ implementation of 12 DiMI Technology and Training Platforms (DiMI-TTPs); addition of new 

DiMI-TTPs throughout the five year period is possible and will be based on the complementarity to 

the DiMI-TTPs which are established in the initial period; 

‣ creation of the European Society for Molecular Imaging 

‣ allocation of the Annual Meeting of the Society for Molecular Imaging to one of the DiMI-TTP sites 

‣ number of early-staged researchers involved in the training program;


‣ participation of European students and scientists to training courses; 

‣ number of imaging sessions of newly developed technology and molecules; 

‣ the equivalent capital expenditure of prototypes and number of SME man-days spent in DiMI-TTPs 

Ethical Issues 

One of the major advances of Molecular Imaging technology is the investigation of molecular processes in 

vivo in the same subject over time (molecular kinetics). In that, molecular imaging promises not only to 

detect molecular mechanisms of disease at an early disease stage and potential molecular therapeutic targets 

in vivo, but also the investigation of a therapeutic intervention in the same experimental animal or patient 

over time. This kinetic analysis of target molecular events in vivo by molecular imaging will have a hugh 

impact in the way animal experiments are conducted in the future. Imaging experiments will spare timeconsuming 

pathological examinations in a large number of animals but will focus on direct localization and 

quantification of the target molecular process in vivo in a small number. This will save animal resources as 

well as experimental time. In that molecular imaging is by nature following the 3R principle of refinement, 

reduction and replacement. 

References 

1. Jacobs AH, Voges J, Reszka R, Lercher M, Gossmann A, Kracht L, Kaestle Ch, Wagner R, Wienhard K, Heiss 

WD. Non-invasive assessment of vector-mediated gene expression in a phase I/II clinical glioma gene therapy trial 

by positron emission tomography. Lancet 2001; 358:727-729. 

2. Jacobs AH, Li H, Winkeler A, Hilker R, Knoess C, Ruger A, Galldiks N, Schaller B, Sobesky J, Kracht L, 

Monfared P, Klein M, Vollmar S, Bauer B, Wagner R, Graf R, Wienhard K, Herholz K, Heiss WD. PET-based 

molecular imaging in neuroscience. Eur J Nucl Med Mol Imaging 2003;30:1051-1065 

3. Massoud, TF, Gambhir SS. Molecular imaging in living subjects: seeing fundamental biological processes in a new 

light. Genes Dev. 2003;17:545-80. 

4. Rudin M, Weissleder R. Molecular imaging in drug discovery and development. 

Nat Rev Drug Discov. 2003;2:123-31.


3. Participant List 

Particip. Partic. Participant name 

Participant Country Date enter Date exit 

Role* Number 

short name 

project** project** 

CO 1 Prof. Dr. A.H. Jacobs MEK D month 1 month 60 

Prof. Dr. K. Herholz 

Prof. Dr. W.D. Heiss 

CR 2 Prof. Dr. J. Clark UCAM- GB month 1 month 60 

WBIC 

CR 3 Prof. Dr. S. Aime UniTo I month 1 month 60 

CR 4a Prof. Dr. Guilloteau UniTours F month 1 month 60 

4b = 46 Prof. Dr. Benderbous 

CR 5 Prof. Dr. A. Planas IDIBAPS E month 1 month 60 

CR 6 Prof. Dr. A. Maggi UNIMI I month 1 month 60 

CR 7 Prof. Dr. G. Knudsen RH-NRU DK month 1 month 60 

CR 8 Prof. Dr. A. van der Linden UA B month 1 month 60 

CR 9a Prof. Dr. C. Moonen CNRS F month 1 month 60 

9b = 28 

9c = 30 

Dr. L. Bridal 

Prof. Dr. P. Laugier 

Prof. Dr. R. Mastrippolito 

CR 10 PD Dr. F. Bengel 

NUK_TUM D month 1 month 60 

Prof. Dr. M. Schwaiger 

CR 11 Dr. H. Carlsen 

UiO N month 1 month 60 

CR 

12a 

12b = 23 

12c = 38 

Prof. Dr. R. Blomhoff 

Prof. Dr. B. Tavitian 

Prof. Dr. P. Hantraye 

Dr. P. Rizo 

CEA F month 1 month 60 

CR 13 Dr. M. Meynadier BIOSPACE F month 1 month 60 

CR 14a Prof. Dr. V. Baekelandt K.U.Leuven B month 1 month 60 

14b = 41 Prof. Dr. K. van Laere R&D 

CR 

15a 

15b = 16 

Prof. Dr. A. Verbruggen 

Dr. D. Kirik 

Prof. Dr. A. Björklund 

Prof. Dr. T. Blom 

Prof. Dr. R. Holmdahl 

ULUND S month 1 month 60 

CR 17a Prof. Dr. D.J. Brooks Imperial UK month 1 month 60 

17b Dr. H. Jones 

College Lo# 

CR 18 Prof. Dr. I. Carrio IRSCSP E month 1 month 60 

CR 20 Prof. Dr. K. Ebmeier UEDIN GB month 1 month 60 

CR 21 Prof. Dr. B. Fleischmann UKB D month 1 month 60 

CR 

22a 

22b 

Prof. Dr. C. Halldin 

Prof. Dr. A. Nordberg 

Prof. Dr. Langström 

KI 

KI Neurotec 

S month 1 month 60 

CR 24 Dr. A. Bauer FZJ D month 1 month 60 

CR 25 Prof. Dr. M. Hoehn MPIfnF D month 1 month 60 

CR 26 Dr. L. Hofstra CARIM NL month 1 month 60 

CR 27 Prof. Dr. M. Horn CBI S month 1 month 60 

CR 

29a 

29b 

Prof. Dr. K. Leenders 

Dr. P.H. Elsinga 

AZG 

Groningen 

PET Center 

NL month 1 month 60 

CR 31 Dr. C.M. Morris UNEW GB month 1 month 60 

CR 32 Prof. Dr. K. Nicolay TU/e NL month 1 month 60 

CR 33 Prof. Dr. S. Pappata CNR-IBB I month 1 month 60 

CR 34 Dr. A. Auricchio FTELE.IGM I month 1 month 60 

CR 35 Prof. Dr. D. Parker DUR GB month 1 month 60 

CR 36 Prof. Dr. D. Perani UVita-P I month 1 month 60


CR 37 Prof. Dr. R. Poelmann LUMC NL month 1 month 60 

CR 39 Prof. Dr. E. Salmon ULG B month 1 month 60 

CR 40a Prof. Dr. M. Schäfers UKM D month 1 month 60 

40b PD. Dr. C. Bremer 

CR 42 Prof. Dr. D. Vivien CYCERON F month 1 month 60 

CR 43 Dr. H. Carlsen MT N month 1 month 60 

CR 45 Dr. J. Masdeu UNAV-FIMA E month 1 month 60 

CR 47 J. B. Deloye Cyclopharma F month 1 month 60 

CR 48 S. Wecker MEDRES D month 1 month 60 

CR 49 Dr. S. Köks Visgenyx EST month 1 month 60 

CR 50 Prof. I. Lukes Charles 

CZ month 1 month 60 

University 

CR 51 Dr. R. Mikolajczak POLATOM PL month 1 month 60 

CR 52 Prof. E. Sykova IEM ASCR CZ month 1 month 60 

*CO = Coordinator 

CR = Contractor 

** Normally insert “month 1 (start of project)” and “month n (end of project)” 

These columns are needed for possible later contract revisions caused by joining/leaving participants


4. Relevance to the Objectives of the LifeSciHealth Priority 

Molecular imaging is a fast developing technology spanning a broad field of research areas aiming towards 

the non-invasive localization of biological and molecular processes of interest in normal and diseased cells in 

animal models and humans in vivo. The field of molecular imaging is influenced to a great extend by the 

advances in genomics and proteomics allowing the determination of the molecular nature of a disease and on 

the other side by the technological achievements made during the past decade with respect to resolution and 

sensitivity of radionuclide, magnetic resonance and optical imaging technology. The main and most 

intriguing advantage of molecular imaging is the kinetic analysis of a given molecular event in the same 

experimental subject over time. This will allow a non-invasive characterization and “phenotyping” of animal 

models of human disease at various disease stages, under certain pathophysiological stimuli and after 

therapeutic intervention, respectively. After a period of validation of in vivo imaging data with a broad panel 

of invasive data, molecular imaging will lead to an overall decrease of the amount of animals and of the time 

spent for invasive procedures currently used for phenotyping. From the ethical perspective, this will increase 

the overall acceptance of basic animal research in the public domain. 

The potential broad applications of imaging molecular events in vivo are in the study of cell biology, 

biochemistry, gene/protein function and regulation, signal transduction, transcriptional regulation, and 

characterization of transgenic animals. Most importantly, molecular imaging will have great implications 

• in the pre-clinical (early) diagnosis of a disease, 

• in the monitoring of disease progression with and without therapy, 

• in the identification of potential molecular therapeutic targets, 

• in the implementation of molecular treatment strategies including gene and cell-based strategies, and 

• in their successful implementation into clinical application. 

Especially in translational research (“from bench to bedside”) molecular imaging will allow the non-invasive 

follow-up of individual patients with respect to a given molecular imaging marker revealing important 

information about the possible way of action of a new drug at a very early stage (Phase I/II clinical trials) 

avoiding time- and resource-consuming Phase III trials in the case of drug failure. Moreover, treatment 

strategies based on gene therapies and stem cells will rely to a great part on molecular imaging technology for 

their safe and successful implementation into the clinical application, because molecular imaging technology 

will allow the determination of the transduced tissue dose of vector-mediated gene expression as well as the 

visualization of the migration and differentiation of stem cells. Especially in gene and cell-based research the 

aspect of “seeing is believing” is highly important in the determination of efficiency and safety of these 

treatment regimens. 

The scope of the current proposal is to create a European network involving groups from basic research to 

clinical application, from basic chemistry to applied radiopharmacy, from basic physics to instrumentation 

technology, etc. to coordinate the further development of experimental and translational molecular imaging 

technology through the development of new molecular probes and new imaging acquisition methods for the 

identification of molecular imaging markers which can be used for early diagnosis, disease progression and 

treatment evaluation even in the clinical application. The newly identified molecular imaging markers which 

can be implemented successfully in clinical application will have a great impact on 

• the understanding of molecular mechanisms of disease 

• health care and patient management, and 

• the design of multi-center drug trials.


The proposed multidisciplinary network with its high level of basic and translational research in the proposed 

JPR will provide the European research community with 

• a library for new diagnostic molecular imaging probes, which will be tested in 

• a library of defined animal models for human diseases, and 

• which will serve as model markers for application in humans at a later stage. 

Excellence of DiMI 

The DiMI consortium consists of scientific groups of highest quality with a long-standing experience in 

probe development, animal models, development of image acquisition and coregistration, and molecular 

imaging applications in humans with a high critical mass to work as “pace maker” for highly ambitious 

research goals such as molecular imaging for diagnostic purposes. Many of the DiMI groups have longstanding 

interactions with SMEs, local networks of collaborations, and some groups served successfully as 

Coordinators for European funded projects in the past. The DiMI technology and training platforms (DiMI- 

TTPs) will serve as core excellence centres promoting the development of molecular probes and imaging 

technology, serving European infrastructure ready to exploit breakthroughs in these techniques. Improving 

the European science and technology in molecular imaging is essential for fast transfer to in vivo applications 

in humans. In most sectors of biotechnology, immediate reaction is the key to seizing opportunities and gain 

leadership. Rapid reaction requires improved organisational innovation and performance, and a capacity to 

mobilize intellectual power in the use of new technologies. 

Interaction with SME 

The SMEs associated with various members of the DiMI consortium will bring competitiveness to the 

network by reducing the transfer time between academia and the market. Integration of these activities into a 

special SME integration activity will encourage the dialogue with academic labs and ensure market 

orientation of promising devices and products. Innovative SMEs will be offered to test new instruments and 

compounds at the various DiMI-TTPs in different environments and countries to bridge the usual gap 

between fundamental applied sciences. 

Lifelong Health and Healthy Society 

The primary mission of DiMI is to improve health by structuring and conducting interdisciplinary research 

and training in molecular and biomedical imaging. This is achieved through the development and translation 

of emerging technologies that enable fundamental biomedical discoveries and facilitate early disease 

detection and management. 

Among the series of factors likely to induce a general change and restructuring process of the EU health care 

systems, the OECD lists: 

• an ageing population; 

• medical technology development; 

• higher people’s expectations and concerns; 

• information technology diffusion; and 

• changing disease patterns. 

The incidence of neurodegenerative and cardiovascular diseases increases with age, and the European 

population is ageing and has higher health expectations. Treatment efficacy greatly depends on early


diagnosis enabling early targeted intervention making testing of efficiency necessary. Molecular geno- and 

phenotyping is the most precise way to define the basis for disease, to develop targeted therapies, and to 

improve outcome. Diagnostic molecular imaging will, therefore, have a great impact and key role in disease 

management, qualitiy of health care and better life expectancies. The DiMI consortium originates from 

laboratories which institutions have a clinical activity and includes workpackages to monitor the clinical 

passage of pre-clinical technological developments. Several WPs of the Joint Program of Research 

Activities are especially oriented towards clinical application. 

Performance and international position of Europe 

Traditionally, European industry has a world-wide leadership in the field of in vivo diagnostic agents 

(Amersham (UK), Bracco (I), Guerbet (F) and Schering (D)). This commercial dominance on the market has 

been achieved thanks to the excellent work carried out in academic research centres. The breakthrough 

brought about by molecular imaging may cause drastic changes in this scenario if the EU does not take 

action in sufficiently supporting this highly innovative field. It is expected that in the next ten years the 

growth of molecular imaging agents will overcome the growth of imaging instrumentation. The United 

States have undertaken an impressive program of activities, investing over $ 200 million (in 2002) in the 

field of biomedical imaging by the National Institute of Biomedical Imaging and Bioengineering as well as 

by the NCI. DiMI strongly addresses the objectives of gathering cohesion across a critical mass of the most 

important European research centres in the field of Diagnostic Molecular Imaging. Through the DiMI 

network, interdisciplinary collaborations will be facilitated focussing on the most challenging objectives in a 

unique assembly of teams at the frontier of molecular biology, pharmacology, chemistry, radiopharmacy, 

neuroscience and medicine. 

Science and Technology 

DiMI directly addresses several areas of science and technology where world-class competencies and 

exploitation capabilities must be developed and maintained: 

• Knowledge Sciences and Technologies: DiMI builds a network for supporting one of the fastest 

growing areas of Health and Life Sciences. For the first time in the history of science and medicine 

it becomes feasible to study life without destroying it. This is a revolutionary advance in our 

approach to biological knowledge acquisition. 

• Health Sciences and Technologies: Molecular imaging is one of the fields in medicine where 

technological implementations have the greatest impact. Early diagnosis, follow-up of disease 

progression and efficiency of therapy as well as research for new treatments and drugs are being 

more and more dependant on high-level technological platforms and tools such as the proposed 

DiMI-TTPs. 

• Complexity and Complex Systems: The use of molecular imaging markers to non-invasively 

monitor disease progress or remission and to assess therapeutic efficacy will be much more 

successful if we can validate their use in the complex system of a living individual. 

• Fundamental Science: Molecular imaging relies on a multidisciplinary and unique combination of 

physics, chemistry and biology promoted by the DiMI-JPRA.


5. Potential Impact 

Molecular imaging is a multidisciplinary technology relying on the integration of multiple research 

disciplines. The high speed of development of imaging technology for imaging cells, organ systems, animal 

models and humans at high spatial resolution and with high sensitivity has opened various windows for the 

detailed study of physiological, biological and molecular events in the intact living organism. The 

development of specific molecular probes requires the common knowledge of disease specific targets and of 

how these can be used in the follow-up of therapies and in human application. Therefore, molecular imaging 

relies, more than any other science specialty, on an efficient integration of all related basic (physics, 

instrumentation technology, bioinformatics, chemistry and biochemistry, radiopharmacy, molecular and cell 

biology) and disease-related disciplines. 

Existing need to strengthen science and technology in molecular imaging for diagnostic purposes 

Traditionally the links between engineering, chemistry and biology are loose in European laboratories. In a 

field such as molecular imaging, which combines basic sciences with technological developments, this 

fragmentation has created a drawback and loss of potential for new developments in instrumentation and 

chemistry. For instance, excellent chemistry groups are not encouraged to develop pharmacological 

applications if they don’t have an easy access to the evaluation of pharmacokinetics and activity in vivo. As 

a consequence, Europe has lost a momentum in the field of molecular imaging, a field which is and will be 

increasingly important in diagnosis and therapy of major diseases. This low momentum is not irremediable 

because traditionally, European industry has kept a world-wide leadership in the field of in vivo diagnostic 

agents (e.g. Amersham (UK), Bracco (I), Guerbet (F), Schering (D)). This commercial dominance of the 

market has been achieved also thanks to the excellent work carried out in academic research centers. 

Similarly, thanks to its excellent academic breeding ground Europe has strong basic research in imaging 

science, and some US companies keep their research teams based in Europe. Nevertheless, the molecular 

imaging approach may cause drastic changes if Europe does not take proper initiatives in supporting 

innovations in the field. It is expected that in the next ten years the growth of molecular imaging agents will 

overcome the growth of imaging instrumentation. The creation of DiMI will greatly improve the current 

situation by facilitating the presence of engineering and chemistry scientists, and particularly those scientists 

developing equipment and probes in SMEs, inside biology research laboratories fostering close interactions 

between all research disciplines. 

Due to the multidisciplinary nature of molecular imaging, an efficient channelling and structuring of 

activities is required on the European level so that these activities will lead to new common knowledge 

which can be efficiently translated into true value for the health sciences. This structuring shall safe time, 

costs and frustration in the development of new imaging technology which can be applied in a library of 

animal models for human diseases as well as in humans. These structuring efforts will also have a direct 

impact on commercialisation of new technology and industry. 

Restructuring the existing research capacities and the way research is carried out in Europe 

The DiMI NoE will join, bring together and reinforce researchers and scientists from all specialties in the 

field of molecular imaging in a joined program of research activities (JPRA) and in joined target applications 

of highest quality, thus gathering cohesion across the most important European research centres already


identified as excellent in the field of molecular imaging. The overall goal is, that the basic engineer 

understands the model-specific needs and limitations; the basic chemist and radiopharmacist interact with the 

experimental scientists for the identification and development of disease-specific probes; and all these 

specialists interact with the human scientists to study the feasibility and effectiveness in human applications. 

Moreover, as technology, probes and model systems might be similar in the application of imaging 

technology in various diseases, cross-fertilization between the individual human sciences will again stimulate 

the developments in basic research. By bringing together a critical mass of researchers with complementary 

expertise, progress will accelerate and new avenues of research will be identified. The structuring and 

integration of developments in instrumentation, probe development, and well-defined model systems with 

respect to disease-specific applications will greatly speed-up advances in basic research as well as in 

translational applications. Especially the cross-fertilization of all disciplines will give the unique opportunity 

to shed further light from all possible perspectives into the understanding of normal and diseased cells, organ 

systems and living organisms. 

The proposed core centres of excellence (technology and training platforms; DiMI-TTPs) already constitute 

of scientists spanning multiple disciplines. These scientists will strongly interact with other members of the 

DiMI-TTPs as well as with other members of the consortium by the JPRA. Therefore, the JPRA and the 

implementation of DiMI-TTPs will form the basis for synergistic research efforts to bring Europe to the 

world force in molecular imaging for diagnostic purposes. An NoE is probably the most efficient way to 

coordinate the current efforts in molecular imaging for diagnostic purposes in Europe because it permits to 

• develop molecular imaging technologies across a spectrum of major disease applications; 

• offer access to libraries for molecular signatures, data needed for approval of clinical use of tracers, 

probes and animal models; 

• implement new diagnostic tools and molecular targeted therapies; 

• widen the basis of access to the resources in high-technological instrumentation; and 

• successfully integrate SMEs. 

Spreading excellence, dissemination of knowledge and exploitation of results beyond the network 

The proposed technology and training platforms (TTPs) of DiMI span multiple molecular imaging related 

disciplines with extraordinary excellence in specific applications. Therefore, these core centres will function 

in the commercialisation of core-specific technology in conjunction with SMEs and industry (as some of 

them have already done in the past). Moreover, the DiMI-TTPs will attract early and advanced research 

scientists from all over the world for the need of high-level training in the individual molecular imaging 

specialty of each core centre. 

The specific achievements targeted for the five year program for dissemination include: 

• new combined multimodal imaging technology with combinatorial hardware (PET/CT, PET/MRI, 

OI/MRI) as well as software for data analysis, co-registration, and partial volume correction; 

• novel library for disease-specific probes for detection by radionuclide, MR and optical imaging; 

• novel library of animal models for study disease specific questions, evaluation of new therapeutics, 

drugs, and molecular therapies including gene and stem cell therapy; 

• new imaging methods for early detection and disease progression in neurodegenerative diseases 

(AD, PD, HD); 

• new imaging methods for early detection and disease progression of active atherosclerotic plaques 

and heart disease; 

• new imaging methods for severity and fluctuations of various inflammatory diseases; 

• new imaging methods for trafficking stem cell replacement strategies in heart and brain.


The quality of dissemination of knowledge and exploitation of results beyond the network will be performed 

in a quantifiable form (by number) through 

• new patents; 

• new prototype hard ware successfully commercialised; 

• new licensed imaging software; 

• new diagnostic probes implemented in institutions outside DiMI; 

• new diagnostic tests successfully implemented into clinical application; 

• research publications generated within the DiMI-NoE; 

• trainees successfully trained in DiMI-TTPs; 

• research meetings and summer schools (as has been performed successfully by various members of 

the consortium in 2003 already); 

• databases on common molecular imaging knowledge in the internet; 

• the successful implementation of the European Society for Molecular Imaging (www.europeansociety-molecular-imaging.org); 

• communication into the general society and public by 

o world wide web 

o newspapers 

o television/radio interviews (especially at the occasion of DiMI meetings) 

o tutorials for general practitioners and patient organisations 

Durable structuring impact on European research 

The DiMI-NoE will serve as basis for the formation of European molecular imaging centres (EMIC), 

equivalent to the NIH-funded MICs in the US, which will be able to attract local and national funds 

throughout and extending the five-year period. The JPRA will bring together scientists from all research 

disciplines from various centres and countries. Working together in the JPRA will filter those fruitful 

collaborations which will be long-lasting and independent of external structures. Moreover, the creation of a 

European Society for Molecular Imaging is intended to join and reinforce the formation of long-lasting 

connections and dissemination of common knowledge at the European level. 

5.1 Contribution to standards 

The structuring and integration of European forces for multimodal molecular imaging for diagnostic 

purposes shall 

‣ create a set of new common diagnostic tools, tests and data platforms for imaging-guided disease 

evaluation including data interpretation and exploitation; 

‣ facilitate and speed up the process of approval of clinical use of new tracers, in collaboration with 

other organs, such as the European Association of Nuclear Medicine, EU-funded COST actions.


6. JPA for the full duration of the project 

The main objective of this proposal is the creation of a network of excellence 

‣ to integrate multidisciplinary research aiming towards the development of new probes and novel 

multimodal non-invasive imaging technology for early diagnosis, assessment of disease progression 

and treatment evaluation of diseases of the central nervous, cardiovascular and immune system; 

‣ to achieve efficient training of young researchers, dissemination of new common knowledge and 

integration of SMEs and industry; 

‣ to reach the European leadership role in topics related to molecular imaging for diagnostic purpose 

especially with respect to the creation of common data platforms, standards and guidelines. 

To reach these objectives a unique multi-disciplinary consortium has been brought together with all 

necessary expertise and know-how spanning the fields of physics, instrumentation physics, bioinformatics, 

chemistry and radiochemistry, biochemistry, molecular biology, as well as various clinical specialties 

relating to neurosciences, cardiology, radiology and nuclear medicine. 

To achieve the objectives and to reach a significant degree of integration the joint programme of activities 

(JPA) of DiMI includes (responsible DiMI partner in parentheses): 

1. activities for integration (P1+13) 

‣ establishment of DiMI technology and training platforms (DiMI-TTP) for sharing imaging 

facilities, equipment, experience and know-how 

(P1-12) 

‣ exchange and mobility of personnel 

(P1-53) 

‣ integration of SMEs 

(P13) 

2. activities of jointly executed research 

Six main scientific goals of DiMI comprise three horizontal technical aspects serving the basis of 

three vertical experimental and clinical imaging applications. Each of the six main activities contain 

several work packages (WP) serving relation and integration. 

The (1) horizontal activities comprise 

‣ Diagnostic Molecular Imaging Technology (1.1): novel technology for integration of 

multimodal radiotracer, magnetic resonance and optical imaging methods (P2+13); 

‣ Diagnostic Molecular Imaging Probes (1.2): the implementation of a novel library of new 

diagnostic and smart imaging probes 

(P3+4); 

‣ Animal Models (1.3): a unique library of animal models of human neurological, cardiovascular 

and autoimmune diseases to directly study alteration of gene expression, transcriptional 

regulation and molecular events in vivo over a period of time in the same animal (P5+6+11). 

The (2) vertical activities are based upon the horizontal activities of DiMI and comprise molecular 

imaging activities in 

‣ Neuroscience (2.1) 

(P1,7,8) 

‣ Cardiovascular (2.2) 

(P9+10) 

‣ Inflammation and Regeneration (2.3) 

(P11+1) 

Cross-fertilization and networking between the vertical activities are in terms of 

• non-invasive characterization (“phenotyping”) of animal models and patients for early 

diagnosis of neurodegenerative, cardiovascular and autoimmune diseases;


• imaging of key regulators of atherosclerotic plaque formation, cardiac dysfunction and 

inflammation; 

• imaging disease progression and assessment of the effects of molecular targeted therapies; 

• imaging the dynamics after gene and stem cell-based therapies for e.g. ischemic stroke and 

heart disease. 

3. activities for dissemination and spreading excellence (P1+12) 

‣ education and training programme based upon the implementation of DiMI-TTPs, 

‣ dissemination and communication (publications, conferences, internet) 

‣ exploitation. 

4. management activities (P1-13) 

‣ coordinating centre (P1), 

‣ steering committee members (P1-13) responsible for DiMI-TTPs and JPRA (Fig. 2), 

‣ Governing Board (P1-50) 

‣ DiMI advisory boards. 

All parts of the JPA are fully integrated in DiMI and interrelated to each other in order to reach the 

objectives and deliverables in a coherent network (Fig. 2). Therefore, constant interaction of all participating 

DiMI partners is required to obtain the goals, for example, 

• multi-modality imaging is the basis for the transfer of optical imaging-based identification of new 

key transcriptional regulators, which can then be linked to an imaging marker detectable by 3D highresolution 

MRI or 3D high-sensitive PET even in humans; 

• establishment of libraries for probes and animal models forms the basis to analyse key molecular 

events in the various diseases targeted in neuroscience, cardiovascular and inflammation. 

• probe development relies on the specific needs and further pharmacokinetic analysis in vivo for the 

identification of probes suitable for clinical application. 

The JPA serves its deliverables directly to the European Research Area: 

Horizontal activities 

Vertical activities 

Integration & dissemination activities 

Technological tools 

Molecular imaging of major diseases 

Structural connectors 

Technology ERA 

Scientific ERA 

European Leadership


Figure 2: DiMI is structured by its joint programme of activities (JPA) 

2.1 

NEUROSCIENCE 

Phenotyping of animal models/patients 

for early diagnosis 

and imaging disease progression 

2.2 


Early detection of atherosclerosis 

and cardiac dysfunction 

and imaging disease progression 

B.4.2 

6.2 

2.3 

INFLAMMATION & 

REGENERATION 

In vivo detection of transcriptional regulation 

and migration of inflammatory and stem cells 

IntegratingActivities 

Sharing facilities, equipment 

Exchange of personnel 

Integration of SMEs 

1.3 

Animal Models 

“Animal Imaging Library” for validation 

of molecular markers in vitro and in vivo 

1.2 



1.1 


B.4.1 

6.1 B.4.3 

6.3 

Integrating multimodal imaging technology 

(MRI, PET, SPECT, OI) 

DisseminationActivities 

Training / Education 

Communication 

Exploitation 

Innovations , Exploitations , Publications 

Training, Meetings, Common Knowledge 

6.4 

Management of the Consortium Activities


6.A ACTIVITIES 

6.1 Integrating activities 

The integrating activities comprise the 

‣ establishment of DiMI technology and training platforms (DiMI-TTP) for sharing imaging 

facilities, equipment, experience, know-how and for developing mutual and complementary 

specialisation 

‣ exchange and mobility of personnel 

‣ integration of SMEs 

‣ integrated management of knowledge and intellectual properties 

and will be coordinated by partners P1,6,9,13. In due course of DiMI, integrating activities will be managed 

by a Board for Integrating Activities (BIA), which will be chaired by P13. 

Establishment of DiMI technology and training platforms (DiMI-TTPs) 

The establishment of core centres of excellence for technological know-how and training (DiMI-TTPs) will 

form the core of this network. The DiMI-TTPs are viewed complementary to the establishment of Molecular 

Imaging Centres (MICs) in the USA by the NIH. The DiMI-TTPs are responsible for 

• appropriate guidance of the JPRA; 

• training in various independent molecular imaging specific aspects; 

• dissemination within and outside the DiMI-NoE; 

• integration of SMEs. 

These training platforms have been selected on the basis of their level of development in a key technology, 

and on their commitment towards the sharing of their know-how that they have already developed. They 

have agreed to create the conditions (staff and facilities) necessary to welcome, teach and train other 

scientists and students from the DiMI network based on their specific competences. 

Table 1. 12 DiMI-TTPs will be implemented as core centres of excellence within DiMI 

DIMI- 

TTP N O 

PARTNER LOCATION SPECIALTY 

N O 

1 1 (+25) Cologne (D) multimodality imaging in neuroscience including stem cells 

(microPET, HRRT-PET, 1.5+7T MRI, optical imaging) 

2 2 Cambridge (GB) quantification in microPET, hardware development of 

combined MRI/PET and MRI/OI, imaging inflammation 

3 3 Torino (I) MR-related probe chemistry (together with TTP4) 

4 4 (+22, 41) Tours (F) 

Karolinska (S) 

Leuven (B) 

PET- and SPECT-related probe chemistry 

MR-related probe chemistry (together with TTP3) 

5 5 (+18) Barcelona (E) animal models in neuroscience, cardiovascular and 

inflammation, microPET, clinical PET 

6 6 (+36) Milano (I) cell and animal engineering, optical imaging, PET 

7 7 Kopenhagen (DK) PET in neuroscience, quantification 

8 8 Antwerpen (B) microMRI and microCT in neuroscience


9 9 Bordeaux (F) MRI, activatable gene expression, cardiovascular imaging 

10 10 Munich (D) radionulcide imaging in cardiovascular sciences (microPET, 

HRRT-PET, SPECT) 

11 11 Oslo (N) optical imaging in inflammation 

12 12 (+23) Orsay (F) radionuclide imaging in neuro- and cardiovascular sciences 

including stem cells 

The DiMI-TTPs will train early and advanced researchers in key technologies based on the different imaging 

modalities represented in the DiMI network. The DiMI-TTPs will serve as infrastructure bases for practical 

courses of the education activities in DiMI (=> 6.3) and as testing platforms for newly developed prototypes 

and software tools from the SMEs (see below). 

With regards to appropriate resource identification within the DiMI-TTPs, the available equipment, tools and 

facilities from the partners laboratories will be identified and registered in a secured database on the DiMI 

web site (see below). A centralised management of this data base will identify duplications, synergies and 

missing entities and will actively help partners to find and share the facilities, tools or equipment needed for 

their projects. 

The management of DiMI-TTPs with regards to (i) conditions to access, (ii) the necessity to reinforce 

existing facilities, (iii) connections with European, National Research and Education bodies as well as with 

SMEs and industrial partners, (iv) the implementation of new DiMI-TTPs or dismissal of others will be 

conducted at the highest management level of DiMI (=> 6.4) and will be reviewed in 6-months intervals. 

Five partners (1,3,6,8,12) are in the current process of establishing this type of technology and training 

platform in the topic Molecular Imaging for Cancer (EMIL-NoE; receiving funding from 1 st Call). It should 

be pointed out, that these partners will not get funded twice for the same action. As indicated in the table, 

these partners broaden their already existing TTP with respect to inclusion of further technology and partners 

(1+25, 6+36, 12+23) and/or with respect to applications in neuroscience (1,6,8,12) and cardiovascular 

molecular imaging (3), respectively. 

Measureables of performance of DiMI-TTPs: 

• number of research publications resulting from JPRA 

• number of trainees from other research institutions 

• number of trainees from SMEs 

• number of months of training activity 

• number of months testing new prototype hardware 

• number of months testing new prototype software 

• successful long-term establishment of new prototype hard- and software 

Exchange and mobility of personnel 

A key to successful networking is the mobility of personnel around different institutions. Especially in the 

field of molecular imaging, with its many different techniques and its rapid evolution, an increased mobility 

is required. DiMI will serve for a rapid exchange of common knowledge and know-how by providing 

relevant information regarding 

• training courses 

• facilities for individual “hands-on” training 

• student and post-doctoral fellowships 

• open positions at partner organisations including sabbaticals


on their website. All DiMI-TTPs but also the other partners of the network will give opportunities to rapid 

knowledge transfer and act as a resource centre to mobilise young researchers among the partners to spread 

excellence, know-how and expertise. 

Measureables of successful exchange and mobility: 

• number of students, pre-and post-docs trained in DiMI-TTPs from other DiMI partners 

• number of training days/weeks/months per DiMI-TTPs 


Molecular imaging is a rapidly growing scientific and economic area where SMEs have up to now played a 

major role in the development of innovative tools. The SMEs involved in the field of molecular imaging 

span multiple fields including 

• instrumentation (microscopy, optical imaging, MRI, SPECT and PET), 

• biotechnology 

• software 

Close to 100 % of the instrumentation offer for in vivo small animal imaging in the US resulted from SMEs, 

originally as spin-offs from academic centres (e.g. Concord, Xenogen). Meanwhile, Concord holds more or 

less the monopol in production of microPET and Xenogen on the distribution of high-sensitive optical 

imaging cameras. This demonstrates the enormous potential lying in the exponentially growing field of 

molecular imaging. The DiMI network offers the unique opportunity for SMEs developing new 

instrumentation for the initial evaluation of prototype instruments in daily research in terms of feasibility 

testing. This is of high importance in the rapidly changing and developing scientific arena to regulate and 

guide resources and in facilitating the development of new instrumentation. 

With regards to Biotech companies, who are focussing on the development of therapeutic and imaging 

molecules, a rapid testing of new molecules is required. For those companies, access to imaging capacities is 

of paramount importance to accelerate their development by in vivo proof of their molecule’s performance. 

While this has been up to now largely done by ex vivo measurements on laboratory animals, and has led to 

the sacrifice of large numbers of animals, in vivo imaging methods open the way to faster quantitative 

assessment of pharmacokinetics, toxicity and therapy evaluation. Most major pharmaceutical companies 

have invested in small imaging facilities with very high site and capital expenditures (Pfizer, Merck, BMS). 

As SMEs cannot afford such expenditures, they will greatly benefit from access to imaging platforms such as 

those proposed as the DiMI-TTPs. 

As the participation of SMEs in the DiMI network should be flexible and regulated by the specific needs of 

the companies, web-advertisement and active recruitment of SMEs will be performed throughout the funding 

period. This activity will be coordinated by Marie Meynadier (Biospace, Paris, F, P13). It should be pointed 

out that the search for partnering SMEs has been difficult so far. In fact partner 44 (Bionexis) has withdrawn 

its participation from DiMI in March this year due to concern that EU Intellectual Property rules might be 

harmful to their business development. Also, the EMICARE project (1 st call) was cancelled for the sole 

reason that partners Novartis and Amersham felt strongly that the EU Intellectual Property rules were not 

acceptable and therefore withdrew from the project. Many companies (especially pharmaceutical) agree 

with that view of Amersham and Novartis and so far limited SME participation in DIMI may reflect at least 

in part those difficulties. The comment of Thomas Varming, Ph.D., Head of Research Administration of 

NeuroSearch A/S should serve as an example to these critical issues: 

“After internal discussion, we have decided not to participate in the DiMI project. One of the main reasons 

is the new rules regarding publication under the 6 th Framework programme. It is stated that all data 

obtained under the collaboration must be published. For us, as a pharmaceutical company, this implies that


we could contribute only with basic science, for which we have only limited resources. Hence, these rules 

make it difficult for us to participate in EU projects at all.” 

After further search DiMI has chosen to associate in the first stage five SMEs, each representative of one 

domain of activity of the network and of the field of molecular imaging for diagnostic purposes: 

• Instrumentation and Software (1. Biospace Mesures, Paris; 2. MEDRES, Cologne): in this domain 

the main challenges will be 

o potential transfers of academic instrumental developments towards SMEs 

o coupling of instrumental work developed in SMEs with the network activities in the 

academic platforms in order to speed and facilitate the market integration of new 

developments. 

The network activity of the SME in this domain carries both prototype testing and instrumental 

development with academic partners (=>WP1). 

• Tracers (1. Cyclopharma, Clermont-Ferrand): all start-ups involved in the development of new 

tracers face the difficulty of validating their molecules on adequate animal models with good 

performance imaging equipment. Labelling of molecules, and in particular radiolabeling, is a second 

issue that is costly and requires major investment. Cyclopharma will join the network with the goal 

of validating new brain imaging tracers. 

• Animal models (1. Mice Tech, Oslo; 2. Visgenyx, Estland): for start-ups involved in animal models, 

validation by the network expertise and use of the animals in DiMI research will greatly enhance 

their strength on competitive markets, such as the biotech and big pharma markets. By making 

available its animals to the network and participating in the development of new transgenic reporter 

mice, Mice Tech will both enhance the network technical capability and strengthen its development 

on external markets. 

Measureables for successful integration of SMEs: 

• number of SMEs (instrumentation, software, molecules, animal models) involved in DiMI-TTPrelated 

research per year 

• number of test on prototype machines, new software, new molecules 

• successful transfer of prototype testing in full commercialization 

Management of common knowledge and IPR 

The new diagnostic molecular imaging tests and models which will be developed within the DiMI network 

are based on intellectual properties belonging to the developers. Exploitation of this generated knowledge 

will be managed by a Board for Knowledge and IPR Management (BOKIM; =>6.3, =>6.5). The BOKIM 

will be chaired by the Administrator for Knowledge Management (AKM) of the management office (=>6.4). 

In close cooperation with representatives of each participating institution belonging to the Governing Board 

(GB) and the Scientific Management Board (SMB), the BOKIM will be directly involved in successful 

exploitation and commercialization (=>6.3-5).


6.2 Programme of jointly executed research activities (JPRA) 

The JPRA of DiMI will join, bring together and reinforce researchers and scientists from all specialties in the 

field of molecular imaging in six main topics of molecular imaging for diagnostic purposes. The six main 

topics are interrelated to each other: 

• Topic 1.1, 1.2 and 1.3 deal with technological aspects of molecular imaging serving the basis for 

• Topic 2.1, 2.2 and 2.3 aiming at applications in major disease models and patients. 

1. Horizontal JPRA: 

Topic 1.1: novel technology for integration of multimodal radiotracer, magnetic resonance and optical 

imaging methods. This requires the co-registration of molecular information acquired by each of 

these imaging modalities on a voxel-by-voxel basis. The specific technological requirements for 

neurological and cardiovascular diseases and inflammation and regeneration processes have to 

be taken into account (e.g. movement of the heart, migration of single cells). 

Topic 1.2: new library of new diagnostic and smart imaging probes which are specific for a given 

molecular process and which can be detected and localized by at least one imaging modality. 

Topic 1.3: a unique library of animal models for human neurological, cardiovascular and autoimmune 

diseases to directly study alteration of gene expression, transcriptional regulation and molecular 

events leading e.g. to neurodegeneration and plaque formation in vivo over an extended period of 

time in the same animal. These animal models shall serve for adequate validation of in vivo 

molecular imaging markers with other known molecular markers as assessed by “invasive” 

technologies in cellular and molecular biology. 

2. Vertical JPRA: 

Topic 2.1: non-invasive “phenotyping” of animal models and patients for early diagnosis of 

neurodegenerative diseases, imaging disease progression and therapeutic intervention including 

stem cell replacement strategies. 

Topic 2.2: early detection of atherosclerosis and cardiac dysfunction, imaging disease progression and 

therapeutic intervention including stem cell replacement strategies. 

Topic 2.3: in vivo detection of transcriptional regulation and migration of inflammatory and stem cells.


6.2.1 Horizontal Research Activities 

6.2.1.1 Diagnostic Molecular Imaging Technology 

Imaging technologies for in vivo molecular imaging in small animals have undergone a fast development in 

the last five years, starting from a situation in which no dedicated equipment was available to a very intense 

competition about resolution and molecular sensitivity, both within one given technique and amongst 

different techniques. Most technologies used in the clinical field have now been adapted to the small animal 

resolutions (µCT, µPET, µSPECT, µMRI). The following table is taken from a recent review describing the 

important parameters of in vivo imaging techniques (Rudin & Weissleder Nature Rev. Drug Discovery 

2003;2:123). It is obvious that each one of the imaging techniques carries certain advantages and certain 

disadvantages. 

The further goal in molecular imaging research is to combine the advantages of each imaging technology 

(e.g. high resolution for MRI, high sensitivity for PET, low costs and high sensitivity for optical imaging) 

into multimodal imaging to get the best possible answer to a certain scientific question. 

MR 10–100 

µm 

Depth Time Imaging agents Target 

* 

no limit min–h Gadolinium, 

dysprosium, 

iron oxide particles 

Cost 

‡ 

Primary small-animal use 

A, P, M €€€ Versatile imaging modality with 

high soft-tissue contrast 

CT 50 µm no limit Min iodine A, P €€ Lung and bone imaging Yes 

Technique 

Resolution 

Ultrasound 

50 µm mm Min microbubbles A, P €€ Vascular and interventional 

imaging 

Clinical 

use 

Yes 

Yes 

PET 1–2 mm no limit Min 

SPECT 1–2 mm no limit Min 

FRI 2–3 mm


This proposal relies strongly on the access of the various partners to state of the art imaging technologies, 

primarily to those that can be applied to the study live cells, rodents and the human. 

The focus of DiMI is to couple different imaging modalities to enhance the informative content of 

imaging sessions, make use of those developments already available in the various partner’s 

institutions to fasten up their use by biologists and introduce those new technologies in various 

applications spanning the fields of neuroscience and cardiovascular research as well as inflammation 

processes. Most importantly, the imaging information obtained by each of these modalities will be 

validated by in situ techniques (tissue samples, immunohistochemistry, etc.) to really clarify the real 

depth of molecular information obtained in vivo. This is of special importance in situations where the 

molecular probes will be applied in human applications making further in situ test impossible. 

Considering the present technological offer, and many developments being carried by academic centers and 

SMEs, researchers are now realizing the value of multi-modality imaging and of parametric imaging that can 

be obtained by gathering information taken simultaneously by more than one imaging modality, thus 

combining the strengths of each technique. This is, currently, mostly limited to combining anatomical and 

molecular information (PET-CT, SPECT-CT, MRI-CT). The morphological information can thus be used to 

provide rapid low noise attenuation correction and partial volume correction, as well as a priori information 

in the image reconstruction process. DiMI will extend this vision on multimodality in a sense that 

anatomical and a panel of molecular informations are acquired by applying various imaging modalities and 

various probes specific for different pathways involved in the same process. Only this approach for noninvasively 

characterization of disease phenotype will lead to further understanding (diagnosis) and treatment 

evaluation. 

The imaging modalities which are integrated in the DiMI proposal are: 

• MRI, CT 

• Radionuclide techniques (PET, SPECT) 

• Optical imaging 

With regards to PET and SPECT, they both have benefited in terms of resolution from progress in crystal 

technology. Some improvement can still be expected for PET with the test of new crystals with better 

properties at 511 keV. However, the physical limits of PET tracer resolutions linked to the free path of the 

ß-electrons are almost reached, which will call for new breakthroughs to bring PET imaging at significantly 

sub-millimeter resolution. With regards to SPECT, it is now clear that only alternative instrument 

architectures can bring SPECT to sub-millimeter resolutions. Within DiMI, a high-resolution SPECT system 

(TOHR) will be implemented for animal imaging, in particular imaging of the rat and mouse brain and heart, 

a task of particular difficulty unless excessive radiotracer doses are injected. An alternate technology will 

therefore be validated and compared to multi-pinhole approaches that can be developed on clinical cameras. 

Coupling of high resolution scintigraphy to X-ray imaging and, eventually, to MRI is also planned (=>WP1). 

Recently developed high-resolution small-animal PET scanners have facilitated molecular imaging of animal 

models of disease. In certain instances the objective of the study is to determine whether there is tracer 

uptake into an anatomical region, for example, into a particular tumour type or across the blood brain barrier. 

For these studies absolute quantification may not be needed to answer the question posed. However, there 

are other studies where the absolute evaluation of a pharmacokinetic parameter, for example, binding 

potential is required. These studies require accurate image quantification. The aim of this workpackage is to 

improve upon the accuracy of the image quantification of the microPET system attainable with the 

manufacturer’s software (=>WP2).


With regards to MRI and CT, these imaging modalities are challenged by the need to incorporate 

sophisticated technological choices that will improve the sensitivity and that allow to merge dual or triple 

modalities, while remaining compatible with acceptable end prices. Within DiMI, combined MRI/PET and 

OT/PET systems shall be developed combining the high resolution of MRI with the high sensitivity of PET 

or optical and PET information. These novel imaging systems will be tested in the various applications in 

brain, cardiovascular and inflammatory processes (=>WP2). 

Particular emphasis has been placed on the validation of all instrumental developments on animal models 

and tracers developed within the network and targeting the CNS, cardiovascular and inflammatory main 

diseases. 

It should be pointed out again, that at the current stage of molecular imaging, ex-vivo to in vivo correlations 

are of utmost importance. While in vivo imaging develops fast, it has to be taken into account, that 

molecular characterization is still based on in situ markers (histopathology, immunohistochemistry, etc.). 

Therefore, all imaging parameters obtained in vivo will be validated in situ (e.g. coupling of in vivo 

PET/SPECT imaging, optical microscopy, histopathology, immunostaining, digital autoradiography, etc.). 

6.2.1.2 Diagnostic Molecular Imaging Probes 

Molecular Imaging is based on existing technology (PET, SPECT, MRI, Optical imaging), and each of these 

modalities has advantages and disadvantages. The main originality of this project is the exploration of the 

most relevant targets for Molecular Imaging using a combination of different modalities which are 

complementary regarding some of their characteristics. 

Sensitivity 

Spatial resolution 

PET/SPECT very high (pM) medium (5-15 mm) 

MRI low (mM) high (1 mm) 

Optical imaging High limited penetration 

As the main objective of DiMI is to combine the use of these different methodologies in order to explore 

neurodegenerative, cardiovascular and inflammatory diseases including the monitoring of stem cell therapy, 

the consortium will need speficic probes. Some of them have already been developed (existing diagnostic 

probes) but we will need detailed guidelines for their preparation to permit to each member of the consortium 

to produce them efficiently and in the same way. Other probes for a given target involved in a given disease 

still have to be developed (novel diagnostic probes), starting from the chemical design to the 

pharmacological characterisation. 

This non-invasive investigation of molecular targets implies: 

1. to identify the most relevant molecular targets 

2. to develop specific probes for imaging these targets using different modalities (MRI, SPECT and 

PET, optical imaging) (design, synthesis, characterization.) 

3. to select the best imaging modality for a given application 

4. to develop quantification methods for new probes


The different modalities will be tested in the same animal models which will be designed in =>Topic 1.3 

“Animal Imaging Library” for validation of molecular markers in vitro and in vivo, using dedicated devices 

developed in =>Topic 1.1. 

Research on the development of new probes has already started by several partners of the DiMI consortium 

which have established long term collaborations: 

• in the field of radiopharmaceutical development: COST B12 “Radiotracer for assessment of 

biological function.” 

• in the field of MRI: COST D18 “Lanthanides in diagnosis and therapy”. 

These collaborations have led to the publication of numerous articles and books. Hence, it is time to 

combine the findings and expertise of these research teams for the different imaging modalities, and to 

enlarge the complementarity to other groups which possess expertise in the field of development of imaging 

devices, animal models and in vivo applications. This multidisciplinary consortium will in a unique way 

enhance cross-fertilization between these different research areas. In addition, this consortium will lead to 

the use of similar tools in different research centres, thus allowing the merging and confrontation of a large 

panel of findings. 

6.2.1.2.1 Development of radiopharmaceutical probes for PET/SPECT imaging 

A. In neurodegenerative diseases 

The spectacular progress in the knowledge of pathophysiological mechanisms involved in neurodegenerative 

diseases allows to expect new advances in the early diagnosis and follow-up of evolution and treatment of 

these affections. A number of molecular targets such as receptors, transporters or enzymes are known to be 

involved at early stages of these diseases. The strength of imaging techniques for early diagnosis is based on 

the fact that, as illustrated in the figure, significant modifications (increase or decrease) of molecular targets 

(solid line in figure) occur before the appearance of clinical signs (dotted line in figure). It would constitute 

a major progress if diagnosis of neurodegenerative diseases could be made prior to the appearance of clinical 

symptoms (i.e. in the period marked by the rectangle in the figure. 

Natural History of Neurodegenerative Disorders (modified from DeKosky & Marek, Science 2003, 

302:830-834). 

Phase with unspecific symptoms


Alzheimer’s disease (AD) and Parkinson’s disease (PD) are to date the most frequent neurodegenerative 

diseases with an increasing number of patients due to the increase of life expectancy. The improvement of 

early diagnosis of these affections is therefore of utmost importance in order to allow the application of 

existing therapies and/or the development of new therapeutic approaches. Non invasive PET/SPECT 

imaging technologies are particularly relevant methods for both diagnosis and follow-up of treatment. The 

realization of this process requires the availability of appropriate radiopharmaceutical probes allowing 

exploration of targets involved in aimed diseases. One aspect of this proposal is therefore to develop 

PET/SPECT radioactive probes for several molecular targets known to be involved in these diseases in order 

to select the most relevant targets for early diagnosis and treatment follow-up. The choice of the most 

relevant target is a major step. 

vChoice of molecular targets 

Alzheimer’s disease has several characteristic features such as alterations of the acetylcholine system and 

appearance of amyloid plaques and neurofibrillary tangles. This proposal aims at the development of 

different types of markers for this disease: 

1) markers of several components of the acetylcholine function which are affected such as the vesicular 

acetylcholine transporter (VACh), nicotinic receptors (α4-β2 and α7 types), muscarinic M2 receptors 

and acetylcholinesterase activity, 

2) markers of amyloid plaques. 

Parkinson’s disease is characterized by an early and progressive degeneration of the dopaminergic nigrostriatal 

pathway. The best index of this degeneration is the dopamine transporter (DAT) localized on nerve 

endings. 

Common points of neurodegenerative affections are neuronal damage and inflammation. These processes 

can be investigated via the quantification of peripheral benzodiazepine receptors (PBR) localized on glial 

cells and macrophages. 

Development of radioactive probes 

We will develop radiotracers for these different molecular targets, labelled with iodine-123 or technetium- 

99m for SPECT and carbon-11 or fluorine-18 for PET. These probes will be designed starting from 

chemical structures with known affinity/specificity for a given target. Pharmacomodulation of lead 

structures will be realized, and the most efficient structure will be selected using QSAR studies. 

Radiosynthesis methods which can be applied in clinical research will be developed. In vivo validation of 

the new tracer agents will be performed in animal models of =>Topics 1.3 and 2.1. 

Development of quantification methods 

Once the selective probes have been synthesised, their pharmacokinetics and binding characteristics will be 

investigated in rodents, mini-pigs or monkeys. Appropriate modelling with state-of-the-art arterial input and 

brain tissue data sampling will be conducted along with validation and optimisation of methods for 

quantification of dynamic images as well as, when feasible, steady-state infusion. Software developed for 

modelling and quantification within the network will be made freely available to all interested parties. 

B. In Cardiovascular Diseases 

As atherosclerosis is responsible for most of the morbidity and mortality in developed countries there is a 

need to develop molecular imaging targets using radiotracers to improve early diagnosis and treatment of 

these diseases. Various targets have been selected in this proposal: 

• Proteolytic enzymes: radiotracers for PET and SPECT will be developed for molecular imaging of 

the activity of proteolytic enzymes in atherosclerotic plaques. The probes will be developed starting 

from the known MPP (1-methyl-4-phenylpyridinium) inhibitors.


• Apoptosis: Apoptotic activity is dramatically involved in atherosclerotic plaques development and 

progression. Therefore, it is an important objective to develop a probe to allow molecular imaging of 

this process. The probes will be developed starting from annexin. 

C. For monitoring stem cells and exogenous gene expression in vivo 

To combine the high spatial resolution of MRI for stem cell trafficking with the high sensitivity of PET 

imaging, nuclear imaging based approaches of stem cell imaging will be developed primarily relying on gene 

marking with the Herpes simplex virus type 1 (HSV-1) or varicella zoster virus (VZV) thymidine kinase 

gene (tk). 

PET tracers which are a substrate for HSV-1-tk have been described in literature, but these are characterized 

by a limited brain uptake and can therefore not be used for studies in the brain. We will therefore synthesize 

fluorine-18 labelled lipophilic compounds which have affinity for either (VZV-tk) based on bicyclic 

nucleoside analogues (BCNAs) or for (HSV-1-tk) based on tricyclic purine nucleoside analogs (TPNAs). In 

order to widen the potential clinical application of gene expression imaging we will synthesize technetium- 

99m labelled BCNA and TPNA derivatives and assay their affinity for VZV-tk and HSV-1-tk. 

As an alternative to existing reporter systems we will also evaluate fluorine-18 and carbon-11 labelled 

compounds ([ 11 C]methylglucoside and [ 18 F]fluoroethylglucoside) to visualise stem cells transfected with the 

gene encoding for SGLT and fluorine-18 labelled lipophilic galactoside derivatives for visualisation of lacZ 

expression. 

6.2.1.2.2 Development of MRI probes 

The superb spatial resolution and the outstanding capacity of differentiating soft tissues have determined the 

widespread success of MRI in clinical diagnosis. The main determinants of the contrast in a MR image are 

the proton relaxation time T 1 and T 2 . When there is a poor contrast between healthy and pathological regions 

due to a too small variation in relaxation times, the use of a contrast enhancing agent can be highly 

beneficial. Contrast agents are chemicals able to alter markedly the relaxation times of water protons in the 

tissues where they distribute. According whether the dominant effect occurs mainly on T 1 or T 2 , MRI 

contrast agents can be classified as positive or negative agents, respectively. The most representative class 

of T 1 -positive agents is represented by paramagnetic Gd(III) chelates whereas iron-oxide particles represent 

the class of T 2 -negative agents. 

Gd(III) complexes 

Currently about one-third of the MRI scans recorded in clinical settings make use of contrast agents, mainly 

Gd(III) complexes. The effectiveness of a Gd(III) complex to act as MRI contrast agent is first assessed by 

measuring its relaxivity, i.e. the relaxation enhancement of water protons observed for a millimolar solution 

of the contrast agent. In the past 15 years, a number of papers addressing the relationship between 

structure/dynamics and relaxivity of Gd(III) complexes has been published. This has led to a substantial 

advancement of our understanding of the structural, dynamic, and electronic parameters determining the 

relaxivity of a paramagnetic chelate. Thus, high relaxivities can be pursued by improving the hydration state 

around the metal ion and by tailoring the system in order to have optimal correlation times for the 

modulation of the Gd-H 2 O vector. In particular, it has been shown that optimal exchange lifetimes of the 

coordinated water molecules are in the range of tens of nanoseconds and chemists have shown how the 

structure of the complex can be designed to provide the desired exchange rate. Moreover, as high relaxivity 

at the currently available magnetic fields requires the occurrence of long molecular reorientational times, 

slowly moving systems have been suggested ranging from dendrimeric structures, in which several Gd(III) 

chelates are covalently bound to the basic framework, to the exploitation of non-covalent interaction to form 

supra-molecular adducts. Substrates for the non-covalent binding interaction can be endogenous (e.g. serum


albumin) or exogenous (e.g. functionalized polymeric systems). In this project we will make use of Gd(III) 

based Imaging Probes. 

Molecular Imaging applications require the accumulation of a high number of Gd(III) units at the targeting 

site to overcome the intrinsic low sensitivity of the technique. When the target is on the endothelial walls, 

one may eventually use polymeric systems containing many Gd(III) units in addition to the chemical 

functionalities that act as vectors for the targeting of the molecules of interest. More often we will make use 

of suitably functionalized Gd(III) chelates able to self-assembly at the proper targeting site. In this context, 

we intend to develop bis-biotinylated Gd(III) complexes, whose stereochemistry is suitable for the formation 

of multi-layered adducts with streptavidin protein. Basically, the targeting site is addressed by the use of a 

proper Ab or Fab or peptide that has been previously biotinylated. Once the pre-targeting procedure has 

been concluded, the successive addition of streptavidin and bis-biotinylated Gd(III) chelate will allow the 

formation of a multi-layered adduct. A final addition of mono-biotinylated Gd(III) chelate will saturate all 

available positions on the avidin molecules, thus determining the number of imaging units at the given site. 

A very important area of application of MRI-Imaging Probes is represented by the labelling of stem cells, as 

the possibility of their in vivo visualisation will allow the monitoring of their fate and localisalition. 

Radioactive labelling will allow assessment of tissue distribution of transplanted stem cells at high sensitivity 

but with poor spatial resolution. Current MRI technology displays a superb spatial resolution (to < 100 µm) 

and represents the technique of choice for attaining the observation up to a very small number of cells. The 

labelling of stem cells prior to transplantation will be carried out either with iron-oxide particles or with 

Gd(III) chelates. In the latter case, the use of well tolerated, small-sized Gd(III) chelates will allow the 

entrapment in the stem cells of large amounts of Imaging Probes by exploiting the pinocytosis route. 

Preliminary work indicates that, for this type of internalisation process, no saturation effect is detected and 

the amount of internalised Gd(III) chelate is linearly proportional to its concentration in the incubation 

medium. It is known that pinocytosis leads to the formation of small endosomes which may eventually fuse 

into larger lysosomes. The intracellular distribution of the Gd(III) chelate cannot be observed by the 

microscopy techniques currently used in cellular biology. However, the Gd neighbour in the periodic table, 

Eu, owns excellent fluorescent properties. As a characteristic feature of lanthanide(III) ions is their 

remarkable analogous chemical properties, one can expect that Gd(III) and Eu(III) complexes of the same 

ligand have an identical behaviour during the cell internalisation process. Thus, a validation of the 

intracellular distribution of Gd(III) chelates can be attained by confocal microscopy exploiting the 

fluorescent properties of the analogous Eu(III) complexes. 

Another approach to labelling cells with Gd(III) chelates will deal with the use of solid particles made up of 

insoluble Gd(III) chelates (eventually covered by suitable substrates). The insolubility of the Gd(III) chelate 

is granted by the presence of long aliphatic chains on the outer surface of the ligand which are bound through 

a proper biodegradable functionality. Once entrapped into the cell, the insolubilising moiety can be cleaved 

by the action of the desired enzyme leading to the release of soluble Gd(III) chelates. The presence of 

Gd(III) chelates in the cells will then be assessed by the decrease of proton T 1 and by the corresponding 

hyperintense spot in the MR image. 

Chemical Exchange Saturation Transfer (CEST) Agents 

An important goal in this project is the set-up of innovative procedures for neurological and cardiovascular 

diseases. To this regard, we think that the MRI potential will be better exploited by developing agents that 

are responsive of specific parameters of the microenvironment of interest. Of course, one may design 

Gd(III) containing systems whose relaxivity is dependent upon a defined parameter (pH, enzymatic activity, 

temperature, redox potential, concentration of a specific metabolite, etc…). However, upon going from in 

vitro to in vivo applications, this approach has the drawback that it is not possible to associate the observed 

relaxation rate of tissular protons to a change in relaxivity (as a response to the parameter of interest) or to an


overall change in the local concentration of the contrast agent. Therefore, alternative routes have to be 

tackled. We think that the novel class of CEST agents (CEST = Chemical Exchange Saturation Transfer) 

can be particularly valuable in this context. 

CEST agents formally belong to the class of negative contrast agents because they determine a reduction of 

the signal intensity of water protons in MR image. Differently from other negative agents (e.g. iron-oxide 

particles) their effect is not due to the T2-shortening, but to a saturation transfer mediated by chemical 

exchange. 

The fundamental requisite for a molecule in order to act as CEST agent is the presence of a set of mobile 

protons (resonating at a frequency ω CEST ), whose exchange rate with water protons (resonating at ω WAT ) must 

be smaller than the |ω CEST - ω WAT | difference. When this condition is met, the application of a proper radiofrequency 

pulse, centered at the frequency ω CEST , will cause the saturation of the mobile protons of the CEST 

agent. This saturated magnetization will be, then, transferred to the water protons by chemical exchange, 

thus resulting in a decrease of the signal intensity of the latter. A peculiarity makes CEST agents unique in 

the scenario of MRI contrast agents: the contrast is generated only if a specific irradiation frequency, 

characteristic of the given CEST agent, is applied. As a direct consequence, more than one set of mobile 

protons may be irradiated provided that they are encoded with sufficiently different resonance frequencies. 

This property is extremely advantageous, because it makes possible the set-up of ratiometric methods where 

the contrast is made independent on the absolute concentration of the CEST agent. 

The well known remarkable effect on the chemical shift values induced by the presence of a paramagnetic 

center can be exploited for the design of paramagnetic CEST agents, recently termed PARACEST agents, in 

which the exchangeable protons are part of the complexes containing the paramagnetic metal ion. The main 

advantage of such systems, mainly represented by lanthanide chelates (here Ln ≠ Gd), relies on the large 

increase of the |ω CEST - ω WAT | difference that makes possible the irradiation of fast-exchanging protons (e.g. 

water protons directly coordinated to the paramagnetic center), thus leading to very efficient CEST agents. 

Furthermore, for PARACEST agents endowed with more than one set of mobile protons, the spread-out of 

the resonance frequencies induced by the paramagnetic center makes easier the selective saturation required 

by the ratiometric method. Currently, one of the main limitations of the CEST agents is represented by their 

relatively low sensitivity. The goal of designing CEST agents with improved sensitivity may be achieved 

through two principal routes: 

• searching for fast–exchanging mobile protons highly shifted from water protons, and 

• developing systems endowed with a high number of fast-exchanging protons. 

The peculiar properties displayed by CEST agents make them particularly suitable for several tasks in this 

project. The development of responsive Imaging Probes in which the responsiveness towards a given 

diagnostic parameter is not dependent on the absolute concentration of contrast medium can be pursued 

through the set-up of a ratiometric method based on a CEST agent endowed with two pools of mobile 

protons. The ratiometric approach requires that the Imaging Probe has to be properly designed in such a way 

that only the saturation transfer of one of the two pools is sensitive to the parameter to be measured. The 

responsiveness can be obtained by using CEST-active mobile protons whose exchange rate or chemical shift 

is dependent on the parameter of interest. 

Besides their use as responsive probes, CEST agents are also particularly promising for applications 

concerning cell labelling. The possibility to create contrast only through the saturation of a specific 

frequency, only depending on the characteristics of the CEST-active mobile protons, can be conveniently 

exploited for running experiments in which two or more different lines of stem cells are labelled with 

different CEST agents. In this way, each cell line will be encoded with a specific saturation frequency


corresponding to the resonance frequency of the internalised CEST agent. Thus, the cell lines could be 

simultaneously transplanted in a given organ and their respective fate could be easily monitored. 

6.2.1.2.3 Development of Combined and Optical Imaging Probes 

Imaging technologies based on optics have appeared only recently and have been so far restricted to animal 

research. Nevertheless, it is expected that some of them will be in the shorter term adaptable to clinical use. 

Fluorescent imaging (FLI) and bioluminescent imaging (BLI) can be successfully used for studying specific 

cell- and tissue-promoter, to follow trafficking and fate of cells expressing GFP or Luciferase, to assess 

apoptosis, protein-protein interactions and gene-transfer. Due to their high sensitivity, FLI and BLI are 

extremely useful for molecular imaging applications, including cell labelling. Microscopy optical imaging 

by confocal and multiphoton microscopy posses impressive sensitivity and spatial resolution, though they 

suffer of the limited penetration of light through biological tissue. 

In this project novel imaging probes for applications based on optical imaging (OI) modalities will be 

developed. As far as intracellular responsive agents is concerned, most of the attention will be focused on 

Lanthanide(III) complexes whose optical emissions will be made dependent on diagnostic parameters like 

pH, concentration of metabolites or metals of diagnostic relevance. This aim will be achieved by 

synthesising libraries of probes of defined physico-chemical properties (hydrophobicity, surface charge, 

chirality) in order to assess the relevant factors determining the cellular permeability, the intracellular 

compartmentalisation and the responsiveness of the probe. The developed imaging probes will be tested by 

confocal fluorescence microscopy, thus allowing the spatio-temporal distribution of the complexes to be 

assessed. 

The complementarity between MRI and optical imaging modalities will be exploited for developing 

innovative imaging probes able to implement the diagnostic potential of the two technologies. 

Lanthanide(III) ions display favourable magnetic and optic properties and, furthermore, most of the Ln(III) 

complexes are isostructural along the lanthanide series. Consequently, the same ligand, designed for a 

defined molecular imaging application, can be used as MRI probe (by using Gd(III) or can be used in optical 

imaging protocols (by using Eu(III)). Interestingly, in the case of MRI-CEST agents, the same complex 

could be utilized for both imaging technologies. 

A different approach dealing with the combined use of MRI and OI is the development of libraries of 

imaging probes endowed with two different “imaging synthons”. These “dual” systems will contain a MRactive 

probe (e.g. a Gd(III) chelate) and an OI-active probe (e.g. an Eu(III) or a Tb(III) chelate with the 

proper antenna).. The MR-active part will ensure the high spatial resolution whereas the OI-active synthon 

will provide functional information (e.g.via the responsivness to a specific parameter of the 

microenvironment).


6.2.1.3 Animal Models 

Future progress of diagnostic molecular imaging relies on the development of new probes directed to 

molecules that are significant for the onset and development of disease. An intimate and dynamic interaction 

between basic biomedical and imaging research establishments within the DiMI network will lead to the 

identification of new molecular targets suitable for imaging techniques used in diagnosis. Translation of the 

newest basic research advances on the molecular mechanisms underlying human diseases to imaging for 

diagnostic purposes is a complex process that requires this type of network to unify the efforts of highly 

specialized research teams with expertises in separate areas of knowledge. By forming the present network 

we have structured a tool that will allow the diffusion of basic knowledge on diseases to diagnostic imaging. 

This tool is composed of an elaborate set-up among the different expertise teams. This is based on 

multidisciplinary group communication arrangements that will allow further development of basic and 

imaging studies directed to the progress on diagnostic imaging. We expect a bidirectional output in 

promoting knowledge transfer from basic to imaging (a) and viceversa (b), as follows. Transferring 

information: 

a) from basic to imaging laboratories will promote the identification of molecular targets for 

diagnostic imaging and the input for chemical probe development; 

b) from imaging to basic research laboratories will enable us to translate the diagnostic objectives and 

application benefits, accounting for the technical constrains and study limitations of imaging for 

clinical diagnosis. 

We aim to monitor pathological disturbancies in living animals using non-invasive imaging techniques 

including micro-PET, micro-SPECT, micro-MRI, micro-CT and optical imaging. Basic research laboratories 

will provide the experimental in vitro systems for appropriate preliminary probe testing, and the 

experimental in vivo animal models for human diseases to validate the applicability of specific probes to 

disease imaging. We will use a library of defined animal models for human diseases. These animal models 

will be available for testing molecular probes directed to diagnostic imaging in the areas of human health that 

are considered in the present project, i.e. neurological diseases, cardiovascular diseases, inflammation and 

regeneration. In parallel, three of the DiMI technology and training platforms (=>DiMI-TTPs 5,6,11) will 

serve as core centers of excellence for education in translational research from experimental molecular 

models to diagnostic molecular imaging, and for testing the newest advances in imaging technologies in 

experimental models prior to application in diagnostics in humans. The teams working with these animal 

models are engaged in basic research covering: 

a) molecular aspects of the diseases including gene expression and signal transduction pathways 

involved in neuronal cell death, glial reactivity and inflammation; 

b) neurotransmitter alterations; 

c) therapeutics, including gene and cell therapy and pharmacological intervention. 

Studies in animal models will be validated ex vivo with a number of scientific tools -including the use of 

dissectioned tissue regions, tissue sections, organ studies (isolated heart perfusion), tissue and cell cultures, 

and artificial vessel tubes- and techniques such as autoradiography, immunohisto- and cytochemistry, 

hybridisation, radioactive binding, gamma and beta counting, histology, microscopy (optical, fluorescece, 

MRI, and confocal), NMR spectroscopy, flow-mimicking ultrasonic phantoms ultrasonic measurement 

systems (1 – 50 MHz), protein/mRNA/DNA studies (Western, Northern, and Southern Blotting, PCR, 

quantitative PCR, single cell PCR, micro-array), enzymatic studies, cellular and subcellular fractionation, 

preparation and characterization of liposomes for molecular imaging, apoptosis models, microPIV to study 

flow velocity, PV-loops in embryos of small animals, computational fluid dynamics. Other available 

techniques include perfusion estimation with ultrasonic destruction-reperfusion techniques, ultrasonic 

measurements of compressibility of contrast agents, single molecule technique (determination of energetic


landscape of interaction of a single molecule with model membrane), small angle X-ray scattering, 

fluorescence recovery after photobleaching (volume and evanescent), dynamic quasielastic light scattering, 

microfluidic. 

The molecular biology tools for the generation of fusion probes and gene and cell therapy studies (including 

stem cells from various sources and transgenic stem cell lines) are available. Methods for stable expression 

of reporter genes within stem cell populations, without effects on cell viability and function, will need to be 

employed and evaluated in culture before application of cell in models in vivo. Also, experimental optical 

fluorescence imaging systems-including fast single cell imaging setup (TILL Photonics), long term 

fluorescence time lapse set up, combination of single cell physiology and single cell imaging, and fluorescent 

microscopy of beads are also accessible, together with intravital microscopy. 

Development of new markers to be used with the various imaging technologies is a main issue within the 

network. Any toxicity of the new coming molecules will be addressed with in vitro studies in cell culture 

systems and also in vivo in the living animals. 

Description of animal models 

Animal studies will be performed following the legislation of each European country and according to the 

Directives of the European Community and the Helsinki Declaration. Experiments will be performed by 

authorized researchers and experimental protocols will be subjected to the approval of the ethical committee 

of each particular institution. The animals to be studied are rodents, rabbits, pigs, and primates. All mouse 

models are available in any K.O. or transgenic mice. 

A. Neurological disease models 

1. To study molecular basis of neurological disorders 

1.a) List of model systems that are in use and available 

• Alzheimer’s disease (AD): Mice models developing signs of this disease will be used as follows: 

single APP transgenic mice, double APP and tau transgenic mice, and double transgenic mice 

overexpressing huAPP SFAD and Hu PS2 mut N1411, which develop amyloid-β Alzheimer-like 

plaques. 

• Parkinson’s disease (PD): Mice overexpressing α-synuclein will be used. Local lesions of the 

substantia nigra pars compacta. Injection of 6-hydroxidopamine will be performed in the striatum or 

the medial forebrain bundle of rats. 

• Huntington’s disease: Mice overexpressing huntingtin will be used (R6/1: huntingtin mutated with 

115 CAG repetitions). Excitotoxic brain lesions will be carried out by intrastriatal injection of 

quinolinic acid in rats. Metabolic lesions will be carried out by intrastriatal or systemic administration 

of 3-nitropropionic acid in rats. 

• Stroke: Focal cerebral ischemia will be induced in rats and mice by transient or permanent middle 

cerebral artery occlusion, either with intraluminal techniques or by thrombus injection followed by 

thrombolytic therapy. Transient global ischemia will be carried out in rats by the four-vessel 

occlusion technique or in gerbils by the two-carotid occlusion method. 

• Epilepsy: Experimental models will be studied by systemic or local intrahippocampal administration 

of excitotoxins in rodents. 

• Spinal cord injury: This will be examined in rats subjected to spinal cord sectioning. 

• Multiple Sclerosi models:


o Relapsing experimental allergic encephalomyelitis (EAE): Spinal chord homogenate 

immunization of DA rats (E3 resistant). 

o Chronic relapsing experimental allergic encephalomyelitis (CREAE): Myelin basic protein 

(MBP) and proteolipoprotein (PLP) peptides induces chronic relapsing encephalomyelitis in 

B10.RIII and C3H.NB mice 

• Disorders affecting neurotransmission, incluging anxiety, depression and schizophrenia: The 

neurochemical basis of drug-addiction (cannabinoid dependence) as well as the affective disorders 

that could be related to drug dependence will be studied by using a biochemical and behavioural 

model of cannabinoid withdrawal in mice and knockout mice lacking different receptors -µ-opioid 

receptor, δ-opioid receptor, κ-opioid receptor, µ/κ-opioid receptors, D2 dopaminergic receptor, CB-1 

receptor- and underlying transcription factors -CREM, CREBα/δ, inducible null CREB-). 

1.b) Generation of new animal models for neurodegenerative diseases 

• Parkinson’s disease: Development of a new in vivo model based on Lentivirus vector (LV)-mediated 

expression of α-synuclein, parkin anf synphilin in rodent brain. 

• Alzheimer’s disease: Development of a new in vivo model based on Lentivirus vector (LV)-mediated 

expression of disease associated genes. 

1.c) Imaging targets for in vivo imaging disturbancies associated to brain lesions and neurological 

disturbansces: 

• Neuroinflammation: Areas of cerebral inflammation can be detected by MRI by using 

superparamagnetic iron oxide particles (SPIO). A specific response in neuroinflammation is the glial 

reaction: Most of the listed animal models of neurological disease involve a response in glial cells 

that can emerge shortly in the evolution of the disease. For instance, microglial reactivity is a 

hallmark in stroke and it is involved in the immune response of multiple sclerosis. Activated 

microglia show induction of the peripheral benzodiazepine receptor (PBR) and its expression is 

upregulated in numerous brain injuries. Imaging microglial activation with labelled PBR ligands will 

provide key information for diagnostic purposes regarding regional localisation, disease progression, 

and secondary degeneration in regions that are remote from the primary site of injury. Monitoring 

the microglial reaction can be achieved with a ligand to the PBR (PK11195) which can be labelled 

with 11 C or 18 F to be used in PET studies and with [ 123 I]iodo for SPET studies. In addition, 

alternatives to PK 11195 for imaging of PBR are under current study. 

• Neurochemical targets: Dopamine transporters will be imaged in animal models with SPECT using 

123 I-FPCIT. Quantitative imaging by PET of dopamine transporters using 18 F-FPCIT and of 

dopamine receptors using 11 C-raclopride and 18 F-fluoroethylspiperone. In addition, we aim to obtain 

[ 18 F] PET tracers from the chemical structure of the iodinated derivative of cocaine PE2I, which has 

very high specificity for the dopamine transporter. Currently a fluorinated derivative is under 

development. Markers of brain cholinergic function ( 11 C-MP4A or 11 C-PMP for acetylcholinesterase 

enzymatic activity and 18 F-Fluoro-A-85380 for nicotinic receptors) will be used. In addition, markers 

for the vesicular acetylcholine transporter (VAChT), nicotinic receptors (α7 and α4 β2 types), 

muscarinic M2 receptors, acetylcholinesterase activity (AChE) will be developed and studied with 

SPET/PET radiotracers in order to obtain more selective markers. For the VAChT, the marker (-)-5- 

[ 123 I]iodobenzovesamicol ([ 123 I]IBVM) is used by SPET. In order to improve in vivo quantification 

of the VAChT, PET tracer derived from the chemical structure of IBVM will be developed, such a 

fluorinated derivative that is currently under study. For serotonine transporters ( 11 C-McN5652), 

serotonine receptors ( 18 F-altanserine (5-HT 2A ), 18 F-MPPF (5-HT 1A )). For the serotoninergic system, 

given the existing difficulties in displacing antagonist ligands from serotonin 5-HT 1A and 5-HT 2A 

receptors with endogenous 5-HT released by pharmacological challenges (e.g., [ 11 CO]WAY-100635 

from 5-HT 1A receptors, [ 11 C]M100907 from 5-HT 2A receptors) an interest will be placed in testing 

newly developed agonist ligands directed towards these receptors.


• β-amyloid-like plaques: Using in vitro models of primary neural cell cultures and in vivo models of 

Alzheimer’s disease, β-amyloid deposition and plaque formation will be monitored by fluorescence 

techniques. Also, specific MRI contrast agents will be developed for non-invasive in vivo monitoring 

plaque formation. Development of new tracers with affinity for amyloid plaques to be used in SPET 

and PET will be also investigated. 

• Tau-related alterations: For PD and related taupathies, and for AD. Tau phosphorylation and 

formation of neurofibrillary tangles will be examined ex vivo with fluorescent markers. 

Microinjections of manganese chloride (MRI contrast agent and biological calcium analogue) will 

allow to visualise and to quantify in vivo associated disturbances in axonal transport. 

• α-Synuclein aggregates: Development of new tracers with affinity for α-synuclein aggregates for 

application in PD. 

• Cerebral gene expression: Studies will be carried out as a function of the new developments of 

radiolabelled tracers for in vivo monitoring gene expression (VZV-tk, HSV-1-tk). Development of 

(PET) radiolabeled nucleoside analogues that penetrate the blood-brain barrier and are 

phosphorylated by TK. Luciferin will be used to visualise luciferase as a reporter gene in the brain of 

laboratory animals, by means of a camera to detect luminescence in rodent brain. 

• Apoptosis: by Annexin-A5 (optical imaging and development of new tracers for PET, MRI). 

• Cerebral perfusion alterations: Using perfusion-weighted MRI in animals to estimate brain 

perfusion. Brain perfusion will also be monitored by micro-SPECT with 99m Tc-ECD using a pinhole 

collimator. 

• Tracing Blood Brain Barrier leakage: using micro-CT with conventional contrast agents. 

• Tracing neurodegeneration: Micro MRI will be used to determine volume changes in different brain 

structures as a result of neurodegeneration. High resolution MRI fibre tracking (based on diffusion 

tensor MRI) will be developed and applied to discern and quantify alterations in brain connectivity 

and brain-spinal cord connectivity as a result of neurodegeneration. 

• Cerebral activity and metabolism: Haemodynamic/vasogenic responses will be investigated in the 

motor cortex during different degrees of electrical stimulation of the paw and using functional MRI 

based on Blood Oxygenation Level Dependent (BOLD) contrast or Arterial Spin Labelling (ASL) 

contrast. Micro CT will be used to assist the fMRI. Quantitative imaging of metabolism will be 

done by PET using 18 F-FDG. 

• Tracing angiopathy: using micro-CT with contrast agents, implemented on mouse brain and spinal 

cord with a 5 times higher resolution than MRI angiography (10 micron). 

• Imaging integration: Image registration and 3D merging of images obtained with different imaging 

modalities in animals: to compare images, obtained through different imaging modalities and to 

combine the image information obtained from each image separately, registration is required: images 

are positioned in the same reference framework using registration techniques based on mutual 

entropy to map images of different modalities on each other. Registered images subsequently can be 

merged in order to display the separate image information of the modalities in a combined way. 

2. To monitor therapeutic targets for neurological diseases 

2.a) Neurochemical targets: Brain circuits involved in the therapeutic action of antidepressants and 

antipsychotic drugs designed for the treatment of depression and schizophrenia will be studied in rats 

by means of intracerebral microdyalisis and by the use of genetically modified mice with alterations 

in neurotransmission sytems involving dopamine or serotonine. For imaging studies =>part A.1.c 

2.b) 

Modulation of cerebral gene expression: Neuro-lentivectors for over-expression or knock-down of 

genes associated with neurodegeneration will be developed. Neuro-lentivectors encoding luciferase 

for in vivo bioluminescence measurements will be constructed. 

2.c) Signalling for neuroinflammation =>part C.


2.d) Cell therapies 

• Models for experimental application: repair of peripheral nerves and spinal cord injuries, models for 

brain diseases such as those described above for Parkinson’s and Hungtington’s diseases, as well as 

stroke. 

• Cells: Labelled cells with therapeutic potential can be transferred to animals for imaging purposes by 

means of cell transplantation into or nearby the lesion site, or by non-invasive injection into the 

circulation. Cells will be cultured and appropriately labelled in culture and then transferred to the 

animals. 

o Stem cells: rodent stem cells will be obtained from various sources (bone marrow, 

developing brain). Gadolinium derivatives will be developed for intracerebral stereotactic 

injection in stem cells. Further uses and applications will be developed following the 

achievements in cardiovascular research (=>details in part B2.c). 

o Ensheating glial cells: rodent ensheating glia from the olfactory bulb that have shown strong 

therapeutical potential in spinal cord injury will be studied. 

o Genetically modified cells that secrete neurotrophic and neurotropic factors: modified 

epithelial cells. 

These cells will be modified by the transduction of marker genes so that proliferation, migration, 

chemotaxis etc. can be non-invasively imaged by PET, MRI (magneto-liposomes) and optical 

imaging (luciferase and/or GFP labelled). 

B. Cardiovascular disease models 

1. To study the biological and molecular basis of the diseases 

1.a) List of model systems that are in use and available 

• Rat and pig models of myocardial gene transfer 

• Infarct models: in rats, and an ischemia/reperfusion model will be studied in mice. Model of heart 

failure (KO of antiapoptotic gene). Acute cardiac pressure overload in the mouse, through transverse 

aortic constriction. Reversible cardiac infarction method. Transgenic mouse models of infarct 

healing. Mouse models of coronary ischemia. 

• Pig model of chronic ischemia 

• Vascular injury: Several models of mechanical lesions in the mouse vasculature are available. 

• Cardiac injury: models in mouse and rat, based on LAD occlusion. 

• Atherosclerotic plaque: in ApoE-deficient mice with hypercholesterolemic diet, and in ApoEdeficient 

mice with carotid ligation and hypercholesterolemic diet, acute vascular injury in the 

mouse. Experimental atherosclerosis in the rabbit: hyperlipidemic Watanabe rabbit model. 

• Angiogenesis: A model of angiogenesis in the chorion-amnionic membrane of the chicken 

• Alterations of the coagulation system: Mice genetically modified for certain proteins involved in the 

coagulation cascade. 

• Additional models of interest: Embryonic cardiovascular development of mouse and chicken. 

1.b) Imaging targets for in vivo imaging disturbancies associated to cardiovascular lesions: 

• Vessel wall morphology: this will be assessed with MRI techniques 

• Macrophage infiltration: High-resolution MRI with ultrasmall superparamagnetic ironoxide 

nanoparticles (USPIO), and imaging glucose consumption by PET with 18 F-DOG as surrogate marker 

of macrophage activity. 

• Extracellular matrix proteins, inhibitors and receptors: Measurements of the level and time-course 

of α v β 3 -integrin expression and MMP activity following myocardial ischemia. Correlation with 

imaging parameters of regional blood flow, metabolism and function. Molecular imaging of the


enzymatic activity of in plaques using high-resolution SPECT/PET with radiolabelled matrix 

metalloproteinase inhibitors ( 123 I, 18 F, 11 C) and optical imaging with fluorescent MMP substrate. 

α v β 3 -integrin and MMP ligands as molecular imaging markers will be developed for more specific 

characterization of biologic effects of myocardial ischemia. 

• Apoptosis: in plaques by Annexin-A5. 

• Smooth muscle proliferation: molecular imaging with ( 111 In-Z2D3) in plaques by SPECT 

• Combined molecular and morphological imaging: in hyperlipidemic watanabe rabbits with PET/CT. 

• Endogenous gene expression: A non-invasive imaging approach for general detection of endogenous 

gene expression. Reporter gene imaging based on HSV-1-tk will be used for detection of regional 

differences of endogenous gene expression in ischemic and non-ischemic myocardium. 

• Angiogenesis: efficient multimodality approach for specific noninvasive monitoring of myocardial 

angiogenesis in vivo, including imaging the extracellular matrix protein-related system. 

2. Therapeutical targets for diseases 

2.a) Gene therapy 

• Exogenous genes: Genes driven by tissue-specific promoters will be administered for targeted genetherapeutic 

purposes (e.g. myocardial angiogenesis therapy), using coexpression with a reporter gene. 

• Angiogenesis gene therapy: using adenoviral vectors coexpressing VEGF and HSV-1-tk under 

control of controllable (heat sensitive) or tissue-specific promoters. 

2.b) Signalling 

• Extracellular matrix proteins, inhibitors and receptors: targeting this system to promote 

angiogenesis. Imaging specific changes of α v β 3 -integrin and MMP expression and their relation to 

gene expression and functional effects during angiogenesis therapy. 

2.c) Cell therapies 

• Stem cells: Adequately labelled stem cells with therapeutical potential in cardiovascular diseases can 

be transferred to animals, following several procedures: 

o Specific stem cell populations will be labelled with para- or super-paramagnetic markers 

detectable by MRI (ultra-small super-paramagnetic iron-oxide particles, USPIO will be used) 

for the visualisation of stem cell distribution inside the tissue, and their local migratory 

capacity over several days (cell tracking). 

o Labelling of a specific stem cell population based on the use of HSV-1-tk detectable by PET. 

o Labelling of a specific stem cell population based on the use of the luciferase gene detectable 

optical imaging. 

o Evaluation of different administration routes for transplantation of stem cells. MRI guided or 

fluoroscopy guided direct injection, local intravascular injection, as well as systemic 

injection will be evaluated with respect to side effects (risk of pulmonary embolism) and 

efficacy of homing. 

o Assessment of differentiation of transplanted stem cells into cardiocyte will be carried out by 

examining specific gene expression. Non-invasive assessment of stem cell differentiation 

will be achieved using enhanced expression of cell markers. Also, imaging biomarkers will 

be used as functional surrogates for stem cell differentiation. Angiogenic therapies can be 

evaluated with quantitative assessment of perfusion using ultrasound, MRI and PET/SPECT 

approaches. Membrane permeability will be evaluated using uptake of macromolecular 

contrast agents (MRI, PET). Cardiac muscle contraction and ejection fraction can be 

evaluated by MRI. Improvement of metabolism will be studied using PET, specifically 

[18F]FDG-PET.


o 

o 

Development of image-guided control mechanisms for stem cell differentiation in order to 

guide their differentiation proces. Development of local control of expression of cytokines 

and chemokines within the transplanted stem cells. The model that will be explored is the 

recently developed method of expression control based on local heat (using MRI guided 

Focused Ultrasound) and a heat-sensitive promoter (Heat Shock Protein HSP70). In 

addition, tissue specific promoters will be explored. 

Tracking labelled stem cells as vectors for gene therapy in order to promote growth of new 

vessels (pro-angiogenesis therapy). The objective is to modify stem cells with transgenes 

coding for growth factors (VEGF) under control of tissue specific promoters or under control 

of the HSP70 promoter allowing an image guided expression control mechanism. 

C. Inflammation disease models 

1. To study the biological and molecular basis of the diseases 

1. a) Experimental models of inflammation 

• Inflammatory Bowel disease: Experimental models of colitis by chemical induction in mice and rats. 

• Transgenic mice: Idiotype-specific TCR tg mice crossed with a transgenic mouse model expressing 

Ig λ 315 (idiotype), leads to excessive production of autoantibodies – develop multiple autoimmune 

diseases. 

• Acute pancreatitis: Chemical induction of pancreatitis in rats and mice by systemic drug injection. 

• Collagen induced arthritis (CIA): Type II collagen (CII) in haplotype 2q-or 2r-mice or DA rat strain 

• Chronic arthritis induced with type XI collagen (CXIIA): Type XI collagen immunization of DA or 

LEW.1F rats (E3 resistant) 

• COMP induced Arthritis (COMPIA): Cartilage oligomeric matrix protein (COMP) immunization of 

E3 and LEW.1W rats 

• Collagen antibody induced arthritis (CAIA): Antibodies directed against CII transferred onto 

BALB/C or B10.Q mice 

• Chronic arthritis induced with pristane (PIA): Pristane injection in DA or LEW.1 F rats (E3 

resistant) 

• Relapsing polychondritis (MIRP): Matrilin-1 immunization of LEW.1F rats and B10.Q mice. 

• Relapsing exp. allergic encephalomyelitis (EAE): Spinal chord homogenate immunization of DA rats 

(E3 resistant) 

• Chronic relapsing experimental allergic encephalomyelitis (CREAE): Myelin basic protein (MBP) 

and proteolipoprotein (PLP) peptides induces chronic relapsing encephalomyelitis in B10.RIII and 

C3H.NB mice 

• Non-oil collagen II induced arthritis (NOCIA): Type II collagen in oil-free carrier with adjuvant 

enhancers 

• Neuroinflamamtion: Cerebrovascular diseases (stroke) and neurodegenerative diseases as 

Alzheimer’s disease and multiple sclerosis (=>Part A). 

1.b) Targets for disease imaging 

i) Signalling targets 

• Adhesion molecules: Induction of cell adhesion molecules that are involved in leukocyte adhesion to 

the endothelial wall, a key event for leukocyte infiltration (i.e. ICAM-1, VCAM-1 and selectins) will 

be studied in animal models with methods that allow for adequate quantification and imaging. 

Antibodies against adhesion molecules will be labelled with 123 I and will be injected into the 

circulation for SPECT imaging. Validation of the technique will be done with 125 I-labelled antibodies 

that will be quantified in a gamma counter after dissection of the regions of interest.


• Extracellular matrix proteins, inhibitors and receptors: Increased activity of metalloproteinases 

(MMP-1, MMP-2, MMP-3, MMP-13) are evident in several autoimmune diseases. Existing and 

novel near infrared optical probes will be imaged in various rodent models of inflammation using 

reflectance fluorescence imaging. In addition, imaging changes of α v β 3 -integrin and MMP 

expression and activity will be done using markers as in =>part B.1.b. 

• NF-κB: NF-κB mediated luciferase activity will be imaged (bioluminescence) in transgenic reporter 

models in combination with various models of chronic inflammation. 

• Complement activation: Novel near infrared probes (protease sensitive) will be developed that are 

activated by the complement system. 

• Reactive oxygen species (ROS): As oxidative stress is most likely an important contributing factor in 

autoimmune disease. We therefore aim at establishing ROS sensitive probes for optical imaging in 

mice, validated in models of inflammation. 

ii) Imaging neuroinflamamtion: => part A.1.b) 

iii) Imaging by transfering labelled cells to animals 

• Models for experimental application: Animals models of inflammation. 

• Cells: Adequately labelled macrophages can be transferred to animals for imaging purposes with 

MRI following injection into the circulation of the animals. Optical imaging of cells stably 

transfected with luciferase can be imaged by bioluminescence. 

• Leukocytes: Infiltration of leukocytes can be imaged by intravital microscopy in rats developing 

colitis. 

2. Therapeutical targets for diseases 

• Targeting these systesm to inhibit inflammation. 

o Extracellular matrix proteins, inhibitors and receptors. 

o To block endothelial adhesion molecules to prevent leukocyte infiltration.


6.2.2 Vertical Research Activities 

6.2.2.1 Diagnostic Molecular Imaging in Neuroscience 

Phenotyping in neurodegenerative disorders 

Neurodegenerative disorders as diverse as Alzheimer’s disease (AD), Parkinson’s disease (PD), the prion 

disease, and Huntington’s disease all share a conspicuous common feature – aggregation and deposition of 

abnormal protein. Although the composition and location of the aggregates differ from disease to disease, 

this common feature suggest that protein deposition or some related events may be toxic to the neurons. 

Several chronic neurodegenerative disorders, including AD and PD are characterized by a selective loss of 

specific subsets of neuronal populations over a period of years or even decades. While the underlying causes 

of the various neurodegenerative diseases are not clear, the death of neurons and the loss of neuronal 

contacts are key pathological features. Identifying molecular events that control neuronal cell death is 

critical for development of new strategies to prevent and treat neurodegenerative disorders. 

Longitudinal studies in experimental animals permit unique insight into progression of disease models. 

Thus, researchers will be able to sort out the time sequence of the consequences of genetic alterations in 

transgenic mice with respect to changes in the activity of key enzymes, deposition of abnormal proteins, 

inflammatory reactions, alterations of neurotransmitter systems and their interaction with the degenerative 

process. The DiMI network will create a unique framework to relate such studies performed by different 

participating groups with different methods in a set of well defined animal models. Animals will be 

exchanged between research groups to study the progression of each disease model with a much broader 

battery of techniques than could be achieved by any individual research group. By entering the results into a 

common database, this will provide an anchor to relate findings obtained with some of the same imaging 

techniques in less easily shared animal models by other participating groups. 

The main five-year goals in phenotyping by multimodal molecular imaging technologies are: 

• development of MRI and PET methods to localize and quantify AD plaques at high spatial 

resolution and with high sensitivity and to correlate the findings with in situ and behavioural 

measures; 

• investigation of other models of neurodegeneration (PD, HD) by novel MRI and PET probes 

developed in =>Topic 1.2. 

• search for novel markers which could be used for in vivo diagnostic imaging markers; 

• establishment of combined in vivo PET/MR imaging protocols for linking neural energy 

consumption with blood supply and discern potential mismatch as one of the factors having an 

important impact on the induction and progression of neurodegeneration. Here, we will use also a 

combination of 2-photon microscopy, electrophysiological recordings and fMRI to obtain a set of 

measures which shall be directly compared to multi-tracer PET information on neuronal metabolism 

and function. 

• Investigate whether pharmacological MRI could be used as a high resolution variant of PET in the 

CNS and a novel tool to map neurotransmitter-receptor binding in the brain. 

Early diagnosis in neurodegenerative disorders 

The most important events in neurodegenerative diseases occur at the very beginning, when potentially 

reversible changes set the stage for all subsequent and often irreversible damage to neurons, their axons, 

dendrites and synapses. With its non-invasive approach molecular imaging is ideally suited as a research and 

clinical tool for assessment of very early changes. Further it also allows for follow-up to document the 

subsequent events, and possible treatment effects. Potential human treatment with highly specific 

interventions will greatly be enhanced by early and specific diagnosis. The effect of neuroprotective


treatment can be effectively monitored by using imaging techniques as surrogate markers in phase I and 

phase II studies. 

Because of the high costs, most molecular imaging data in neurodegenerative disorders have been carried out 

in small numbers of individuals. For this reason, human imaging data will need to be linked in a database 

containing clinical and neuropsychological data, to be collected by all participating groups in a tightly 

standardized manner, building on pre-defined protocols. This will allow for important post-hoc data 

analysis, thereby increasing the sample size and creating a true synergy-effect. 

This proposal also contains multiple other innovation aspects, including: 

• Improved nosological classification of patients with neurodegenerative disorders, thereby providing 

a basis for classification of disorders and establishment of drug targets; 

• Improvement in the definition, indications, and use of imaging techniques for the study of patients 

with brain disorders with possible use in clinical practice and in experimental studies; 

• Improvement and standardization in brain imaging implementation, data storage, transmission, and 

analysis; 

• Basic knowledge neuroreceptor imaging may contribute significantly to a better and earlier 

discrimination of the underlying causes of MCI; 

• The establishment of a tool for early diagnosis is of proven interest for pharmaceutical companies for 

identification and development of drugs potentially effective in prevention, treatment of established 

deficits, and slowing disease progression. The application of functional imaging with in-vivo 

mapping of, e.g., neuroreceptor disturbances in the human brain provides a unique opportunity to 

develop new lines of drug development 

• Development of a sensitive tool which potentially could predict a good response to currently 

available therapy in neurodegenerative disorders 

Inflammation in CNS disorders 

It is well-established that glial cells play an important role during injury and degenerative processes in the 

central nervous system. The glial cells include the astrocytes, oligodendrocytes and the microglia, which 

play a role in neuronal homeostasis, myelination, and phagocytosis, respectively. Gliosis is a prominent 

neuropathological feature found in many neurodegenerative diseases. In the past, this finding has been 

viewed as a secondary event to neuronal dysfunction, with the role of glia cells to remove cellular debris. 

Mounting evidence indicates, however, that the role played by gliosis in pathological situations may not be 

restricted to its homeostatic function but also includes actions that significantly and actively contribute to the 

death of neurons (Hirsch et al. 2003). For example, the disease may progress even when the initial cause of 

neuronal degeneration has disappeared, suggesting that toxic substances released by the glial cells may be 

involved in the propagation and perpetuation of neuronal degeneration. Glial cells can release deleterious 

compounds such as proinflammatory cytokines (TNF-alpha, Il-1beta, IFN-gamma), which may act by 

stimulating nitric oxide production in glial cells, or which may exert a more direct deleterious effect on 

neurons by activating receptors that contain intracytoplasmic death domains involved in apoptosis. The 

expression of receptors for complement by glial cells, and the release of soluble cytokines is a key event in 

multiple sclerosis (MS) plaques strongly suggesting that inflammatory processes may play an important part 

in the complex pathophysiological interactions that occur in this disorder. For this reason, molecular 

imaging of inflammatory responses in the brain constitutes an important way to explore and follow the 

pathophysiological alterations in brain disease. 

Conventional MRI is widely acknowledged as a tool of key importance in the diagnosis of multiple sclerosis 

(MS). Further, it is now recognized for its potential to monitor disease progression and treatment efficacy in 

clinical drug trials track (Miller et al. 1998; Sellebjerg et al. 2003). The currently applied conventional MRImethodologies 

offer the possibility for non-invasively, with a high sensitivity and a low test-retest 

variability, to detect lesions. At the same time these conventional methods unfortunately suffer from a low


specificity for pathological brain alterations. That is, MR-demonstrated hyperintensities may represent 

edema, demyelinization, re-myelization, gliosis, or axonal loss. Retention of contrast agents, such as Gd- 

DTPA, is taken as a sign of blood-brain barrier rupture and inflammation, but the images do not themselves 

disclose the underlying pathophysiology in the MS-lesion (Miller 1998). Nor does the summed lesion 

volume represent very well either present or long-term disease progression, as measured with the Expanded 

Disability Status Scale (EDSS). More recent approaches, such as MR-spectroscopy seem to correlate better 

with the clinical status of the MS-patient and measurements of the neuronal marker N-acetyl-aspartate (Sager 

et al.) have revealed that neuronal loss or dysfunction is present in apparently normal white matter. Also in 

closed head injury, gliosis is taking place to a very large extent and microglia activation is known to 

potentiate the damage. Again, results from currently available conventional structural imaging do not 

correlate very well with symptom severity or long-term prognosis, nor are they able to disclose the 

underlying molecular events. 

Visualization of microgliosis in age-associated neurodegenerative disorders provides a new tool to detect and 

monitor the disease process. Recent studies have convincingly demonstrated that cerebral binding of the 

peripheral T 3 -benzodiazepine radioligand [ 11 C]PK11195, associated with microgliosis and cellular 

inflammation, is regionally increased in the brain of patients with Alzheimer’s disease (Cagnin et al. 2001) 

and multiple system atrophy (Gerhard et al. 2003). It is not known, however, to what extent microgliosis is 

associated with amyloid plaque burden alone, nor has the time course of inflammation been uncovered. With 

the amyloid tracer [ 11 C]PIB is now being available for PET-imaging of humans, it can be tested whether the 

extent of microglia inflammation in terms of [ 11 C]PK11195 binding is related to the presence of amyloid 

plaques, as well as the correlations with disease severity. Further, for neuroprotective treatment intervention 

to become effective an early diagnosis of paramount importance. Since microglia activation is likely to come 

early into play the prognostic value of [ 11 C]PK11195 images in early stages of Alzheimers disease should be 

assessed. 

In order to assess inflammation in the CNS, methodological developments are needed. In this context, we 

will exploit 

• parallel imaging and faster gradient switching capabilities (and multi-slice echo planar techniques) to 

reduce acquisition times for spectroscopic measurements. This will potentially allow for studies in 

awake animals and will at the same time improve current limitations on sensitivity due to low 

physiological metabolite concentrations and resulting vulnerability of spectroscopic methods to subject 

motion. 

• diffusion tensor imaging (DTI) acquisition techniques to take advantage of a new head gradient insert 

coil using Q-space methodology with a 3 Tesla MR-scanner. The gradient performance expected with 

this coil, available in very few centres worldwide, is ideal for acquiring multi-directional DTI. Such 

improvements are needed for investigations of the brain's fiber tracts, especially in multiple sclerosis 

where the disruption of such tracts is a primary cause of symptoms, or in closed head injury. 

• specific super paramagnetic iron oxide particles (SPIO) and MRI to detect inflammation 

• micro-CT and contrast agents for detection of vasculopathy in inflammatory CNS disease. This 

methodology is known to provide a 5 times higher resolution than MRI angiography. 

• serial echo-planar 3T MR-imaging following a single inversion pulse and GdDTPA for sensitive 

detection of blood-brain barrier damage and visualization of the associated extravasation. 

PET-studies of microglia activation will be done. Activated microglia can be detected with the peripheral T 3 - 

benzodiazepine receptor ligand [ 11 C]PK11195 and PET. Quantitative data will allow testing of specific 

pathophysiological hypotheses, such as the contribution of inflammatory reactions to deposition of abnormal 

proteins and neurotoxicity, as assessed from post-mortem histological and gene expression studies in tissue 

from animals that have been investigated with molecular imaging methods.


Stem cells in Neuroscience 

Cell transplantation has over the last two decades emerged as a promising approach for restitution of 

function in neurodegenerative diseases, in particular Parkinson’s and Huntington’s disease. Since 1987 about 

300 patients with advanced Parkinson’s disease and about 20 patients with Huntington’s disease have 

received transplants of fetal mesencephalic or striatal neuroblasts at several centers in Europe and America. 

There are now convincing data to show that early postmitotic neurons, taken at a stage of development when 

they have started to express their dopaminergic phenotype, can survive, integrate and function over a long 

time in the parkinsonian human brain. Long-lasting graft survival and function, and symptomatic 

improvement have been observed in about 2/3 of the grafted patients, and in the most successful cases L- 

dopa treatment has been possible to withdraw (for review, see Björklund and Lindvall 2000). 

Studies in rodents and non-human primate models have shown that the ability of grafted neurons to become 

functionally integrated into the host brain depends not only on the developmental potential of the implanted 

cells, but also on the plasticity of the host environment, i.e., the capacity of the brain tissue to accept new 

cellular elements to become integrated into the developing or established neuronal circuitry. Both these 

factors depend on the developmental stage of donor and host. In the adult brain the capacity of transplanted 

fetal neuroblasts to grow, integrate and establish functional efferent and afferent connections is in many 

cases substantially increased when the host circuitry is damaged suggesting that some of the plastic 

properties that are present during development, such as mechanisms that regulate and guide axonal growth 

and synaptogenesis, can be reactivated by lesions, e.g. stroke or neurodegenerative changes. These lesioninduced 

cellular and molecular changes, which have yet to be clarified, form the basis for the remarkable 

ability of the lesioned adult brain to incorporate new functional elements, and thus to a degree rebuild itself. 

Cell transplantation as an approach to replace lost or damaged brain cells, is thus, in its most effective form, 

a technique for reconstruction of damaged neuronal circuitry. 

The recent demonstration that immature neural progenitor cells (NPCs) with multipotent properties can be 

isolated from both the developing and adult central nervous system (CNS) and that these cells can be 

maintained and propagated in culture, has provided a new interesting tool for restorative cell replacement in 

the damaged or diseased brain. A major limitation of the current fetal cell transplantation procedure is the 

difficulty to obtain sufficient amounts of cells for grafting in patients. The possibilities to use stem cells as a 

renewable source of cells for transplantation, therefore, provides an attractive approach to solve these 

problems. Neural stem cells (NSCs) obtained from the developing CNS provide renewable sources of cells 

for therapeutic purposes, and could eventually offer a powerful alternative to primary fetal CNS tissue in 

clinical transplantation protocols. Alternatively, it has been shown that various types of injury induce a 

recruitment response of endogenous progenitor cells to the affected region (Magavi et al., 2001). It would be 

of great interest to see if this latent capacity for self-repair of neural precursor cells could be boosted in situ. 

Molecular imaging technology will greatly enhance the further understanding of the dynamics of recruitment 

of neural progenitor and stem cells and their action in response to various stimuli as individual monitoring of 

these processes in the living experimental animal is possible over extended periods of time. Superparamagnetic 

ironoxide particles (SPIOs) have already been used successfully by P25 to label stem cells in 

vitro allowing to track them in vivo using MRI after implantation. Similarly, radiolabelled compounds will 

be developed allowing tracking with improved sensitivity. Furthermore, molecular imaging probes are 

explored to allow monitoring of the process of differentiation and the production of novel therapeutically 

active proteins. These imaging approaches will significantly enhance the identification of factors involved in 

the main aspects of graft integration into the host brain circuitry stem cell migration as well as in the clinical 

establishment of regenerative therapy within the CNS. 

The major long-term goals of the jointly executed research activities of the DiMI program for stem cell 

imaging in the CNS aim towards:


• establishment of reproducible labeling and imaging techniques of NPC and NSC for detection by 

MRI, PET and OI; 

• assessment of the dynamics of proliferation, migration, differentiation and synapse formation of 

NPC and NSC; 

• identification of factors controlling targeted migration, axonal growth and synaptogenesis; 

• assessment of reestablishing functional neuronal networks. 

Quantification 

Whenever possible, parametric images, i.e., quantified and thus within-centres comparable data will be 

obtained. For this reason, a common basis for image analysis and kinetic modelling would be particularly 

useful. In this respect, the establishment of a DiMI-TTP (P7) training centre for image analysis, kinetic 

modelling, data storage and database processing within the network, as describe elsewhere in this proposal 

(=>B.8.1), will be of key importance. 

The interaction between basic and clinical science 

Most of the nuclear molecular imaging methods, and also some of the magnetic resonance techniques, will 

not only be applied to experimental animals, but also to humans. By these means, the following goals can be 

achieved: 

• Testing which animal models actually reflect best the pathophysiology and progression of human 

disease. 

• Testing which imaging techniques are best suited to provide a specific diagnosis of 

neurodegenerative disease in humans at an early stage before irreversible damage and severe 

cognitive or motor impairment occurred. 

• Guiding further development of experimental molecular imaging techniques and tracers with 

potential for use in humans. 

Thus, these clinical projects will be based on and made possible by the basic science projects, but will give 

information back to basic science with respect to their actual potential to study and ameliorate human 

disease. To further improve the comparison between animal experiment and human studies, behavioral 

measures will be obtained in the experimental animals and their comparability with symptoms of human 

disease will be analyzed on the background of associated molecular imaging findings. Creation of a true 

network of excellence involving both basic scientists as well as clinicians working with neurodegenerative 

disorders will provide a unique opportunity for sharing ideas and data. Thus, we will obtain detailed 

knowledge about the correspondence of disease stages in experimental animals and humans, increasing our 

ability to judge possible intervention points with respect to their potential for human treatment. 

European added-value 

Improvement of molecular imaging techniques will facilitate the development of new therapeutic strategies. 

This will be achieved by 

• improved definition of intervention points 

• detailed monitoring of treatment effects 

• translational research based on the comparison of animal models with human disease 

Links to external activities 

The impact of this project will be enhanced by horizontal integration with links with external activities 

related to neurodegenerative disease. Apart from genetic studies in families with hereditary 

neurodegenerative disorders that will be done by the local activities and cooperations of participating groups, 

molecular investigations and pathoanatomical diagnosis relies mainly on tissue samples obtained postmortem. 

Therefore, we have established a first link to the current EU-funded brain-bank project “Brain Net 

Europe II”. The main goals of this collaboration are to work on common legislation issues with regards to 

tissue donation and use of donated tissue for various research purposes.


References: 

1. Cagnin A, Brooks DJ, Kennedy AM, et al.. In-vivo measurement of activated microglia in dementia. Lancet. 2001;358:461-7. 

2. Gerhard A, Banati RB, Goerres GB, Cagnin A, Myers R, Gunn RN, Turkheimer F, Good CD, Mathias CJ, Quinn N, Schwarz J, Brooks DJ. 

[(11)C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy. Neurology. 2003;61:686-9. 

3. Hirsch EC, Breidert T, Rousselet E, et al.. The role of glial reaction and inflammation in Parkinson's disease. Ann N Y Acad Sci. 2003;991:214- 

28. 

4. Miller DH, Grossman RI, Reingold SC, McFarland HF. The role of magnetic resonance techniques in understanding and managing multiple 

sclerosis. Brain 1998;121:3-24. 

5. Miller DH. Multiple sclerosis: use of MRI in evaluating new therapies. Seminars in Neurology 1998;8:317-225. 

6. Sager TN, Topp S, Torup L, Hanson LG, Egestad B, Moller A. Evaluation of CA1 damage using single-voxel 1H-MRS and un-biased 

stereology. Brain Res. 2001;892(1):166-75. 

7. Sellebjerg F, Jensen CV, Larsson HB, Frederiksen JL. Gadolinium-enhanced magnetic resonance imaging predicts response to 

methylprednisolone in multiple sclerosis. Mult Scler. 2003;9:102-7. 

8. Bjorklund, A. and O. Lindvall, Cell replacement therapies for central nervous system disorders. Nat Neurosci, 2000. 3(6): p. 537-44. 

9. Bjorklund, A. and O. Lindvall, Self-repair in the brain. Nature, 2000. 405(6789): p. 892-3, 895. 

6.2.2.2 Diagnostic Molecular Imaging in Cardiovascular Research 

At present, diagnostic imaging methods allow for assessment of structure, function and physiology of the 

heart. Changes of these parameters are often associated only to the late stages of cardiovascular disease. It is 

expected that the advances in genomics and proteomics will have a tremendous impact on prevention and 

cardiologic care of the future. However, already today, the advances in molecular biology are redefining 

heart disease in terms of molecular abnormalities. With the knowledge of molecular pathology a new 

generation of diagnostic imaging can be defined that aims at the detection of those molecular processes in 

vivo. 

Today 

Future 

Target tissue 

Morphology, 

Physiology, 

Metabolism 

Target tissue 

Receptor-binding contrast agent 

inactive contrast agent 

biologically activated contrast 

agent 

Imaging mechanisms at the anatomical versus molecular level. Today, imaging systems can only assess changes at a 

gross physiological level, due to contrast agents and radiotracers of little specificity. With the availability of more 

specific agents, imaging systems could detect the presence and even the function of molecules in early stages of 

cardiovascular disease processes. 

From a clinical point of view, versatility and effectiveness of medical, interventional and surgical treatment 

for cardiovascular disease have continuously improved within recent years. The large number and


complexity of therapeutic strategies have resulted in a paradigm change for diagnostic algorithms. It is 

increasingly emphasized that pure characterization of myocardial and vascular morphology and structure is 

not enough for adequate and cost-effective therapeutic decision making. Disease-specific biologic 

information is sought as a guide to individual patient characteristics and thus as a predictor of risk. Molecular 

imaging approaches which aim at the non-invasive visualization of specific biologic targets within 

myocardium and vasculature may thus be ideally suited to pre-select individuals which benefit most from a 

given therapeutic strategy, and to monitor the success following onset of therapy. 

The major long-term goals of the jointly executed research activities of the cardiovascular programme within 

DiMI will be: 

• To establish a molecular imaging toolbox of new noninvasive diagnostic tests for in vivo 

identification of various precursors and early biologic changes of cardiovascular diseases. 

• To develop molecular imaging approaches for non-invasive monitoring of novel molecular therapies 

for cardiovascular disease. 

• To use these molecular imaging tools for translational research from animal models to clinical 

application to increase possibilities and effectiveness of cardiovascular therapy, and finally 

• To use these molecular imaging tools for monitoring of disease progression, risk stratification and 

assessment of therapeutic efficacy in the clinical setting. 

Current areas of major development in cardiovascular disease are included in the DiMI programme, and 

comprise 

1. biologic characterization of atherosclerotic plaques; 

2. myocardial ischemia and angiogenesis as a pathobiologic and therapeutic target; 

3. molecular features of left-ventricular remodeling as a predictor for the development of heart failure, 

and 

4. the usage of cell transplantation for preservation and restitution of myocardial and vascular integrity. 

Ad 1): Atherosclerotic plaques represent a major health care problem, since plaque rupture may lead to 

vessel obstruction as the primary cause of stroke and myocardial infarction. Current diagnostic imaging is 

aimed at the anatomical description (level of vessel obstruction) and the evaluation of flow abnormalities. 

However, strong indications are that the stability of plaques depends on molecular processes, and improved 

diagnosis of unstable plaques should therefore be targeted towards the early detection of such processes 

using multi-disciplinary molecular imaging approaches. Biomarkers, specific for plaque activity and related 

pathophysiological processes, will be identified for imaging. Vessel wall structure and tissue perfusion will 

be evaluated additionally. The final goal is to develop a multi-modality molecular imaging algorithm which 

allows for accurate idenitification of localization and instability of plaques, and thus for determination of 

individual risk in clinical atherosclerotic disease. 

Ad 2): Angiogenesis, the growth of new blood vessels, occurs both in normal processes such as wound repair 

and in disease states. The body controls angiogenesis through a balance of angiogenesis-stimulating growth 

factors and angiogenesis inhibitors. In cardiovascular disease, pro-angiogenic therapies are currently being 

explored to stimulate the growth of new vessels in chronically ischemic regions and to preserve vascular 

integrity following angioplasty-induced vessel damage. Molecular imaging techniques, which can provide 

readouts that are specific to angiogenesis itself or to factors mediating angiogenesis will play a key-role in 

the future understanding of its role in the diagnosis and management of those major diseases. Multiple 

strategies will be pursued in the design of molecular imaging approaches aimed at visualizing targets 

involved in angiogenesis. The goal is to establish probes for cardiac imaging, utilize them for description of 

basic alterations during ischemic tissue damage, and ultimately evaluate the effects of novel pro-angiogeneic 

therapies. For evaluation of therapy, additional strategies will be used including MRI-based assessment of 

density of blood vessels, local blood volume and vascular permeability, and scintigraphic assessment of 

tissue perfusion and metabolism.


Ad 3): For clinical management of ischemic heart disease, a predictive method for the transition from focal 

ischemia to global heart failure is of major importance. Molecular alterations occur very early in the process 

and are therefore a major target for novel imaging approaches. Apoptosis, protease activity, autonomic nerve 

tone and post-synaptic signal transduction are thought to be involved in the development of left-ventricular 

remodelling during chronic ischemia and after myocardial infarction. This phenomenon, which occurs in a 

subset of patients, is a major contributor to the development of ischemic heart failure. Careful 

characterization using specific molecular probes may allow not only for an improved perception of the 

biology of precursors of heart failure. Molecular imaging may also allow for early identification of those 

patients which are at increased risk for future progression to overt cardiac failure. Finally, refinement of the 

understanding of molecular alterations in heart failure will serve as the basis for development and monitoring 

of novel molecular therapies. 

Ad 4): Stem cell therapy for cardiovascular disease is considered part of the medicine of the future, and a 

possible replacement for heart transplantation. Stem cells have the potential of differentiating into a variety 

of cardiac cell types. In addition, the homing capabilities of stem cells towards cardiac lesions makes stem 

cells a good candidate as a vector for gene delivery. However, at present little is known about the migration 

of stem cells towards the lesion, their passage through the vessel wall, and the molecular processes guiding 

their differentiation in vivo. Small super-paramagnetic ironoxide nanoparticles (SPIOs) can be used to label 

stem cells in vitro allowing to track them in vivo using MRI after re-injection. Similarly, Nuclear Medicine 

labels will be developed allowing tracking with improved sensitivity. Further, molecular imaging probes are 

sought after that allow to monitor the differentiation process and the production of novel therapeutic 

proteins. Such imaging approaches may enhance significantly the clinical establishment of myocardial 

regenerative therapy. 

It is a goal of DiMI to establish novel molecular imaging techniques which will play a key role in the 

cardiovascular disease research areas described above. Evaluation of gene expression and control of 

expression in molecular therapy approaches, are additional essential elements to reach the objectives of the 

joint programme. As a consequence, a methodologically focussed program is included, which aims at multidisciplinary 

imaging of gene expression with a special emphasis on marker genes and endogenous genes. 

In order to achieve the goals of the cardiovascular programme of DiMI, several critical components are 

essential, such as 

• establishment of molecular targets and specific probes for detection, 

• highly sensitive imaging systems and quantitative measurements, 

• demonstration of the in vivo feasibility of probes to detect changes in health and disease, 

• extensive validation vs ex vivo techniques, and 

• initiation of algorithms to control and to monitor molecular therapies. 

Below, major components are briefly addressed. 

New Molecular Imaging Agents 

In order to obtain information on molecular processes that participate in cardiovascular pathology, imaging 

modality-specific agents have to be engineered that enable sensitive measurements of the in vivo distribution 

of their related molecular targets. Targeted probe design ideally should allow multi-modality imaging. In 

general, molecular imaging requires ligands that bind with high affinity and specificity to a chosen target.


Newly developed probes are available for the cardiovascular section of DiMI, which will be employed in 

interactive projects to develop improved techniques for early diagnosis and therapy monitoring in 

cardiovascular disease. Those probes will specifically target early steps of apoptotic cell death, extracellular 

matrix proteins, cellular adhesion molecules and other surface antigens, receptors for endocrine and 

paracrine regulators, and products of regulated reporter genes. Additionally, several strategies for specific 

labelling of cells for magnetic resonance, nuclear and optical imaging techniques will be evaluated, and 

established techniques for measurement of vascular structure and myocardial function, geometry, perfusion, 

metabolism as well as innervation are available for correlation. 

In Vivo Imaging Methodology 

In addition to optical fluorescence and bioluminescence imaging systems, various MRI scanners (1.5 to 17.6 

Tesla), ultrasound systems and PET and SPECT cameras are available which allow for repetitive multimodality, 

multi-tracer imaging of small and large experimental animals, as well as humans using the same 

imaging methodology, thus providing an ideal network for basic, translational and clinical research. 

Molecular and Cellular Biology 

For successful establishment of noninvasive imaging techniques using molecular probes, supportive 

background including state-of-the-art molecular biologic knowledge and methodology is necessary. 

Expertise in cloning of DNA and vector construction for reporter gene transfer along with experience in 

generation and ex vivo biologic characterization of stem cell lines is available at specific centers of the 

network and will be distributed to other participants. Additionally, techniques of PCR, blotting and 

immunohistochemistry for characterization of specific molecular pathways, identification of novel targets, 

and ex vivo validation of in vivo imaging results will be available and interchanged among participating 

groups. 

Linkage to Molecular Therapy 

Apart from the early diagnosis of molecular processes, cardiovascular research is also directed towards the 

development of new molecular therapies. A major limitation of molecular therapies has been the inability to 

achieve controlled and effective delivery of these therapies to target region, and to monitor the success 

noninvasively. 

While establishment of molecular imaging techniques for diagnosis involves their evaluation in suitable 

animal models of disease, the establishment of molecular imaging for therapeutic monitoring requires early 

linkage with novel experimental therapeutic models. In addition to basic disease models of atherosclerosis, 

ischemia, infarction and heart failure, therapeutic models available to the cardiovascular group of the 

network include strategies for stabilization of atherosclerotic plaques, angiogenesis induction for biologic 

bypass of chronically occluded vessels and cell transplantation for heart failure and regeneration of 

myocardial infarction. Translational aspects from experimental research to clinical application will be 

covered by extension of successful preclinical work to suitable clinical situations. 

The unique combination of imaging systems, molecular probes, basic molecular biology methods, animal 

models and therapy models within the cardiovascular programme, along with the interaction between groups 

and continuous contribution of innovations from various areas will provide an optimal organisation for 

breakthrough developments and establishments in the field of cardiovascular molecular imaging.


6.2.2.3 Diagnostic Molecular Imaging in Inflammation & Regeneration 

Inflammation is the process characterized by the body’s reaction against infectious agents, antigenchallenges, 

such as seen in autoimmune diseases, or as a response to physical damage to tissues or cells. 

This process is hallmarked by increased blood flow and enhanced capillary permeability to the site of where 

the inflammatory process is triggered. This is followed by an invasion of immune cells, initially neutrophils, 

which are particularly prevalent in the earlier stages of the inflammation, followed by monocytes and 

lymphocytes, which migrate to the site of inflammation during later stages. The last migratory cells to arrive 

at the inflammatory site, the white blood cells, release chemokines, cytokines and other inflammatory 

mediators that control the activity of the cells involved in the progression of the inflammatory process. 

The inflammatory process is an evolutionary ancient mechanism designed to swiftly combat harmful or 

stressful insults, and ideally, as the damaged or inflamed tissue undergoes the process of healing or 

regeneration, the inflammatory process rapidly subsides to the point of pre-injury. Therefore the response to 

infection and physical or chemical insult is often acute, and generally subsides in 24-48 h. However, a 

persistent or repeated exposure of an inflammatory insult, or disruption of normal host control mechanisms 

such as in autoimmune diseases may develop into chronic inflammation. Chronic inflammation is 

furthermore associated with the pathogenesis of certain cancers, atherogenesis, neurodegenerative diseases 

and diabetes. 

Perhaps not surprisingly, there is great interest in chronic inflammation as such a large proportion of the 

European population is affected by autoimmune diseases of one form or another. It is estimated that one in 

five people in the Western world suffer from autoimmune disease. Rheumatoid arthritis (RA), systemic lupus 

erythematosus (SLE), multiple sclerosis (MS), Crohn’s disease, and psoriasis represent a few of these 

afflictions and are characterized by the presence of autoantibodies directed against one or several 

autoantigens. The autoantibody can be targeted to a specific organ such as the thyroid (e.g. Hashimotos 

thyroiditis), or diametrically, to virtually every cell in the body, such as what is seen in SLE. This initial 

antibody-autoantigen interaction event triggers the infiltration of immune cells to the site of inflammation, 

subsequent release of cytokines, and frequently to the attack on, and destruction of the inflicted organ. 

Despite efforts to elucidate the mechanisms and causes of autoimmune diseases, their etiology is basically 

unknown, and it is not impertinent to state that autoimmune diseases are among the last widespread diseases 

for which we have very limited clues to their pathogenesis or to treatments that can prevent or revert the 

disease course. The diseases can affect humans at any age and are usually lifelong and chronic. 

Molecular imaging techniques are valuable tools which provide the ability to not only visualize, or follow, 

the events occurring in the cells that are initiating the inflammation process; these techniques also have the 

ability to image the events that occur during the completion, or the chronic state, of the inflammatory 

response. Associated with the invasion and proliferation of immune cells that orchestrate the inflammatory 

process, there are a multitude of factors that are key elements in the chronic inflammation process which are 

excellent candidates as targets for molecular imaging. Of particular interest are certain transcription factors, 

protein kinases, metalloproteinases, the complement system and toxic factors such as reactive oxygen species 

(ROS). Many of these elements are not only surrogate markers of inflammation, but are also potential 

targets for drug development: 

Transcription factor NF-κB 

The group of transcription factors constituting the NF-κB family plays an essential beneficial role in normal 

physiology. However, inappropriate regulation of NF-κB activity has been implicated in the pathogenesis of 

several diseases: cardiovascular disease, diabetes, cancer, ischemic brain damage and chronic inflammation 

to name a few. Although many other transcription factors have been described as being involved in


pathogenesis, NF-κB stands out as an exceptionally important factor due to the rapidity of its activation, its 

unique regulatory mechanisms, and a large number of both activating signaling pathways, and number of 

genes that it controls. The long list of functions regulated by NF-κB, in both sickness and health, indicates 

that the pharmaceutical or nutritional modulation of NF-κB activity and action gives great promise as an 

effective therapeutic strategy to combat diseases in which NF-κB is involved. NF-κB is not only activated by 

proinflammatory stimuli, but it also induces the expression of many genes that code for proinflammatory 

mediators such as chemokines, cytokines and adhesion proteins. Several strategies to inhibit NF-κB, or 

selected proinflammatory cytokines such as TNF α have been successful in animal models, such as in RA, 

Crohn’s disease, ankylosing spondylitis, psoriasis and psoriatic arthritis. Models in which NF-κB activation 

can be assessed repetitively and reliably by molecular imaging has therefore great value. 

Protein kinases 

IκB kinase (IKK), and mitogen-activated protein kinases (MAPK) are central components in the 

inflammation process. Proinflammatory cytokines rapidly activate IκB kinase (IKK) and mitogen activated 

protein kinases (MAPK), which through a series of phosphorylation steps may activate NF-κB and activator 

protein-1 (AP-1) respectively, although activation of NF-κB is influenced by components in MAPK 

signaling pathway. AP-1 is also intimately associated with the inflammatory process, being an important 

regulator of TNF α and metalloproteinases. Therefore there is an enormous interest among the largest 

pharmaceutical companies for development of kinase inhibitors to cure diseases or alleviate disease 

symptoms. Particularly p38MAPK inhibitors seems interesting as they control both production of pro 

inflammatory agents such TNF α and IL1 and their receptor mediated signal transduction, thereby control 

the vicious cycles in inflammation and immune responsive diseases. Several inhibitors are in clinical trials, 

particularly for treatment of rheumatoid arthritis. 

Matrix metalloproteinases 

Matrix metalloproteinases (MMPs) are a family of enzymes that degrade different components of the 

extracellular matrix (ECM). Balanced expression of these enzymes and their inhibitors ensures maintenance 

and integrity of the ECM. As chronic inflammation progresses abundance of MMPs may lead to excessive 

degradation of connective tissue associated with the inflamed tissue. Several studies have demonstrated a 

strong correlation between the levels of various MMPs such as MMP-2,-3, -9 and -13 and inflammatory 

disease state making them good candidates as markers for chronic inflammation. 

The complement system 

The complement system is a central component of the innate immune system, and is activated as part of the 

inflammation process. Its prime function is killing and eliminating pathogens. During autoimmune disease, 

however, the complement system may aggravate the inflammation by triggering the release of inflammatory 

mediators from Mast-cells. Preclinical experiments aimed at inhibiting various members of the complement 

system have demonstrated amelioration of several of the most common autoimmune diseases such as RA, 

MS and SLE. Importantly, complement activity influence the different autoimmune inflammatory diseases 

differently, for example RA and SLE. Deficiency of C2 and C4 promote SLE whereas a deficient function of 

C5 will protect against RA. In addition various complement proteins play different role along the 

inflammtory procerss with different functions in immune priming than in the inflammatory effector phase. 

This diversity can be precisely addressed in the animal models. 

Reactive oxygen species (ROS) 

As oxidative stress may be an important contributing factor in inflammation, it is important to establish and 

validate imaging probes sensitive to reactive oxygen species (ROS), such as superoxide anion, hydroxyl 

radical, hypochlorous acid, hydrogen peroxide, singlet oxygen and peroxynitrite. ROS, are produced by 

macrophages and granulocytes during inflammation. When reaching too high levels ROS may exacerbate the 

disease progression by altering or damaging cells in the area of inflammation. For instance, mutations in


certain genes such as p53 seen in rheumatoid arthritis inflicted synovium are indicative of a persistent attack 

by reactive oxygen species during inflammation. In addition ROS may alter the intracellular redox-balance 

which, as a consequence may affect intracellular signaling pathways. Several studies have demonstrated 

altered NF-κB-, and AP-1 activation as well as various kinases and phosphatases in the MAPK-pathway as a 

consequence of oxidative stress. Importantly, oxidation of cellular pathway through induction of ROS may 

also have protective effect on pathologic inflammation. This has been shown by positional cloning of the 

major gene controlling arthritis severity. This showed that a mutation in the Ncf1 gene, in both rats and mice, 

leading to a markedly reduced capacity to mount an oxidative burst in response to an inflammatory challenge 

(Ref I). Thus, ROS may in some diseases play an anti-inflammatory, protective role. 

At a preclinical point of view, imaging specific molecular events in animal models is of particular interest. 

The DiMI network currently has the access to several mice models for inflammatory diseases either as a 

consequence of genetic alterations in transgenic mice or induced by chemicals or antibodies. Inflammatory 

models include arthritis, MS, inflammatory bowel’s disease and psoriasis. In addition, transgenic reporter 

mice utilizing luciferase from the firefly has been developed, whose expression is controlled by transcription 

factors intimately associated with development of inflammation, such as NF-κB. Because of their favourable 

size, laboratory animals allow flexibility in imaging with various modalities, enabling thus optical imaging in 

addition to MRI and PET-imaging. Optical imaging, which utilizes bioluminescence and fluorescence, has 

successfully been employed in small animal models for a number of years. So far optical imaging has been 

hampered in larger experimental animals and humans due to the high absorption of light in tissue. Major 

effort is therefore to develop models and optical technologies aimed at larger animals and humans. The 

advantage of optical imaging modalities includes the low cost and that such techniques allow imaging of 

several mice in relatively short time. 

Progress towards establishing better treatment regimes, accurately determine the stage of the disease and to 

monitor the role of key regulatory factors is therefore of paramount importance. In this respect tools to 

diagnose and unfold mechanisms of the wide range of inflammatory diseases, which to a large extent share 

common features, must be given high priority. Molecular imaging provides not only a tool to more precisely 

determine the stage of the disease (diagnosis) and to evaluate the effect of various treatments. It also 

provides the opportunity to visualize basic processes in the disease, such as the regulation of key regulatory 

genes (NF-κB) and enzymes that contribute to the pathogenesis in living subjects. This proposal aims at 

establishing a plethora of imaging agents that have the ability to monitor a wide range of inflammatory 

diseases. 

Our main goal in the five year period of this proposal is to use optic imaging tools to visualize events 

described above that are crucial in the inflammatory process as follows: 

1. Investigate NF-κB activation using bioluminescence imaging. As NF-κB is regarded as a key regulator 

of the various inflammatory mediators such as cytokines, chemokines and adhesion molecules, there is 

great value in assessing the dynamic regulation of NF-κB during the various phases of chronic 

inflammation, from the early phases of initiation to the progression of the disease. To address this, we 

will utilize transgenic reporter mice integrated with the firefly luciferase gene whose expression is 

regulated by NF-κB. Imaging NF-κB activation will be performed in already existing NF-κBluciferase 

mice which will be either crossed into transgenic mice that are designed to develop a variety 

of autoimmune diseases (TCR-λ 315 -model described in WP-1) or inflammation-inducible mice. As the 

activity of luciferase is present in all cells, the detection of NF-κB activation in specific cell types is 

therefore a challenge. Within the five year period we aim at developing improved reporter mice whose 

expression of the reporter gene is tissue specific (Cre-lox-directed), which would be helpful to resolve 

which cells are being activated.


2. Validate and establish metalloproteinase specific imaging probes. Near infrared imaging 

fluorochromes specifically activated by proteinases (MMP-2 and cathepsin B) has been described 

previously. In addition we aim at establishing additional metalloproteinase activatable imaging probes 

for optical in vivo imaging (MMP-1, MMP-3, MMP-9 and MMP-13). 

3. Develop and validate novel optical imaging probes for complement activation Within the five year 

period we aim at developing novel imaging probes for detection of complement activation. Several of 

the products of complement activation are proteases (C3- and C5 convertases), enabling cleavage of a 

peptide fragment that release a fluorochrome covalently associated with a quencher. 

4. Develop novel and existing optical imaging probes for in vivo imaging of ROS. Within the first part of 

the period we will use existing chemiluminescent probes such as lucigenin, luminol and H 2 DCF in 

models of inflammation/oxidative stress. At a longer term we aim at developing novel fluorophorestable 

radical conjugates whose emission is switched on following encounter with radical species such 

as hydrogen peroxide and hydroxyl radical. 

5. Label immune cells characteristic for the inflammatory process with imaging probes to monitor 

migration and proliferation of such cells. I.v. injection of various stably transfected leukocytes or 

monocytes expressing luciferase is one approach. These cells will home to the inflammatory site. 

Another approach is to inject imaging agents that are selectively taken up, or activated in specific 

immune cells. Near infrared probes activated by Cathepsin B can be used for imaging of macrophages. 

6. Develop novel transgenic reporter models for kinase activity. Experiments in the area of kinase 

inhibitors are hampered by unspecific effects of most currently available kinase inhibitors and tools for 

both measuring specificity and ability to reach target cells and tissues are required. Such a tool must be 

able to report inhibitory activities in vivo as well as to provide the necessary specificity. In vivo 

imaging has the potential to fulfill both criteria. It is therefore of great interest to create molecular 

imaging tools designed to monitor the activity of specific protein kinases. This may be feasible in 

transgenic mice, where the reporter gene activity is specifically altered by the addition of phosphate 

groups. This has been demonstrated for luciferase, modified in such a way that sequences within the 

luciferase protein is recognized, and subsequently phosphorylated by a kinase of choice. A five year 

goal is therefore to develop transgenic reporter mice whose activity of the reporter gene is modulated 

by specific kinase activities. 

7. Improve technology for fluorescence imaging. The cooperation with a group focused on instrumental 

techniques will make it possible to devise probes optimized to the capability of existing systems, or to 

influence the design of imaging systems so that they match the optical properties of the new probes. 

This work could ultimately lead to the industrialisation of imaging systems by a EU company, such a 

technology transfer being a mission of LETI. 

Imaging Regeneration 

With respect to stem cells, the potential of molecular imaging technology to profoundly contribute to the 

assessment of their therapeutic potential, the identification of important factors involved in guided and 

targeted integration as well as the assessment of their safety has been detailed in the respective sections in 

Neuroscience and Cardiovascular Research.


6.3 Activities to spread excellence 

The activities of DiMI-TTPs to spread excellence in terms of training and practical courses, communication 

and exploitation will be coordinated by P1+12. As P12 is the Project Coordinator of EMIL, close personal 

interaction between P1+12 will facilitate complementary action of DiMI and EMIL with respect to the 

activities in training and dissemination, as indicated in the ESR. In due course of DiMI, activities to spread 

excellence will be managed by 

• a Board for Training Activities (BOT), chaired by P12 

• a Board for Dissemination and Communication Activities (BODIC), chaired by P12 

• a Board for Knowledge and IPR Management (BOKIM), chaired by the AKM (see below). 

Education and Training 

A major task of DiMI will be the training of researchers in all respective fields of molecular imaging. These 

activities will be coordinated by P1 and P12 and the Board for Training Activities (BOT consisting of four 

members from the SMB). Several partners within the consortium have specific experience in training 

activities on the European level (4 th and 5 th FW, Marie Curie). The DiMI-TTPs will attract early and 

advanced research scientists from all over the world for the need of high-level training in the individual 

molecular imaging specialty of each core centre. The individual DiMI-TTPs are listed in =>6.1 and 

described in detail in =>9.A. The DiMI-TTPs will be also available for higher education of students, 

whether they belong to the DiMI consortium or not, under conditions that will be defined by the steering 

committee (SMB) and the partner in charge for Training and Dissemination (P12). The DiMI-TTPs will 

educate and train scientists and students in the different imaging technologies represented in the consortium, 

such as MRI, CT, PET, SPECT, OI. Education and training will start at the beginning of the program in 12 

centres of excellence as described in =>table 1 (6.1). A detailed description of the education activities is 

given in =>9.A. 

Measureables for platform activity are: 

• number of trainees 

• number of months of training activity; 

• number of training contracts with national bodies and industry 

• successful establishment of a European MD, PhD programme for Molecular Imaging (together with 

the EMIL consortium) 

Dissemination and Communication 

P1 and P12 are responsible for close coordination of the DiMI dissemination activities of DiMI and in due 

course by the Board for Dissemination and Communication Activities (BODIC consisting of four members 

of the SMB). These activities aim at making all possible users aware of DiMIs projects output (e.g. patents, 

novel prototype hard ware, new licensed soft ware, new diagnostic probes, specific conferences of interest 

related to diagnostic molecular imaging) in a coherent and consistent way. A specific annual plan for 

dissemination and communication (APDAC) will be implemented and upgraded each year before the annual 

review. The way of dissemination will be via 

• research publication; 

• research meetings and summer schools; 

• advertisements;


• the internet through the website: www.diagnostic-molecular-imaging.org, which has been 

implemented in October 2003. This website is also meant to facilitate the flow of information within 

the DiMI consortium. 

The target address of dissemination activities are (i) scientists in the ERA; (ii) SMEs promoting related 

technologies; (iii) international, national and regional authorities in the EU countries; (iv) research 

organizations and other European associations involved in molecular imaging, neuroscience, cardiovascular 

disease, immunology and stem cell research; (v) Universities involved in teaching in the topics related to 

molecular imaging; (vi) international organizations where some of the consortium members are active 

members (e.g. Society for Molecular Imaging, Academy of Molecular Imaging, Society for Nuclear 

Medicine, IEEE Nuclear Science/Medical Science, European Society of Radiology, European 

Neuroscience). 

DiMI will implement an annual Conference for Molecular Imaging in Europe. Five of this type of 

conference have been organized since 2003 

• (i) from P12 on the topic “New in vivo imaging modalities for Molecular Biology, Cell Biology and 

Physiology” in Roscoff (F) (http://www.cnrs.fr/SDV/cjmtavitian_e.html); 

• (ii) from P1 and P9 on the topic “Cellular and Molecular Imaging in Diagnostics and Therapy” in 

Bordeaux (F) (http://www.ismrm.org/workshops/molecular_imaging/index.htm); 

• (iii) from P1 as the 4 th Cologne PET Symposium on “High resolution imaging of gene expression by 

HRRT and microPET” in Cologne (D) (http://www.mpifnf.de/ivpet04/); 

• (iv) from P3 on the topic "New Diagnostic Probes and Imaging Modalities in Biomedical Research" 

in Torino (IT) (http://www.bracco.com); 

• (v) from P3 on the topic "From Structural Genomics to Molecular Medicine: the challenging role of 

NMR" in Torino (IT) (http://www.fobiotech.org). 

• Moreover, P1 and P9 are also involved in the organization of the annual meeting of the international 

Society for Molecular Imaging (SMI; http://www.molecularimaging.org/meeting3/home04.php3) in 

2004. 

The Conference for Molecular Imaging in Europe will be co-organized with both the DiMI-NoE and the 

EMIL consortium 

• to foster opinion exchanges between the consortium members over hot issues and their perspectives 

in the light of the progress made during the network’s activities; 

• to attract all stakeholders of an implementation plan into an open discussion about the most recent 

findings dealing with the specific issues of DiMIs activities. 

• to promote further interactions with SMEs and industry; 

• to generate common knowledge. 

Measureables of the quality of dissemination of knowledge and communication beyond the network will be 

performed in a quantifiable form (by number) through 

• research publications generated within the DiMI-NoE; 

• research meetings and summer schools; 

• databases on common molecular imaging knowledge in the internet; 

• the successful implementation of the European Society for Molecular Imaging (www.europeansociety-molecular-imaging.org); 

• communication by world wide web into the general society.


Exploitation 

A detailed description of exploitation activities is given in =>6.5. In summary, DiMI will hire an 

Administrator for Knowledge Management (AKM) with responsibilities for intellectual property queries, 

exploitation, dissemination, publicity and external liaison. To ensure his duties, he will chair the Board for 

Knowledge and IPR Management (BOKIM) and communicate their advice to the coordinator (P1). The 

BOKIM will be the central organisation for handling questions regarding intellectual property and for 

coordinating the knowledge management activities of the DiMI consortium. The BOKIM will be composed 

of four members appointed among the participants by the steering committee (SMB), and will be chaired by 

the AKM. The BOKIM will issue opinions and take its decisions on a qualified majority basis. The duties 

of the BOKIM will consist of ensuring the definition of the plan for the dissemination and will deal with all 

questions with regards to intellectual property and any other activities promoting innovation in the network’s 

project. Moreover, the BOKIM will be the instrument of a durable integration of the research capacities of 

the network participants advancing knowledge on the scientific and technological network topic. A coherent 

joint management of the network knowledge arising from the jointly executed research of the network will 

ensure an appropriate use and dissemination of the network results in compliance with the general 

arrangements stipulated in the contract with the European Commission. 

The plan for dissemination will be designed and reviewed by the BOKIM on a yearly basis with regards to 

dissemination of basic research knowledge, new technical and methodological developments, new software 

developments, any document or data in support of these outputs, and media related to the yearly conference 

proceedings. An overview of DiMI’s activities for web-based Dissemination and Communication is 

summarized as follows: 

Structure of DiMI web-based information 

Communication 

Internal 

External 

Management tools 

Knowledge Management 

Knowledge database 

WEB site 

Legal documentation 

Validated 

Partners' data 

Discussion Forums 

Success Stories 

Image Processing 

& Management 

Informations 

on DiMI project 

Thesaurus 

Campaigns of 

Dissemination 

of the Results 

and awareness 

of the Public 

to Scientific issues 

Information on 

Congress 

Workshops 

Training 

Workgroups 

One level 

ofvalidation: 

Coordinator 

Scientific 

Results 

Progress 

Reports 

Two levels 

of validation: 

Coordinator 

+ team leader


Potential Synergies between DiMI and EMIL Networks 

P1 and P12 as Coordinators of DiMI and EMIL have agreed upon the following common activites, partially 

overlapping activities and independent actions to ensure synergy between both networks and to ensure that 

funding is not obtained twice for the same action. 

1. Common activities 

1.1 Training/ Education actions: 

- Joint training activities through the EMIL “Summer school” and the DiMI “Winter school” 

- European MD, PhD programme 

1.2 Dissemination/ Meetings actions: 

- DiMI & EMIL joint annual meetings 

- Creation of the European Society of Molecular Imaging 

1.3 Research activities: 

- Research WP dedicated to Instrumentation e.a. EMIL WP1 related to “Software and Hardware tools 

for Multimodality imaging ” and DiMI WP1 and WP2 dedicated to microSPECT and combined MRI 

and PET imaging 

2. Partially overlapping activities 

2.1 Partially common dissemination/ training activities: 

- Similar concept with regards to technological and trainings platforms (TTP) between DiMI and 

EMIL with the following common platforms that will share both DiMI and EMIL applications: 

o Cologne (P1) 

o Orsay (P12) 

o Torino (P3) 

o Milano (P6) 

o Antwerp (P8) 

- Similar information system with easy & visible links between DiMI and EMIL websites. Both sites 

will share information about: 

o Positions available 

o Events calendar 

o Common links 

o … 

2.2 Partially shared Management Methodology: 

- on the network governance structure 

- on procedures, organisation, scheduling 

- …. 

3. Independent actions 

All research workpackages of the JPRA except for the technological WPs (WP1 and WP2 of DiMI) which 

are interrelated and complementary to WP1 of EMIL.


6.4 Management of the Consortium Activities 

The management structure of DiMI is based on the overall (JPA) and scientific (JPRA) organizational 

structure of DiMI. In four main circles with supporting and integrating flanking actions the structure of 

management takes the overall complexity of DiMI into account reaching the necessary integration required 

for its overall success. 

1. The central core DiMI Management Office (MO) constitutes of the coordinator (P1), two scientific 

administrators, the administrator for knowledge management (AKM) and a scientific secretary. 

2. The second circle, the Scientific Management Board (SMB) constitutes all partners of the steering 

committee (P1-13). 

3. The third circle, the Ethical Management Board (EMB) constitutes a subset of partners of the steering 

committee (P1, P5-P12) and P37 from the Governing Board. 

4. The fourth circle, the Governing Board (GB), constitutes one representative of all partners in the DiMI 

consortium. 

5. In addition, various Boards and Committees will be constituted responsible for integrating activities 

(BIA), training (BOT), dissemination and communication (BODIC), knowledge and IPR management 

(BOKIM) as well as advice in ethical and safety affairs (EAC) and the scientific component of the 

network (SAC). 

DiMI Management 

Board for Training Activities (BOT) 

Board for Dissemination & Communication (BODIC) 

DiMI 

Members 

Board for Integrating Activities (BIA) 

GB 

Neuroscience 

(P1,7,8) 

Cardiovascular 

(P9,10) 

SMB 

Technology 

(P2,13) 

Probes 

(P3,4) 

MO 

Coordination 

(P1) 

Animal Models 

(P5,6,11) 

SMEs 

Inflammation & Regeneration 

(P1,11) 

Integration 

(P13) 

Training & 

Subcontractors 

EMB 

Dissemination 

P1,5-12,37 

(P12) 

Board for Knowledge and IPR Managment (BOKIM) 

Ethical Advisory Committee (EAC) 

Scientific Advisory Committee (SAC) 

Section =>8 describes in detail the management structure of DiMI. At this point is should be emphasized 

that the management activities are circled around the governing bodies of the JPA and JPRA indicating the 

importance of the Scientific and Ethical Management Boards (SBM, EBM) as the key strategic/ethical review 

and decision-making structure, and the DiMI Management Office (MO) at MEK (D) as the nerve centre 

responsible for coordinating activities between partners and for communication at all levels, including 

dissemination outside the consortium. Moreover, the flanking action and advisory boards play an important 

role for the efficiency of the overall JPA of DiMI. These boards and committees serve for sound integration, 

facilitate decision making and guide the overall direction of the DiMI network over the 5-year period. A 

summary of goals, tasks and members of each board of DiMI is as follows:


Goals, tasks and members of each board of DiMI 

Board Members Tasks 

GB • representative of each 

partnering institution 

• deciding on the overall direction of the JPA and JPRA 

• chaired by project coordinator 

SMB • Steering Committee • coordination of subprojects and WPs in the six main topics of the 

members 

JPRA and the two topics of the JPA 

• chairpersons of BIA, • linking individual project partners from the GB with the project 

BOT, BODIC and coordinator 

BOKIM 

• preparation of annual implementation plans 

• appropriate resource allocation 

• evaluation of membership and partner performance 

• review of proposals submitted for future calls 

• chaired by project coordinator 

EMB • 9 members of the 

Steering Committee and 

1 member of the GB 

• control and review of ethical aspects 

• preparation of a common list of laws regulating animal experiments 

and human studies in various countries 

• annual review of animal and human studies performed in the 

framework of the JPRA 

• preparation of an annual ethical implementation plan 

• chaired by P1+P37 

BIA • 4 members from SMB • establishment of DiMI-TTPs 

• program for exchange of personnel within the consortium 

• integration of SMEs, which changes over time according to specific 

needs and developments 

• chaired by P13 

BOT • 4 members from SMB • control of training within DiMI-TTPs 

• establishment of summer schools and special training courses 

• establishment of a European MD,PhD program for molecular 

imaging 


BODIC • 4 members from SMB • design of a yearly dissemination and users plan 

• design of website: www.diagnostic-molecular-imaging.org 

• organization of an annual European Conference on Molecular 

Imaging 

• control and review of gender aspects 


BOKIM • 4 members from SMB • responsible for intellectual property queries and exploitation 

• chaired by administrator for knowledge management (AKM) 

SAC • recognized researchers 

from the field of 

molecular imaging 

EAC 

MO 

• recognized organizations 

dealing with ethical and 

safety aspects of 

research in medicine on 

the European level 

• Project Coordinator 

• AKM 

• 2 Scientific 

administrators 

• Secretary 

• general and specific input into the overall road map of the JPA and 

JPRA 

• to provide insight into international collaborations 

• visiting DiMI-TTPs on request 

• general and specific input into the ethical and safety aspects of the 

JPA and JPRA 

• administrative management (contractual, legal, financial, ethical) 

• design and guidance of JPA (integration, training, dissemination, 

exploitation) 

• design and guidance of JPRA (management of experimental and 

clinical science with translation into health and societal value) 

• communication with Commission including timely reporting and 

delivery of required documents


Summary of positions defined within the individual boards 

Board Members Project Coordination 

SMB • P2: John Clark 

• P13: Marie Meynadier 

• P3: Silvio Aime 

• P4: Denis Guilloteau 

• P5: Anna Planas 

• P6: Adriana Maggi 

• P11: Harald Carlsen 

• P1: Karl Herholz 

• P7: Gitte Knudsen 

• P8: Annemie van der Linden 

• P9: Chrit Moonen 

• P10: Frank Bengel 

• P1: Andreas Jacobs 

• P12: Bertrand Tavitian 

• Integrated technologies (PET, MRI, OI) 

• Integrated technologies; integration of SMEs 

• MRI and combined probes 

• Radionuclide and combined probes 

• Animal model library (PET) 

• Animal models for combined imaging (OI, PET) 

• Animal models inflammation (OI) 

• Clinical neuroscience (PET, MRI) 

• Neuroscience, PET quantitation 

• Experimental neuroscience (MRI) 

• Cardiovascular imaging (MRI) 

• Cardiovascular imaging (PET, OI, MRI) 

• Imaging stem cells in CNS (PET, MRI, OI) 

• Training & Dissemination 

EMB 

BIA 

BOT 

BODIC 

BOKIM 

• P1: Andreas Jacobs, Karl Herholz 







• P11: Harald Carlsen 


• P37: Robert Poelmann 

• P13: Marie Meynadier 





• P4: Dennis Guilloteau 







• AKM: TBA 

• P2: John Clark 

• P3: Silvio Aime 



• Animal models, human studies neurodegeneration 

• Animal models (CNS) 


• Animal models, human studies neuroinflammation 


• Animal models (cardiovascular) 

• Animal models, human studies cardiovascular 

• Animal models (inflammation) 

• Training & Dissemination 

• Extensive experience as Head of Ethics Committee 

• Chair person 




SAC • Ralph Weissleder (Boston), Sam Gambhir (Stanford), Chet Mathis (Pittsburgh), Ronald G. 

Blasberg (New York), Tom Mead (Northwestern), Konrad Beyreuther (Heidelberg), Hein Wellens 

(Maastricht), Johan Lugtenburg (Leiden) 

EAC • Ludger Honnefelder (Bonn) 

• Michael Fuchs (Bonn) 

• Didier Sicard (Paris) 

MO • P1: Andreas Jacobs 

• AKM, scientific administrator and 

secretary: TBA 

• Project Coordination


The core management of DiMI relies on the members of the Scientific and Ethical Management Boards 

(SBM, EBM), which are responsible for the success of the JPA and the JPRA of the network. The SMB 

comprises all members of the Steering Committee which function as coordinators of the subprojects. The 

SMB will meet at least twice a year, telephone conferencing will also be used, meetings will be chaired by 

the Coordinator. The SMB has to enact its decisions through the Project Management Office. All partners 

within the DiMI consortium will report the project progress and achievement of milestones and deliverables 

to the Project Management Office using agreed reporting procedures that will be set up on the DiMI 

database. The coordinators of subprojects will review this information prior to the 3-monthly meetings of 

the SMB, and feedback to the partners will be communicated via the Project Management Office. The 

coordinators of subprojects will also call meetings of scientists involved in projects operated by their 

subproject. The coordinators of subprojects and specific partners will be responsible for particular activities 

and for the DiMI-TTPs. The Project Management Office will provide day-to-day communication with all 

partners as described in section =>7. 

DiMI is envisioned as a long-term, multidisciplinary scientific consortium focussing on the advancement of 

molecular imaging technology for diagnostic purposes. DiMI first originates from those institutions in which 

multidisciplinary research involving imaging and molecular technologies are currently ongoing. It is 

expected that with the overall exponential growth of molecular imaging-related experimental and clinical 

research, the consortium will grow in order to comprise a critical mass and the decision-making groups as 

well as innovative SMEs in order to generate common diagnostic test, common data and knowledge. On the 

other hand, those partners with lose contacts or inappropriate performance will be excluded from DiMI. 

Most importantly, DiMI will seek contacts and interactions outside the consortium with 

• research groups that focus on a specific scientific goal which is a component of a molecular imaging 

research project, but do not have the critical mass or do not wish to make molecular imaging an 

essential part of their activity; 

• clinical departments that have a particular interest in a specific drug yet lack the overall 

infrastructure to perform molecular imaging themselves; 

• groups that initiate projects in response to new discoveries and wish support from DiMI to explore 

molecular imaging applications; 

• drug companies that require molecular imaging at specific drug development stages; 

• biotech companies, that have an interest in molecular imaging for the development of drugs, 

diagnostic applications, or generic instrumentation or services.


6.B PLANS 

6.5 Plan for using and disseminating knowledge 

All the issues and questions related to Knowledge Management including intellectual property queries and 

exploitation of Knowledge will be dealt with within the Board for Knowledge and IPR Management 

(BOKIM). The BOKIM consists of 4 members from the SMB and is chaired by the Administrator for 

Knowledge Management (AKM) who belongs to the Management Office. The individual members of the 

BOKIM are listed in =>6.4. 

The tasks of the BOKIM include 

• the responsible management of intellectual property queries and exploitation; 

• the design of an annual plan for the management of knowledge, intellectual property and any other 

activities promoting innovation in the project; 

• the integration between the Project Coordinator and the partners (GB) through its guidance of 

decisions for the protection, dissemination and use of knowledge. 

The BOKIM shall issue opinions and take its decisions on a qualified majority basis. The BOKIM will be the 

instrument of a durable integration of the research capacities of the network participants, advancing 

knowledge on the scientific and technological network topic. A coherent joint management of the network 

knowledge arising from the jointly executed research will ensure an appropriate use and dissemination of the 

network results, in compliance with the general arrangements stipulated in the contract with the European 

Commission. 

The annual plan for the management of knowledge and intellectual property will describe each Scientific and 

Technological Development as well as Innovations within the following activities: 

• technological and methodological developments 

• software tools 

• new diagnostic probes 

• specific animal models 

• other basic research 

• documents and data in support of the above outputs 

• media related to teaching course, summer schools and annual conference proceedings 

The annual plan for the management of knowledge and intellectual property will also describe the list of endusers, 

the user description and the dissemination/exploitation mode. 

6.6 Gender Action Plan 

The participation of women in DiMI is an important issue as illustrated by the following numbers: 

6.6.1 Participation of women and gender action plan 

Women are directly involved in the scientific management of the project as well as in the scientific 

partnership as team leaders in the project. The percentage of women scientists involved in the project is as 

follows:


• 179 out of 578 researchers are women (31 %) 

• 107 out of 240 early-staged researchers are women (45 %) 

• 15 out of the 60 representatives from 52 partnering institutions are women (25 %) 

• 1 out of 6 CEOs or R&D managers of SMEs is a women (17 %) 

• 5 out of 14 members from 13 partnering institutions of the steering committee are women (36 %). 

The proportion of female scientists in DiMI is relatively high at the highest level responsibility. This 

situation is opposite to that encountered in laboratories and private companies where top management women 

account for a much lesser fraction of the overall female population. The above mentioned numbers will be 

followed by the Scientific Management Board of DiMI along the course of the project on a yearly basis. 

With the strong participation of women at the decision making level, DiMI will keep the highest attention to 

the promotion of female researchers within the network. All job advertisements within DiMI will have the 

equal opportunity statement within the job description included. One of DiMI’s goals is to facilitate and 

improve female representation especially in the research program. This task will be carried out primarily on 

the recruitment of PhD students and postdoctoral fellows within DiMI. 

Action plan 

• follow the above listed numbers on a yearly basis and, whenever necessary, issue warnings to DiMI 

partners; 

• ensure that exchanges of personnel contain a high percentage of women, and whenever needed help 

women scientists encountering specific difficulties with mobility; 

• organize child care facilities at the DiMI-TTPs to facilitate mobility of women researchers with 

family; 

• create a Women in DiMI chat forum for exchange about issues encountered by female DiMI 

researchers; 

• include a specific page in DiMI’s website to introduce every three months one of DiMI’s female 

scientific figures and personal experience. 

6.6.2 Gender aspects in research 

DiMI involves the following gender/sex aspects: 

Yes 

• Involvement of human subjects X 

• use of human cells / tissues / other specimens X 

• use of animal subjects or animal tissues / cells / other specimens in X 

such a way that it is expected that may have implications for 

humans? 

• use of collection of data related to human subjects, human X 

materials, animal subjects or animal materials 

No 

Are gender/sex differences with respect to the research documented in 

the literature? 

Yes 

X 

No


Three issues of the research conducted in the DiMI proposal are related to gender/sex aspects: 

a) Sex and gender differences in the incidence, prevalence and severity of neurodegenerative, 

cardiovascular and autoimmune diseases; 

b) Gonadic irradiation in imaging experiments; 

c) Animal models using sex hormones. 

Ad a) In the animal models used to study neurodegenerative, cardiovascular and autoimmune diseases, 

animals from both sexes will be tested and data will be compared between the two sexes to test for 

possible differences in coincidence, rate, etc. 

Ad b) Gonadic irradiation during the course of CT, PET or SPECT experiments, is not to be neglected. 

Because female germinal cells are more sensitive to radiation, it is advisable to exclude female 

healthy volunteers from the pools of control subjects, whenever this is compatible with the data 

interpretation. 

Ad c) Partner 6 has developed inducible models of gene expression in mice under control of a receptor for 

estrogens. In this particular case it will be essential to use animals which respond in the appropriate 

manner to female hormonal stimulation. 

Systematic studies on the importance of gender/sex effects in tracer kinetics have not been performed 

exhaustively. Special attention towards this specific aspect will be given in the DiMI program of activities. 

Partners will be required to record and report the sex of the animals used in any given experiment. If 

appropriate, further investigations will be pursued. 

6.7 Raising public participation and awareness 

To ensure the appropriate spreading of awareness of DiMI’s activities into related patient organizations, selfhelp 

organizations, health insurance companies and the general public an annual plan for dissemination and 

communication into general public will be drafted and released by the BODIC (=>6.4) to DiMI partners and 

other relevant audiences. The media to be used for dissemination shall involve 

• local newspaper 

• radio, television 

• world wide web 

• educational courses for patient’s self-help organizations. 

The DiMI BODIC will distribute a request for information to the different bodies of DiMI (SBM, EBM, BIA, 

BOT, BOKIM, subproject leaders, organizers of workshops and meetings) at regular intervals and collect and 

organize the data in a releasable form every 6 months. This will set the basis for the organization of 

campaigns targeted towards specific audiences. Particular occasions where going into public will be 

especially helpful are: 

• conferences (Annual Meeting of the European Society of Molecular Imaging, Summer and Winter 

Schools, extraordinary meetings) 

• special technological and scientific break throughs. 

• discoveries with regards to new applications and novel patient diagnostics and management.


6.C MILESTONES 

6.8 Major Milestones over the full project duration 

The main objective of this network of excellence is the structuring of molecular imaging related research in 

Europe 

‣ to integrate multidisciplinary research aiming towards the development of new probes and novel 

multimodal non-invasive imaging technology for early diagnosis, assessment of disease progression 

and treatment evaluation of diseases of the central nervous, cardiovascular and immune system; 

‣ to achieve efficient training of young researchers, dissemination of new common knowledge and 

integration of SMEs and industry; 

‣ to reach the European leadership role in topics related to molecular imaging for diagnostic purpose 

especially with respect to the creation of common data platforms, standards and guidelines. 

The Major Milestones over the full duration of the project are related to the various activities of the 

consortium in terms of 

1. activities for integration 

2. activities of jointly executed research 

3. activities for dissemination and spreading of excellence 

4. management activities 

1. Major Milestones of Activities for Integration 

Timing 

Major Milestones with respect to expected results, achievements, deliverables 

Start of Program • Establishment of 12 DiMI-TTPs 

• Organisation of SME interaction 

Year 1 

• 12 DiMI-TTPs are established, resource identification stored in secure database 

• first trainees, first winter school, first annual meeting (together with EMIL) 

• practical aspects of exchange of personnel clarified 

• SMEs are integrated into TTP-guided research 

• BIA and BOKIM established 

• Annual implementation plan for Year 2 

• Link of DIMI SMEs to national and European biotech organisations 

Year 2 

• Fully functioning TTPs 

• continuous training, winter school, annual meeting 

• SMEs are integrated into TTP-guided research 


• Opening to new SMEs 

• Link of DIMI SMEs to other NoE SMEs (EMIL, etc…) 

Year 3 • As for Year 2 

• Search for new TTPs 

• Federate SMEs involved in all molecular imaging activities across Europe 


Year 4 • As for Year 3 

• Implementation of further TTPs (depending on further funding sources) 

• Create organization for European Molecular Imaging SMEs 

• Annual implementation plan for Year 4


Year 5 

• at least one TTP per participating country 

• integrated JPRA with continuous training and research activities extending funding period 

2. Major Milestones of Activities of Jointly Executed Research 

Topic 1.1 Diagnostic Molecular Imaging Technology 

Timing 

Start of Program 

Year 1 

Year 2 

Year 3 

Year 4 

Year 5 


• Common meeting of partners for initiation of activities and agreement on tasks 

• Monte Carlo model of microPET using SimSET+GEANT4 

• 3D PROMIS image reconstruction of microPET data on PC-cluster 

• Characterisation of 1T split pair magnet imaging characteristics 

• results on neuroimaging on TOHR and multipinhole design 

• Windowed coincidence and singles transmission scanning on microPET 

• Bayesian reconstruction of microPET transmission data 

• Monte Carlo based scatter correction for microPET 

• Verification of microPET data corrections and image reconstruction 

• Assessment of the performance of PET block detector operating in MR imager 

• Initial design for combined optical/MR scanner 

• results on cardioimaging, multipinhole validation, coupling with MRI & CT 

• Limited array of PET detectors operating in MR imager 

• First simultaneous PET/MR images of phantoms 

• Feasibility study of initial optical scanner design 

• optical tomograph testing 

• Full ring microPET FOCUS operating inside split pair MR imager 

• coupling of optical tomography and radioisotope modalities 

• Imaging experiments using combined PET/MR imager 

• quantitative optical imaging


Topic 1.2 Library of Diagnostic Molecular Imaging Probes 

Timing 


Year 1 

Year 2 

Year 3 

Year 4 

Year 5 


• Common meeting of partners for initiation of activities and agreement on tasks 

• Development of one step radiolabelling with fluorine-18 or carbon-11 of tracer agents for 

dopamine transporter 

• Attain an improved sensitivity with MRI-CEST agents; 

• Get an in-depth understanding of the determinants of the relaxivity of Gd-based MRI 

contrast agents; 

• Set-up of different procedures for cellular labelling with CEST and Gd-based agents; 

• Set-up of efficient conjugation routes between the MR-Imaging Probes and the 

targeting/delivery synthons; 

• Optimisation of the energy transfer step between a lanthanide-based luminescent probe and 

selected chromophores 

• Identify “dual” Imaging Probes (MRI/Optical/Radiotracer) through analysis of the the 

correlated behaviour of Lanthanide systems; 

• Characterization of 18F or 11C labelled tracer agents for dopamine transporter in vitro and 

in vivo in animal models 

• Modelling software for in vivo quantification of dopamine transporter using developed 18F 

or 11C labelled tracer agents 

• Development of tracer agents, labelled with carbon-11 or fluorine-18, for non-invasive 

visualisation of amyloid plaques in brain 

• Characterization of developed tracer agents for amyloid plaques in vitro 

• Identify MRI-CEST agents/procedures responsive to a specific parameter reporter of physio- 

/pathological state; 

• Acquire efficient procedures for the accumulation of MR-Imaging Probes at the targeting 

sites; 

• Set-up of “in vivo” procedures with cells labelled with MRI-CEST and Gd-based agents; 

• Define structure/activity relationship between probe complexes and their ability to permeate 

the cell nucleus 

• Imaging Probes targeting atherosclerotic plaques; 

• Development of “dual” Imaging Probes in “in vivo” applications. 

• Characterization of developed tracer agents for amyloid plaques in vivo in animal models 

• Modelling software for in vivo quantification of amyloid plaques in brain using developed 

18F or 11C labelled tracer agents 

• Development of tracer agents, labelled with carbon-11 or fluorine-18, for non-invasive 

visualisation of vesicular acetylcholine transporter (VAChT) and peripheral benzodiazepine 

receptors ( PBR) 

• Define the key determinants (e.g. complex structure vs localisation profile)of the cell 

internalisation process of lanthanide optical probe. 

• Set-up of Imaging Probes/procedures for MRI visualization of gene therapy; 

• Set-up of Imaging Probes/procedures for MRI visualization of vascular receptors; 

• Characterization of tracer agents, labelled with carbon-11 or fluorine-18, for non-invasive 

visualisation of VAChT and PBR in vitro and in vivo 

• Set-up practicable probes for in situ real-time monitoring of defined intracellular low MW 

analytes 

• Set-up of Imaging Probes/procedures for MRI visualization of amyloid plaques and other 

signatures of neurodegenerative diseases; 

• Set-up of Imaging Probes/procedures for MRI visualization of infection/inflammation 

diseases; 

• Modelling software for in vivo quantification of VAChT and PBR using developed 18F or


11C labelled tracer agents 

• Optimisation of dual-imaging probes for MRI/Optical and /or Optical/PET imaging 

• Optimization of the design of MR-Imaging Probes for specific applications in 

Cardiovascular, Neurological,Infective and Imflammatory diseases. 

Topic 1.3 Library of Animal Models 

Timing 


Year 1 

Year 2 

Year 3 

Year 4 


• Organization of the specific workplan and establishement of detailed interactions between 

partners 

• Coordination of the exchange and establishments of animal models 

• Characterization of disease hallmarks (in the selected animal models) that can be studied by 

imaging 

• Characterization of histopathological and behavioural correlates of imaging alterations 

• Test of anti-inflammatory drugs on the progression of neurodegeneration 

• Optical imaging of reporter gene expression (NF-kB mediated) in inflammation models 

• Development of vectors allowing multimodal imaging of NF-kB in inflammation 

• Characterization of molecular correlates of imaging alterations. 

• Validation of imaging studies with invasive techniques. 

• Correlation of findings between different imaging modalities. 

• Exchange of animal models 

• Identification of molecular targets of interest for further development of imaging markers 

• Generation of novel vectors suitable to imaging of protein-protein interactions 

• Establishment of second inflammation model (spontaneous arthritis) for imaging NF-kB 

activity 

• Production of transgenic reporter mice allowing multimodal imaging of NF-κB activation 

• Testing newly developed imaging markers in in vitro cell culture systems and ex vivo in 

tissues to identify the biological targets 

• Dynamic cooperation between related WPs to allow further implementation of imaging 

studies in selected animal models of interest, and to get further insight into the biological 

correlates of imaging studies. 

• Implementation of experimental animal models to the study of neurological and 

cardioascular diseases 

• generation of vectors for in vivo imaging of inflammatory processes 

• Novel transgenic reporter models for tissue specific expression of reporter gene 

• Novel reporter models for imaging protein kinase activity tissue specific expression of 

reporter gene 

• Testing newly developed imaging markers (by other WPs) in in vivo animal models of 

diseases 

• Dynamic cooperation between the different WPs to allow further development of 

histological, biochemical, metabolic and molecular correlates of imaging data, and for 

potentiating imaging in animal models. 

• Comparison between results in animal and human studies 

• Validation of innovative methodologies for protein-protein interaction in stably transfected 

cells 

• Novel reporter models for imaging protein kinase activity in inflammation 

• Exchanging relevant models to other members of the consortium for validation of various 

imaging modalities


Year 5 

• Testing newly developed imaging markers in in vivo animal models of diseases 

• Validation of the biological targets of imaging probes for clinical studies of neurological and 

cardiovascular diseases. 

• Validation of vectors suitable for in vivo imaging of inflammatory processess in stably 

transfected cells 

Topic 2.1 Neuroscience 

Timing 


Year 1 

Year 2 

Year 3 

Year 4 


• Establishment of in- and exclusion criteria for all patient groups 

• Specification of ethical aspects with particular emphasis on patients with degenerative brain 

disorders and dementia and national regulations 

• Specification of ethical aspects in animal models with particular emphasis on national 

regulations 

• Specification on animal mobility amongst the different partners to allow consecutive 

multimodal imaging 

• Phenotyping of rat models for Parkinson and Huntington Disease 

• Phenotyping of mice models for Amyotrophic Lateral Sclerosis 

• Establishment of [ 11 C](R)-PK11195 in other DiMI laboratories 

• Implementation of protocols for MR-imaging 

• BBB, microglial probes or tPA probes validated 

• Establishment of the ability of tPA and tPAstop-tPA complexes to cross the blood-brain 

barrier and tissue distribution 

• Initial in-vivo studies in models of cerebral ischemia 

• Biochemical inflammatory markers, gene expression, and proteomics in patients 


• Phenotyping of primate models for Parkinson and Huntington Disease 

• Implementation of animal brain atlases for automatic VOI definitions 

• Initial histopathological validation of current neuroimaging markers of inflammation 

• Initial blood-brain barrier integrity studies in patients with multiple sclerosis 

• Cross-sectional MR and/or PET in patients with MS, parkinsonism, memory dysfunction, 

HD, and prion disease 

• Paramagnetically labeled tPA made available to other partners 



• Improved multimodality diagnostic tools for Alzheimer Disease mice models 

• Improved in vivo amyloid detection in Alzheimer Disease models 

• Implementation of new probes derived from Topic 1.2 in other DiMI-centres 

• Publication: MR-methodology of Q-space and BBB passage in MS patients 

• Publication: New tracers for microglia activation: Validation study 

• Publication: tPA probes validation study 

• Publication: in-vivo studies in models of cerebral ischemia 

• Establishment of the ability of tPA and tPAstop-tPA complexes to cross the blood-brain 

barrier and tissue distribution 

• Initial in-vivo studies in models of cerebral ischemia 



• Evaluate pharmacological MRI for receptor binding as a competitive imaging tool for


Year 5 

microPET/SPECT in animal models for neurodegenerative disorders 

• Feed-back to Topic 1.2: Need for new probes 

• Publication: Characterization of a rat model of meningitis: MR-studies in the course of 

meningitis 

• Publication: MR and PET in patients with MS 

• Publication: fdopa and PK11195 binding in parkinsonian syndromes 

• Publication: FDG and eldepryl binding in memory dysfunction 

• Publications: PK11195 in patients with dementia, HD, prion disease 

• Clinical implementation of new probes derived from Topic 1.2 

• Publication: Blood-brain barrier integrity studies in patients with multiple sclerosis 


• Publications: Clinical implementation of new probes derived from Topic 1.2 in patients with 

neurodegenerative disorders 

• Publication: fdopa and PK11195 binding in parkinsonian syndromes: Longitudinal 

assessments 

• Publication: Biochemical inflammatory markers, gene expression, and proteomics in MS 

patients as compared to MR-findings and disease progression 

• Establishment of structure for future DiMI-networking 

Topic 2.2 Cardiovascular 

Timing 


Year 1 

Year 2 

Year 3 

Year 4 


• Exchange existing knowledge among groups 

• Define individual contributions to short and long-term goals 

• Establishment of a vector library for imaging of reporter gene expression in myocardial cells 

and for induction and monitoring of angiogenesis therapy 

• Establishment of myocardial ischemia and angiogenesis as a pathobiologic and therapeutic 

target using animal models mouse using cryoablation and coronary artery ligation 

• Establishment of molecular imaging techniques which provide readouts specific to 

angiogenesis itself or to factors mediating angiogenesis 

• Evaluation of macrophage infiltration and other suitable biologic targets in atherosclerotic 

plaques 

• Establishment of a molecular imaging toolbox for in vivo identification of various precursors 

and early biologic changes of myocardial diseases 

• Molecular Imaging assessment of protease activities of macrophages in atherosclerotic 

plaques 

• Establishment of different administration methods of labelled stem cells near ischemic 

cardiac lesion using image-guided intracardiac injection, local intravascular injection, 

systemic intravascular injection 

• Evaluation of further specific imaging probes for angiogenesis targets, such as binding 

agents for receptors stimulated by growth factors (e.g. VEGF) 

• Establishment of molecular imaging approaches for non-invasive monitoring of novel 

molecular and cellular therapies for cardiovascular disease 

• Use of stem cell transplantation for preservation and restitution of myocardial and vascular 

integrity 

• Evaluation of apoptosis processes, protease activity (such as MMP), autonomic nerve tone 

and post-synaptic signal transduction in the development of left-ventricular remodelling 

during chronic ischemia and after myocardial infarction


Year 5 

• Use of molecular imaging tools for translational research from animal models to clinical 

application 

• Use of molecular imaging tools for risk stratification and assessment of therapeutic efficacy 

in the clinical setting 

• multi-modality molecular imaging algorithm for accurate idenitification of localization and 

instability of atherosclerotic plaques, and for determination of individual risk in clinical 

atherosclerotic disease 

Topic 2.3 Inflammation & Regeneration 

Timing 


Year 1 

Year 2 

Year 3 


• Determine short and long-term goals 

• Imaging NF-κB dependent luciferase activation in transgenic autoimmune model 

• Validation of fluorescent macrophage ligand (PK 11195) in cell cultures 

• Imaging of cathepsin B and H, and apoptosis (Annexin 5) in inflammation models 

• Cross-breed NF-kB luciferase mice into mouse strain with spontaneous development of 

arthritis for imaging of NF-kB activity 

• Construction of plasmids allowing multimodal imaging of NF-kB activity-preliminary 

testing in cell cultures 

• Improved techniques for labelling neural progenitor and stem cells 

• Multi-modality tracking of stem cells based on various marker genes 


• Publication: NF-kB activation in autoimmune disease model 

• Imaging NF-κB activation in model of arthritis-assessment of NF-kB dynamics 

• Employ fluorescent macrophage ligand (PK 11195) in mouse models of inflammation 

• Effect of specific NF-kB inhibitors on optical and clinical markers of disease 

• Development of utility of probes for optical imaging of complement activation and ROS 

detection 

• Targeted probes against (α β integrins)-validation in cell cultures 

• Experimental studies of constructs for multimodal imaging of NF-kB activation in cell 

culture studies 

• Production of transgenic reporter mice allowing multimodal imaging of NF-κB activation 

• Targeted probes against (α β integrins)-validation in cell cultures 

• Develop transgenic reporter mice for in vivo imaging of specific protein kinase activityproof 

of principle 

• Development of DNA constructs allowing imaging of various protein kinases 

• Multi-modal imaging and trafficking of NP/NCS in various models (stroke, PD) 

• Controlled expression of marker and therapeutic genes in transplanted stem cells in animal 

models 

• Validation of image-based functional assessment of novel stem cell therapies 


• Publication: NF-kB activation in autoimmune disease model combined with optical imaging 

probes and effect of NF-kB inhibitors 

• Publication of in vivo imaging of protein kinase activity- validation study (proof of 

principle) 

• Development of Cre-dependent expression of luciferase regulated by NF-kB for tissue 

specific assessment of NF-kB activity 

• Optical imaging probes against ROS and complement activation used in mouse models after 

successful validation in in vitro systems


Year 4 

Year 5 

• Targeted probes against integrins-in mouse models of inflammation 

• Develop novel transgenic reporter models for kinase activity relevant for inflammationvalidation 

in models of inflammation 

• Further identification of factors influencing proliferation, migration and differentiation of 

NP/NCS 

• Establishment of different administration methods of labelled stem cells near ischemic 

cardiac lesion using image-guided intracardiac injection, local intravascular injection, 


• Validation of stem cells as vectors for therapeutic gene delivery, notably with therapeutic 

genes coding for factors involved in angiogenesis 

• Validation of modified stem cells for therapy using marker genes allowing non-invasive 

assessment of differentiation 


• Publication of multimodal imaging of NF-kB in transgenic reporter mice 

• Development of Cre-dependent expression of luciferase regulated by NF-kB for tissue 

specific assessment of NF-kB activity 

• Guidance and control of NP/NCS in vivo 

• Use of stem cell transplantation for preservation and restitution of myocardial and vascular 

integrity 

• Validation of non-invasive, spatial and temporal control of expression of therapeutic genes 

in vivo in the heart 


• Publication of tissue specific Cre-dependent expression of luciferase regulated by NF-kB 

• Publication of novel optical probes against ROS in inflammation models 

• Publication of novel optical probes against complement activation in inflammation models 

• Common data and guidelines for reproducible labelling and imaging techniques of NP/NSC 

for detection by MRI, PET, OI 

• Detailed non-invasive description of the dynamics of proliferation, migration, differentiation 

and synapse formation of NPC and NSC 

• Validation of novel image-guided stem cell therapies in vivo using genetically modified 

stem cells based on stem cells as vectors 

• Validation of novel image-guided stem cell therapies in vivo using genetically modified 

stem cells based on controlled differentiation of stem cells for cardiac tissue replacement 

3. Major Milestones of Activities for Dissemination and Spreading Excellence 

Timing 


Year 1 

Year 2 


• organization of first winter school and annual meeting together with EMIL 

• designing and implementation of the DiMI-Newsletter 

• updating web-based communication system and DiMI-Newsletter 

• organization of school and annual meeting together with EMIL 

Year 3 • as for Year 2 

Year 4 

• Annual Meeting of the ESMI 

Year 5 

• structured molecular imaging related research in Europe with a European Society of 

Molecular Imaging (ESMI), Annual Meeting of the ESMI, training programme including 

summer and winter school (together with EMIL),


4. Major Milestones of Management Activities 

Timing 


Start of Program • Establish Management Office 

Year 1 

• management of budget, reports and deliverables 

• establishment of the BOKIM 

• establishment of the Governance structure (setting up of committees, bodies, council) 

• designing and implementation of the web-based communication system 

• adoption of the JPA and its related budget allocations 

• Preparation and Implementation of JPRA 

• organization of first winter school and annual meeting together with EMIL 

• search for new SMEs, industrial partners, funding opportunities 

Year 2 

• updating consortium agreement if necessary 

• guide activities of the BOKIM 

• management of budget, reports and deliverables 

• search for new SMEs, industrial partners, funding opportunities 

• Adoption of the current JPA and its related budget allocations 

Preparation and Implementation of the next JPA and JPRA 



Year 5 

• long-term research cooperations between DiMI partners, involvement of industry and SMEs, 

formation of new SMEs as spin-offs from DiMI related research


7. Quality of integration and performance indicators 

The overall aims of the integrating activities of DiMI are to effectively tackle fragmentation within the 

European groups working in the field of molecular imaging as well as understanding and cross-fertilization 

between the various research disciplines. This then will lead to bridge the gaps between basic and imaging 

scientists and to synergistic effects in molecular imaging related research. The JPRA under the direction of 

representatives of the technology and training platforms (DiMI-TTP) shall tie these centres of excellence 

together in a collaborative and complementary manner necessary to gain European leadership. Integration is 

a non linear process, with a growth rate accelerating over time and with links getting tighter as common 

experience accumulate. DiMI is envisioned as a major construction in the European Research Area. Its core 

participants constitute an extremely dedicated and highly skilled backbone, which opted for a relatively large 

network opened to all institutions that perform excellent research in the field. More scientific leverage will 

be obtained by a large network with a well coordinated research program as well as true networking activities 

such as dissemination, training and exchanges of personnel. 

The integrating activities outlined in =>6.1 and pre-existing collaborations between several partners will 

serve for a high quality of integration within the DiMI NoE, which will be managed and adapted to specific 

needs by the Board of Integrating Activities (BIA) chaired by P13. 

Pre-existing collaborations 

Pre-existing collaborations within the DiMI on the European level have been shown to have worked very 

successfully in the past: 

• P1 coordinating Nest-DD (5 th FW) involving P20, P33, P36, and P39; 

• P1 and P9 co-organizing the Workshop on “Cellular and Molecular Imaging in Diagnostics and 

Therapy” in Bordeaux (F) (http://www.ismrm.org/workshops/molecular_imaging/index.htm) 2003; 

• P4 and P22 are involved in the management of COST B12 Radiotracers for assessment of biological 

function 

• P4, P22 and P23 have continuous scientific cooperations (INSERM-MFR grants) 

• P7 coordinating NCI-MCI (5 th FW) involving P22, P33 and P34; collaborating within COST (5 th 

FW) with P4 and P22; 

• P29 organizing summer courses of the Society for Cerebral Blood Flow and Metabolism on “PET 

Quantification” since 1999 

• P12 involved in OLIM (5 th FW) together with P5; coordinating EMIL (6 th FW) including P1, P3, P6, 

P8, P13, P25, P38; 

• P14 involved in the development and non-invasive monitoring of new animal models based on local, 

somatic transgenesis for a better diagnosis and therapy of neurodegenerative diseases together with 

P8 and P41; 

• P25 having continuous scientific cooperations with P1, P3, P8, P21, and P32; 

• P32 having continuous scientific cooperations with P25 and P26. 

These preexisting connections and fruitful collaborations indicate, that DiMI will be able, despite its 

relatively large consortium, to efficiently integrate and join forces to gain the European leadership in 

molecular imaging for diagnostic purposes.


Integration by the JPRA 

The JPRA of DiMI is especially designed and suitable to serve for efficient integration and collaboration 

between participating institutions. Direct links exist between each of the three horizontal activities 

(technology, probes, models) to each of the vertical activities. Moreover, the vertical activities are also 

interrelated to each other. For example, atherosclerotic plaque imaging is not only of interest from the 

cardiovascular point of view but also with regards to imaging in cerebrovascular disease and inflammation; 

technologies for labelling and imaging of stem cells are the same for the applications in the field of 

neuroscience and cardiology, and they can be transferred to track inflammatory cells in autoimmune diseases, 

neurological diseases (multiple sclerosis, activated microglia in neurodegenerative diseases) as well as 

atherosclerosis. Therefore, various aims of the JPRA in the vertical activities require similar technological 

and probe developments, thus leading to cross-fertilization between previously unrelated, and now partnering 

and networking groups. 

Measureables for integration by JPRA 

• number of publications 

• number of novel technological achievements 

• number of newly developed probes 

• number of validated animal models 

• number of applications of novel probes and technology in the vertical tasks 

Integration through the network of DiMI-TTPs 

The DiMI-TTPs will function as the major means for high level integration 

• by creating centres with the critical mass to compete at the international level (e.g. MICs); 

• by building platforms with a high capacity to adapt and implement new technological developments and 

integrate SMEs; 

• by guidance of the JPRA; 

• by dissemination of common knowledge and know-how to various actors; 

• by serving as core for a European educational program in molecular imaging for diagnostic purposes. 

Measureables of performance of DiMI-TTPs as integrating centres: 








Integration by exchange of personnel (post-Docs, PhD students) between partnering institutions 

The DiMI-NoE will greatly facilitate the exchange and mobility of PhD students and postdoctoral fellows 

between labs of the consortium and especially into the DiMI-TTPs. This will have immediate consequences 

with regards to cross-fertilization as well as significant long term consequences beyond the end of the EC


financial support to the network. Current observations of scientific networking show that specific links are 

tied by PhDs and postdoctoral fellows during these particularly important years to the laboratories that foster 

their research; and that these links tend to last long after the postdoctoral time into a greater facility to 

communicate, collaborate and exchange with the fostering team. In engineering and biology, it is more than 

common that previous PhD students or postdoctoral fellows, once in a permanent position in their own 

country, will in return accept PhD students or postdoctoral fellows from the lab they did their thesis or 

postdoctoral work in. The integration of young individuals in DiMI through the training program is therefore 

probably the longest term integrative process stimulated by DiMI. 

Measureables of successful exchange and mobility within DiMI: 




European SMEs in the field of molecular imaging are behind those in the USA due to the lack of venture 

capital on tools and a slower start of in vivo imaging technologies in European academic institutions. This 

situation is perceptible in scientific meetings, where US-based companies have already reached a critical 

mass and get full attention. Integration is one of the ways that European SMEs have to fill in the current gap. 

A strong aspect of integration by DiMI of European SMEs will arise from the SME’s integration work 

package (=>WP14), in which all SMEs are represented and will act as one body. This action will be 

specifically guided by P13 and the Board for Integration (BIA). The participating SMEs in DiMI will not be 

a static but a dynamic process regulated by the specific needs and opportunities for integration of SMEs 

within the WPs of the JPRA. It is expected that DiMI will be very beneficial to European SMEs in 

technology, software and biotech in helping them constitute a body of a larger critical mass where 

intelligence, strategic marketing and scientific information can be exchanged. Although more driven by short 

term objectives than academic laboratories, SMEs often rely on long term collaborations with laboratories 

with which, after common confidence and efficiency have been found, they have contractual agreements for 

technology trials and transfers. By helping to regulate the official agreement context for collaboration 

between SMEs and academic labs, DiMI will greatly facilitate these collaborations. 

Measureables for successful integration of SMEs: 

• number of SMEs (instrumentation, software, molecules, animal models) involved in DiMI-TTPrelated 

research per year 



Integration through scientific annual meetings 

Scientific meetings are at the core and the substance of scientific networking. To integrate European 

molecular imaging directed groups with respect to DiMI-specific as well as to other applications, DiMI will 

organize an annual European Meeting targeting various aspects in molecular imaging for diagnostic purposes 

and related scientific fields. This annual meeting will be organized together with the EMIL-NoE. During 

every annual scientific meeting of DiMI, participants will interact through a strong federative scheme to 

materialize the people, the achievements and the success of the network. Because it will drain a limited 

number of people, its size will be compatible with a true networking environment. It is expected that such a


meeting, once established and carried out for 5 consecutive years, will continue beyond the end of the ECfunded 

period because of its value to the European ERA. 

Most importantly, these annual meetings will serve as a basis for a strong interaction with and integration of 

representatives from industry and major stakeholders (such as medical imaging, contrast media, biotech and 

pharma companies), venture capital authorities (private and public bodies), and regulatory authorities 

especially those dealing with radiation protection and drug development. 

Measureables for integration through an annual European meeting for molecular imaging: 

• number of attendees from DiMI labs 

• number of foreign speakers that have expressed interest in attending 

• number of attendees from representatives from industry, venture capital and regulatory authorities 

Integration through electronic communication activities 

It is well known that the most used websites are those who are regularly updated and deliver valuable 

information that cannot be found elsewhere. For this reason, the first objective of the already installed 

website for DiMI (www.diagnostic-molecular-imaging.org) will be to secure rapid renewal of the 

information. In our experience, this is more reliably done when non-scientists are in charge of the web site 

updates. Scientists tend to consider web publication as a secondary priority when it comes to dissemination, 

while management personnel have a stronger commitment towards ensuring useful information. Accordingly 

the day-to-day management of the web site will be secured by the Management Office (MO) of DiMI, with an 

initial objective of the web site to inform inside and outside the DiMI consortium on. Information which will 

be delivered through the website will cover 

• research activities of the DiMI network; 

• research outcomes in terms of publications, common protocols, regulatory issues, new patents; 

• career opportunities; 

• courses for training and education. 

This will have an integrating action on the DiMI members who will visit their website to gather information 

on the network events and activities. Members access will be enforced progressively, with different levels of 

security. Once the DiMI website is operating in good conditions, it will be upgraded with the final objective 

to create the DiMI database. This database will function as a reference server for molecular imaging for 

diagnostic purposes. Moreover, the web is a unique means to disseminate kinetic image information and 

animated data which cannot be presented in usual means on paper (=>WP4.2). 

Measureables for successful integration through web site: 

• number of visitors to DiMI’s website 

• rate of renewal of information


8. Organisation, management & governance structures 

The management activities of DiMI are designed to adequately tackle 

• the size of the consortium 

• the complexity of the JPA and JPRA and 

• the necessary degree of integration needed to achieve durable integration and an overall success of 

DiMI. 

The management of DiMI is based on the structure of the organization of the overall (JPA) and scientific 

(JPRA) activities of DiMI consisting of 

• three horizontal activities of the JPRA 

o integrated imaging technologies 

o diagnostic probes 

o animal models 

• three vertical activities of the JPRA based on the horizontal activities, which are partly interrelated to 

each other 

o neuroscience 

o cardiovascular 

o inflammation and regeneration 

• and the vertical and horizontal activities spanning all activities for 

o integration 

o training 

o dissemination and communication 

o knowledge management and 

o ethical issues. 

The central organizational structure of DiMI with the respective responsible representatives of the DiMI 

consortium has been depicted in =>2. This central organizational structure implies the overall management 

activities and composition, members, chairs and representatives of the various boards. 

4. 

TRAINING 

& 

DISSEMI- 

NATION 

Bertrand 

Tavitian 

3. 

INTE- 

GRATION 

OF 

SMEs 

Marie 

Meynadier 

2.1 

NEUROSCIENCE 

Phenotyping of animal 

models and patients for 

early diagnosis and imaging 


Gitte Knudsen 

Annemie van der Linden 

Karl Herholz 

2.2 


Early detection of 

atherosclerosis / cardiac 

dysfunction and imaging 


Frank Bengel 

Chrit Moonen 

2.3 

INFLAMMATION / 

REGENERATION 

In vivo detection of 

transcriptional regulation and 

migration of inflammatory 

and stem cells 

Harald Carlson 

Andreas Jacobs 

1.3 

Animal Models 

“Animal Imaging Library” for validation of molecular markers in vitro and in vivo 

Anna Planas, Adriana Maggi, Harald Carlson 

1.2 



Denis Guilloteau, Silvio Aime 

1.1 


Integrating multimodal imaging technology (MRI, PET, SPECT, OI) 

John Clark, Marie Meynadier


Management of a large Network of Excellence requires an efficient organisational structure that embodies 

broad representation from the participants together with transparency and accountability of decision-making 

structures. In addition, it is important that such a project is committed to communication. Within the 

network, this is required to maximize effectiveness, integration of resources, skills and technology platforms, 

and to maintain the focus of project personnel on the achievement of agreed milestones and deliverables. 

Moreover, to maximize the value to stakeholders outside the project, promoting dissemination and uptake of 

the results of the project is essential. This will be ensured by establishment of an efficient web-based 

communication system within DiMI. 

The network management organisational structure is based on two major decision-making bodies which are 

the Governing Board and the Scientific Management Board. To ensure an efficient and complementary 

strategic decision-making mechanism, the GB will decide mainly upon proposals of the SMB. The 

Management Office is designed to assist the Project Coordinator and the SMB in the day-to-day 

administration and implementation of the network goals within the different consortium bodies. This 

organisation shall strengthen a high degree involvement of the participants in the common policy of the 

consortium. The network management is described in more detail as follows: 

Governing Board (GB) 

Members: 

Tasks: 

Decision making: 

The Governing Board (GB) is composed of a high representative of the participating 

organisations and is chaired by the Project Coordinator. 

The GB decides on the overall aims and goals of DiMI. Specifically, the GB has to 

approve the proposals made by the Scientific Management Board with regards to the 

JPA, JPRA and the plans for budget allocation. 

The GB will have at least one meeting per year which may coincide with the annual 

scientific European Meeting for Molecular Imaging. These meetings shall contain 

the progress reports from selected WPs and the planning for future directions and 

implementation. The decisions are based on a simple majority. Exceptions, where a 

higher majority is required will be specified in the consortium agreement. 

Scientific Management Board (SMB) 

Members: 

Tasks: 

The Scientific Management Board is the main working committee of the network and 

the forum for strategy review and decision-making. It is composed of the members 

of the Steering Committee and the chair persons of the individual flanking advisory 

boards (see below) and is chaired by the Project Coordinator. The individual 

members are listed in =>6.4. Subproject leaders may serve in the Steering Committee 

for the duration of the project, but there will be opportunities to engage other 

members nominated by the GB. The SMB is under control of the Governing Board 

and the contractual obligations. 

The tasks are based on a proposal towards the GB and include 

• coordination of JPA and JPRA including sub-project leaders; 

• preparation of annual implementation plans; 

• on-time preparation of reports and deliverables to the Project Coordinator; 

• design of specific control measures to ensure effect progress in JPA and JPRA; 

• approve the allocation of the budget with respect to specific needs and the 

contract after the proposal of the project coordinator;



• design rules in case of deadline, obligation and contract violations; 

• deciding on membership of the consortium 

• review of proposals submitted for future calls 

• review and taking specific advices from the SAC into consideration for future 

work 

The SMB will get together on a regular basis (3-months intervals), which may be 

performed as telephone conference and more often, if the Project Coordinator 

indicates the necessity. The decisions are based on a presence of two thirds of the 

members and a 75% majority of votes with one vote per member. 

Ethical Management Board (EMB) 

Members: 

Tasks: 


As indicated by the ERR, an Ethical Management Board has been established and is 

the main working committee of the network to follow the national, European and 

international ethical rules and guidelines of the related joint project activities, 

especially in the design of animal experimentation and clinical studies. The EMB is 

composed of 9 members of the Steering Committee who are in the lead of a TTP and 

WP where animal experiments and clinical studies are being performed. The EMB is 

being chaired by Professor Robert Poelmann (P37) from the University of Leiden. 

For over 15 years Robert Poelmann has been a member of the Animal Ethics 

Committee of the Leiden University and of the University Hospital. Since 1996 he 

served as President of these Committees advising on the use of over 40.000 

experimental animals each year and being extensively involved in ethical conferences 

at the national level. Robert Poelmann will be coordinating the EMB with the goal to 

bridge the internationally complex differences in animal use. The further members of 

the EMB are listed in =>6.4. Subproject leaders may serve in the EMB for the 

duration of the project, and there will be opportunities to engage other members 

nominated by the GB. The EMB is under control of the Governing Board and the 

contractual obligations. 

The tasks of the EMB are based on a proposal towards the GB and include 

• coordination and control of ethical and gender related issues of JPA and JPRA; 

• preparation of a “Table of Rules and Laws” applying to the JPRA for all 

participating countries; 

• preparation of an annual implementation plan; 

• design of specific control measures to ensure that ethical and safety aspects are 

being respected in the JPA and JPRA; 

• design rules in case of deadline, obligation and contract violations; 

• seaking advice from the Ethical Advisory Committee (EAC). 

The EMB will get together on a regular basis during SMB meetings and more often, 

if the Project Coordinator indicates the necessity. The decisions are based on a 

presence of two thirds of the members and a 75% majority of votes with one vote per 

member.


Subproject Leaders 

The Subproject Leaders of individual WPs are the most important links between individual project partners 

represented in the GB on the one side and the SMB and Project Coordinator on the other side. The tasks of 

subproject leaders include: 

• the day-to-day management of the WP 

• ensuring the scientific monitoring and coordination of the individual subprojects and its 

implementation 

• propose budget allocation within limits and needs 

• reporting progress to the subproject coordinator of the SBM 

• being responsible for overseeing the reports and deliverables of the JPA and JPRA 

• organization of research meetings within each subproject among the relevant partners with regards to 

the specific projects tasks and research objectives as required. 

Project Coordinator 

Andreas Jacobs from the University of Cologne will represent the partners in the EU contract and is 

responsible for the overall management and success of the consortium. His specific tasks and duties include: 

• overall scientific coordination 

• day-to-day operations in the Project Management Office (MO) 

• signing the contract with the EU 

• proposing budget allocation to the SMB 

• ensuring the confinement to contract obligations 

• chairing the GB and the SMB 

Management Office (MO) 

Members: 

Tasks: 

The Management Office is the main central resource and “nerve centre” for activities and 

will involve the Project Coordinator and 3-4 staff members fully dedicated to network 

management (scientific administrators: Dr. Alexandra Winkeler and Dr. Lutz Kracht, 

administrator for knowledge management (AKM), scientific secretary). The MO will 

manage the administrative, legal, financial and other non-technical aspects of the project, 

assisting the major decision-making bodies and the Project Coordinator. The MO will be 

supervised by the Project Coordinator and the administration management (Jutta Landvogt) 

from the institution of P1. 

• scientific coordination together with Project Coordinator 

• designing, implementation and updating of the consortium agreement 

• management of budget 

• management of reports and deliverables towards the Commission 

• implementation and updating the web-based DiMI communication system ensuring and 

efficient communication within and outside the network 

• facilitating the exchange of documents, worksheets, etc. 

• handling queries and correspondences 

• arrangements for project meetings and conferences


• coordination of preparation of cost calculations of individual partners 

• calls for proposal for new partners 

• handling responsibilities with regards to intellectual property queries, exploitation and 

dissemination 

• search for new SMEs and potential industrial partners 

• direct interaction with representatives of the GB 

With regards to a dedicated individual in charge of the control of deliverables and milestones, we propose 

the following line of reporting/control: 

Each DiMI partner leading a workpackage will receive funds to hire 0.5 to 1 post-doc. The individual postdocs 

will be responsible for that deliverables and milestones are reached within their respective WP. They 

will report deliverables and milestones on a timely basis to their respective group leader of each partnering 

institution. The group leader of each partnering institution is responsible for timely reporting to the 

management office. Dr. Alexandra Winkeler and Dr. Lutz Kracht in the management office in Cologne will 

collect and control the reports of deliverables and milestones as part of their function as scientific 

administrators of DiMI. For the first 18 months, Dr. Alexandra Winkeler will control the deliverables and 

milestones of WP1-7 and Dr. Lutz Kracht will control the deliverables and milestones of WP8-16. This 

reporting can be graphically summarized as follows: 

Control of deliverables and milestones: 

DiMI-Post-Doc Group Leader of Partnering Institution Management Office 

(Winkeler&Kracht) 

DiMI Flanking Boards 

Several flanking and advisory boards will serve for integration, facilitate decision making, especially with the 

ethical related issues, and guide the overall direction of the DiMI network. The flanking boards include: 

• Board for integrating activities (BIA). The BIA consists of the representatives of 4 partnering 

institutions and is chaired by P13. The individual members of the BIA are listed in =>6.4. The tasks 

of the BIA include the control of successful establishment of DiMI-TTPs, establishment of a program 

for exchange of personnel and flexible integration of SMEs and industrial partners according to the 

specific needs. The BIA will meet during GB and SMB meetings. 

• Board for training activities (BOT). The BOT consists of the representatives of 4 partnering 

institutions and is chaired by P12. The individual members of the BOT are listed in =>6.4. The 

tasks of the BOT include the control of efficient training activities at the DiMI-TTPs and 

establishment of summer schools, training courses as well as a European MD PhD program for 

molecular imaging. The BOT will meet during GB and SMB meetings. 

• Board to Dissemination & Communication (BODIC). The BODIC consists of the representatives of 

4 partnering institutions and is chaired by P12. The individual members of the BODIC are listed in 

=>6.4. The tasks of the BODIC include the design of a yearly dissemination and users plan, control 

of web-site construction (www.diagnostic-molecular-imaging.org) and the organization of scientific 

meetings. Moreover, the BODIC will control and review the ethical and gender related issues. The 

BODIC will meet during GB and SMB meetings. The fact that partner 12 is Project Coordinator of


EMIL will facilitate the coordination of (i) common, (ii) partial overlapping and (iii) independent 

activities of DiMI and EMIL (=>6.3), as requested in the ESR. 

• Board for Knowledge and IPR Management (BOKIM). The BOKIM consists of the representatives of 

4 partnering institutions and is chaired by the Administrator for Knowledge Management (AKM) 

who belongs to the Management Office. The individual members of the BOKIM are listed in =>6.4. 

The tasks of the BOKIM include 

o the management of intellectual property queries and exploitation; 

o the design of an annual plan for the management of knowledge, intellectual property and any 

other activities promoting innovation in the project; 

o to integrate between the Project Coordinator and the partners (GB) through its guidance of 

decisions for the protection, dissemination and use of knowledge. 

The BOKIM shall issue opinions and take its decisions on a qualified majority basis. The BOKIM 

will be the instrument of a durable integration of the research capacities of the network participants, 

advancing knowledge on the scientific and technological network topic. A coherent joint 

management of the network knowledge arising from the jointly executed research will ensure an 

appropriate use and dissemination of the network results in compliance with the general arrangements 

stipulated in the contract with the European Commission. 

• Scientific Advisory Committee (SAC). The SAC will be constituted from recognized international 

researchers from the field of molecular imaging. The tasks of the SAC include consultation and 

evaluation with respect 

o to give general and specific input into the overall road map of the JPA and JPRA 

o to perform site visits at DiMI-TTPs as requested from the Project Coordinator 

o to provide advice and feedback to the Coordinator upon request 

The SAC will not deal with the management of budget. 

Each member of the SAC will enter into a non disclosure agreement prior to beginning of his 

activities. The SAC will get together once a year for a one day briefing or telephone conference on 

the progress of the consortium by the Project Coordinator and the Management Office team together 

with nominated partners from the SMB. 

Individuals who have accepted to participate in the Scientific Advisory Committee of DiMI are: 

o Professor Ronald G. Blasberg, MD, Editor-in-Chief of Molecular Imaging; Professor of 

Neurology, Memorial Sloan Kettering Cancer Center, New-York, USA 

o Professor Ralph Weissleder, MD, Associate Editor of Molecular Imaging; 1 st President of 

the Society for Molecular Imaging, Professor of Radiology, Harvard Medical School, 

Director of the Centre for Molecular Imaging Research at Massachusetts General Hospital, 

Boston, USA 

o Professor Thomas J. Meade, PhD, President-Elect of the Society for Molecular Imaging 

(SMI), Professor of Chemistry, Biochemistry, Molecular Biology, Cell Biology, 

Neurobiology and Physiology at the Ohio State University, Northwestern, Evanston, Illinois, 

USA 

o Professor Sanjiv Sam Gambhir MD PhD, Section-Editor of the European Journal of 

Nuclear Medicine and Molecular Imaging, Director of the Stanford School of Medicine 

Program in Molecular Imaging, Professor of Radiology, Head of the Division of Nuclear 

Medicine, Stanford, USA 

o Professor Chester A Mathis, PhD, Professor of Radiology and Pharmaceutical Sciences, 

Senior Chemist and Co-Director, PET Facility, University of Pittsburgh, USA 

o Professor Hein Wellens, MD, Professor of Cardiology, Cardiovascular Research Institute, 

Maastricht, NL


o Professor Johan Lugtenburg, PhD, Professor of Bio-organic Photochemistry at the Leiden 

Institute for Chemical Research, Netherlands 

o Professor Dr. Dr. h.c. Konrad Beyreuther, PhD, Professor for Molecular Biology and 

Biochemistry, received the Henry M. Wisniewski Award for Lifetime Achievement in 

Alzheimer's Disease Research 2002, Centre for Molecular Biology (ZMBH), Heidelberg, 

Germany 

• Ethical Advisory Committee (EAC). The EAC will be constituted from recognized international 

researchers and institutions well known to give their input into ethical aspects for science in 

medicine. The tasks of the EAC include consultation and evaluation with respect 

o to give specific input into the ethical issues arising in the JPA and JPRA of DiMI; 

o to perform site visits at partners institutions requested by the Project Coordinator 

o to provide advice and feedback to the Coordinator and the EMB. 

Each member of the EAC will enter into a non disclosure agreement prior to beginning of his 

activities. The EAC will get together at least once a year for a one day briefing or a telephone 

conference on the ethical issues coming up in due course of the consortium together with the Project 

Coordinator, the Management Office team together with the EMB. 

Individuals who have accepted to participate in the Ethical Advisory Committee of DiMI are: 

o Professor Dr. phil. Dr. h.c. Ludger Honnefelder, Director of the Institute for Research and 

Ethics (IWE; http://www.iew.uni-bonn.de/fe_iew.htm), University of Bonn, Germany 

o Dr. Michael Fuchs from the IWE; 

o Professor Dr. Didier Sicard, President of the Comite National Consultatif d’Ethique (French 

National Consultative Ethics Committee for Health and Life Sciences) 

The IWE aims to contribute to an ethical reflection of current developments in medicine, science and 

technology in order to facilitate a responsible use of the new potentials emerging in these fields of 

human activity. This goal is motivated by an ever more rapid development of modern science that 

penetrates all spheres of human life and leads to a blurring of the borderline between research and its 

applications. The complexities of the results and consequences of modern scientific understanding 

and activity require the formation of ethical judgments, both within the scientific community and 

within society at large. The Institute has set itself the task to accompany and support the formation of 

such judgments by means of interdisciplinary research. The main focus of the Institute’s work is in 

the field of biomedical ethics and the ethics of science and technology and, therefore, perfectly fits 

into the EAC of DiMI. 

Special Management Issues 

It should be stated that all DiMI partners agreed to sign the future contract agreement with the Commission 

as well as a further DiMI-specific consortium agreement covering special aspects regarding the structure and 

management of DiMI, responsibilities of partners, management of IPR, and confidentiality. 

With regards to the inclusion of new partners and SMEs in DiMI in the future, it is expected that after 18 

months new SMEs will join the consortium in order to ensure appropriate dissemination of research results. 

The Board of Integrating Activities (BIA) will propose the addition of a new group first to the SMB and, after 

approval, to the GB. In case that the legal interests of partnering institutions are not affected, the MO will get 

in contact with the Commission to arrange the necessary steps for legal inclusion into DiMI.


Summary of overall management structure of DiMI 

Board for Training Activities (BOT) 

Board for Dissemination & Communication (BODIC) 

DiMI 

Members 

Board for Integrating Activities (BIA) 

GB 

Neuroscience 

(P1,7,8) 

Cardiovascular 

(P9,10) 

SMB 

Technology 

(P2,13) 

Probes 

(P3,4) 

MO 

Coordination 

Animal Models 

(P1) 

(P5,6,11) 

SMEs 

Inflammation & Regeneration 

(P1,11) 

Integration 

(P13) 

Training & 

Subcontractors 

EMB 

Dissemination 

P1,5-12,37 

(P12) 

Board for Knowledge and IPR Managment (BOKIM) 

Ethical Advisory Committee (EAC) 

Scientific Advisory Committee (SAC)


9. Detailed joint programme of activities (JPA) – first 18 mo 

9.1 Introduction – general description and milestones 

The JPA undertaken by the DiMI-NoE will start immediately at the starting time of the programme. In this 

section the activities proposed for the first 18 months are summarized. It should be pointed out that due to 

the reduction of the overall budget some WPs were joint together, and the numbering of the individual WPs 

has been simplified as follows: 

• WP1.1.4+WP1.1.3 join into => WP2; 

• WP1.3.1+1.3.2 join into => WP5; 

• WP2.2.2+WP2.2.4 join into => WP11.2; 

• WP1.3.3+2.3.1+2.3.2+2.3.3 => WP13 

To achieve the overall aims of durable restructuring and integration only the three following WPs have been 

postponed to be probably included at a later stage: 

• WP1.1.2 

• WP1.2.2 

• WP2.2.3. 

In summary, each member of the SMB will be working for the JPA (TTP-related actions) and the JPRA 

(WP-related actions) with the aid of one post-doctoral fellow. Please find the simplified renumbering of 

WPs as follows: 

WP number (old) WP number (new) Responsible partner 

WP1.1.1 WP 1 P13 

WP1.1.4 + WP1.1.3 WP 2 P2 

WP1.2.1 WP 3 P4 

WP1.2.3 WP 4.1 P3 

WP1.2.4 WP 4.2 P35 

WP1.3.1 + WP1.3.2 WP 5 P5 

WP2.3.4 WP 6 P6 

WP2.1.1 WP 7 P8 

WP2.1.2 WP 8.1 P31 

WP2.1.3 WP 8.2 P1 (Herholz) 

WP2.1.4 WP 9 P7 

WP2.1.5 WP 10 P1 (Jacobs) together with 

P15+P25 

WP2.2.1 WP 11.1 P40a 

WP2.2.2+WP2.2.4 WP 11.2 P10 

WP2.2.5 WP 12 P9 

WP1.3.3+WP2.3.1+WP2.3.2+WP2.3.3 WP 13 

P11 

WP3.1 WP 14 P13 

WP4.1 WP 15.1 P12 

WP4.2 WP 15.2 P12 

WP 16 

P1


The section follows the JPA plan of Section 6 as follows: 

Joint Integration Activities (9.A) 

The goals are the establishment of DiMI technology and training platforms (DiMI-TTP) for sharing imaging 

facilities, equipment, experience and know-how, foster exchange and mobility of personnel, and integrating 

activities for SMEs. See also 

=>WP14 

Joint Research Activities (9.B) 

Six main scientific goals of DiMI comprise three horizontal technical aspects serving the basis of three 

vertical experimental and clinical imaging applications. Each of the six main activities contain several work 

packages (WP) serving relation and integration. 

1. Integration of horizontal activities 

• Topic 1.1: Integration of common Diagnostic Molecular Imaging Technologies for multimodal 

radiotracer, magnetic resonance and optical imaging methods. 

=>WP1, WP2 

• Topic 1.2: Integration of common Diagnostic Molecular Imaging Probes and implementation of a 

novel library of new diagnostic and smart imaging probes. 

=>WP3, WP4.1-2 

• Topic 1.3: Integration of common Animal Models with establishment of a unique library of animal 

models of human neurological, cardiovascular and autoimmune diseases to directly study alteration 

of gene expression, transcriptional regulation and molecular events in vivo over a period of time in 

the same animal. 

=>WP5, WP6 

2. Integration of vertical activities 

• Topic 2.1: Neuroscience =>WP7-10 

• Topic 2.2: Cardiovascular =>WP11-12 

• Topic 2.3: Inflammation & Regeneration =>WP13 

Integration of common technologies leading to cross-fertilization and networking between the vertical 

activities are in terms of 

o non-invasive characterization (“phenotyping”) of animal models and patients for early 

diagnosis of neurodegenerative, cardiovascular and autoimmune diseases; 

o imaging of key regulators of atherosclerotic plaque formation, cardiac dysfunction and 

inflammation; 

o imaging disease progression and assessment of the effects of molecular targeted therapies 

including identification of common biomarkers; 

o identification of common aspects of imaging gene and stem cell-based therapies in models 

for stroke, myocardial infarction and neurodegeneration (common cell labelling techniques, 

common transfection techniques, common cell and molecular biology techniques) 

Joint Activities to spread Excellence (9.C) 

The goal is to establish a concise programme for education and training, for efficient dissemination and 

communication tools and systems and for exploiation activities. See 

=>WP15.1+2


9.A Joint Integrating Activities 

Within the integrating activities three specific actions have been designed: 

• establishment of the joint Technology and Training Platforms (DiMI-TTPs) 

• programme for exchange of personnel between DiMI labs 

• programme for integration of SMEs 

Establishment of the joint Technology and Training Platforms (DiMI-TTPs) 

The key features of the DiMI-Technology and Training platforms are listed in the following table and are 

described in detail on the following pages. 

DIMI- 

TTP N O 

PARTNER LOCATION SPECIALTY 

N O 

1 1 (+25) Cologne (D) multimodality imaging in neuroscience including stem cells 

(microPET, HRRT-PET, 1.5+7T MRI, optical imaging) 

2 2 Cambridge (GB) quantification in microPET, hardware development of 

combined MRI/PET and MRI/OI, imaging inflammation 

3 3 Torino (I) MR-related probe chemistry (together with TTP4) 

4 4 (+22+41) Tours (F) 

Karolinska (S) 

Leuven (B) 

PET- and SPECT-related probe chemistry 

MR-related probe chemistry (together with TTP3) 

5 5 (+18) Barcelona (E) animal models in neuroscience, cardiovascular and 

inflammation, microPET, clinical PET 

6 6 (+36) Milano (I) cell and animal engineering, optical imaging, PET 

7 7 Kopenhagen (DK) PET in neuroscience, quantification 

8 8 Antwerpen (B) microMRI and microCT in neuroscience 

9 9 Bordeaux (F) MRI, activatable gene expression, cardiovascular imaging 

10 10 Munich (D) radionulcide imaging in cardiovascular sciences (microPET, 

HRRT-PET, SPECT) 

11 11 Oslo (N) optical imaging in inflammation 

12 12 (+23) Orsay (F) radionuclide imaging in neuro- and cardiovascular sciences 

including stem cells 

The programmes of how to facilitate exchange and mobility of personnel between labs and DiMI-TTPs and 

the objectives and deliverables concerning the integration of SME activities are outlined in =>WP14. 

A detailed description of the characteristic features of the individual DiMI-TTPs is as follows:


DiMI-TTP1 

Cologne Training Platform for Multimodal Imaging in Neuroscience (P1+25) 

The Cologne Training Platform will cover the imaging facilities hosted by Partner’s 1 (microPET, HRRT- 

PET, optical imaging, fluorescence microscopy) and Partner’s 25 (4.7 + 7.0 T MRI, laser scanning 

microscopy, autoradiography) institutions. They are directed towards 

• phenotyping neurodegenerative diseases by PET (AD, PD; experimental, clinical) 

• molecular imaging in stroke models by PET (experimental, clinical) 

• imaging neuronal networks by PET and MRI (experimental, clinical) 

• imaging gene and stem cell strategies by MRI, PET and OI (experimental, clinical) 

Objectives: 

The Cologne Training Platform could offer training for scientists and students in various specialities: 

• imaging I: microPET and HRRT-PET imaging for phenotyping neurodegenerative diseases and gene 

and stem cell strategies 

• imaging II: high-resolution MRI in stroke models and stem cell strategies 

• molecular biology/biochemistry: development of new marker gene / marker substrate combinations 

for imaging transcriptional regulation 

• radiochemistry: development of new diagnostic PET tracers 

• physics and informatics: image co-registration 

Description of the work: 

a)available training infrastructure 

• radiochemistry laboratory for the development of improved PET marker substrates; 

• radiactive S2-animal laboratory for application of vectors, stem cells and PET marker substrates in 

vivo; 

• radioactive S2-PET laboratory for imaging animals and man harboring one dedicated high-resolution 

LSO-PET-scanner (Siemens ECAT HRRT), a microPET (Concord), and an optical imaging camera 

(Kodak); 

• S1-MRI laboratory haboring a 4.7 and 7.0 T-MRI. 

2) specific training packages 

These are one-day teaching packages which can be extended to a full week for in depth training: 

• Vector and stem cell applications in animal models in vivo including animal handling, anaesthesia, 

stereotactic application and convection-enhanced delivery (1 week) 

• Imaging gene expression by microPET, OI and MRI (1 week) 

• Imaging stem cell trafficking by MRI and PET 

• Radiochemical synthesis of F-18, C-11, and I-123/I-124 probes (1 week) 

• Efficient software development for image coregistration (1 week) 

• PET imaging of patients with neurological diseases including stroke, AD and PD (1 week) 

Moreover, training may include 

• direct involvement in ongoing research projects with daily discussions on progress and problems, 

hard- and software handling of microPET, optical imaging camera, 7TMRI 

• participation in weekly research meetings and selected lectures from the Centre for Molecular 

Medicine Cologne (CMMC; http://www.zmmk.uni-koeln.de/) and its MD/PhD programme 

Deliverables 

The training will be performed in groups of max 6 trainees. Entire training takes 3 full man months and 

3 months of instrument time per year. This involves both postdoc and engineer time.


DiMI-TTP2 

Cambridge Training Platform for Multimodal Imaging in 

Neurology, Neurosurgery, Inflammation and Cardiovascular Medicine (P2) 

The Cambridge Training Platform will cover the imaging facilities including microPET, MRI, 

MRI/microPET, phosphorimaging, and autoradiography. Applications include AD, PD, HD, stroke, Acute 

Brain Injury(ABI), cardiovascular and inflammation, both experimental and clinical. 

Objectives: 

The Cambridge Training Platform could offer training for scientists and students in various specialities: 

• imaging by microPET and GE Advance PET for stroke, ABI, neurodegenerative diseases and carotid 

atheroma; 3T-MRI in stroke and ABI 

• Cyclotron/Radiochemistry: development of new targets, PET tracers and automation. 

• In vitro evaluation of novel PET radiopharmaceuticals 

• Radiopharmaceutical plasma metabolite analysis 

• Imaging Physics and informatics: data corrections, image co-registration MR/PET/CT, quantitation 


1)available training infrastructure 

• Cyclotron and radiochemistry laboratory for the development of novel PET radiopharmaceuticals. 

• radioactive animal laboratory for application of PET radiopharmaceuticals in vivo; 

• radioactive PET laboratory for microPET imaging in animals (mouse, rat, rabbit); 

• MRI laboratory and 3T-MRI for human studies including spectroscopy. 


These are one-day familiarisation teaching packages which can be extended to a full week for in depth 

training: 

• animal handling, anaesthesia, stereotactic application (1 week) 

• Radiopharmaceutical synthesis of 18 F, 11 C-based tracers including quality control (1 week) 

• use of software for image co-registration (1 week) 

• PET imaging of patients with neurological and cardiovascular diseases (1 week) 

Training may also include 


hard- and software handling of microPET. 

• participation in weekly research meetings and selected lectures from the Wolfson Brain Imaging 

Centre and it's affiliates with the University of Cambridge. 

• Postgraduate research opportunities within MSc/MD/PhD programme 

Deliverables 

The training could be performed in groups of max 6 trainees. Entire training takes 3 full man months and 

3 months of instrument time per year. This involves both post-doc and engineer time.


DiMI-TTP3 

Torino Training Platform for Development of Imaging Probes and Test in Animal Models (P3) 

The proposed training program will be carried out at the Uni-To Platform; each training program will 

involve small groups of participants (max 5). The training will be tailored on the background and on the 

specific requirements each scientist/student will expect from the participation to the proposed activity. 

Objectives: 

The Torino Training Platform could offer training for scientists and students in various specialities: 

• preparation of Imaging Probes; 

• “in-vitro” assessment of physico-chemical properties of MRI Probes; 

• set-up of protocols using cell-cultures; 

• construction of animal models. 


Available training infrastructure and specific training packages 

• Training in the field of the synthesis of Imaging Probes will be carried out in the laboratories of 

both the Department of Chemistry IFM at the University of Torino and the LIMA (Laboratorio 

Integrato di Metodologie Avanzate) at the Bioindustry Park (BIPCa). The latter site is a joined 

initiative between the University of Torino and BIPCa aimed at improving the links between 

academy and industry research. Both sites are equipped with advanced analytical facilities (mass 

spectrometry, UV, FT-IR, NMR, HPLC, Electrophoresis etc). Thematic areas already identified deal 

with the field of solid-phase synthesis (speciality peptides) and on the synthesis of Imaging Probes 

based on metal complexes. 

• Training in the field of “in vitro” assessment of the physico-chemical properties of Magnetic 

Resonance Imaging Probes will be carried out. Training at both basic and advanced levels will be 

foreseen. The interested scientist/student will be introduced to relaxometry from both an 

experimental and theoretical point of view. The training will include: i) 1 H-relaxometry at fixed 

frequency and variable magnetic field strenght (Field Cycling Relaxometry) and ii) 17 O-relaxometric 

investigations for the measurement of water exchange rates (a parameter of paramount importance in 

MRI applications). Two field cycling and one fixed frequency relaxometers are available. 

• Training in the use of cell cultures for the assessment of Imaging Probes. Well equipped 

laboratories for cell cultures are available both at the University of Torino and at LIMA. Training at 

both basic and advanced levels will be foreseen. The main aims are to train young researchers to the 

use of cellular models as alternative to animal models in the first steps of the evaluation of novel 

Imaging Probes. 

• Training in the construction of animal models. This activity will be coordinated by Uni-To 

biologists (Silengo, Altruda) with the contribution of other dedicated groups in EMIL. Training in 

both basic and advanced levels will be foreseen. Advanced level includes the construction of 

transgenic and ko mice for dedicated Imaging Probes. 

Deliverables 

The training will be performed in groups of max 5 scientists/students. If more scientists/students are 

attending we will have to split the groups and duplicate the training. The entire training might take 3/6 full 

man months and 3/6 months of laboratory time per year. This will involve both postdoc and technical 

staff time.


DiMI-TTP4 

Tours/Stockholm/Leuven Training Platform for Radiotracer Development 

(design, synthesis, characterization)(P4,22,41) 

The Tours/Stockholm/Leuven Training Platform will combine and offer the synthesis, radiosynthesis, 

pharmacological characterization and imaging facilities hosted by Partner’s 4, 22 and 41 (cyclotron, 

laboratory dedicated to organic synthesis, laboratory dedicated to radiolabelling, animal models, instruments 

for in vitro binding studies, autoradiography equipment, SPECT camera dedicated to small animals, micro- 

PET camera, beta microprobes CERASPECT, Human PET and SPECT cameras) 

Objectives: 

The Tours/Stockholm/Leuven Training Platform will offer training for scientists and students in various 

specialities: 

Radiochemists: 

• Design of probes for a given target (QSAR) 

• Organic synthesis of non-radioactive precursors (including purification and chemical 

characterization, NMR, MS, LC-MS) 

• Radiolabelling with 3 H, 125 I, 123 I, 99m Tc, 18 F and 11 C and purification by radio-HPLC, analysis using 

radio LC-MS 

Biologists, radiopharmacists: 

• In vitro characterization (binding,autoradiography) 

• Autoradiography on post mortem human tissue 

• In vivo characterization in animals 

• molecular imaging in neurodegenerative models by SPECT and PET (experimental, clinical) 

• radiopharmaceutical preparation 


a) available training infrastructure 

• chemistry laboratory for the development of precursors for SPECT and PET tracers; 

• radiochemistry laboratory for the development of SPECT and PET tracers; 

• laboratory dedicated to in vivo and in vitro pharmacological characterization, 



• Design of probes using QSAR (1 week) 

• Organic synthesis and characterization of non-radioactive ligands(1 week) 

• Guidelines for radiopharmaceutical preparation (1 week) 

• Radiochemical synthesis and analysis of 18 F, 11 C, and 123 I and 99m Tc probes (1 week) 

• Tracer studies in neurodegenerative animal models including animal handling, anaesthesia, 

stereotactic administration and convection-enhanced delivery (1 week) 

• Imaging neurotransmission by SPECT and PET dedicated to small animals, and PET in the baboon 

(1 week) 

Deliverables 

The training will be performed in groups of max. 6 trainees. Entire training takes 3 full man months and 



DiMI-TTP5 

Barcelona Training Platform for Animal Models of Diseases (P5+18) 

The Barcelona Training Platform will provide a library of animal models of diseases (specially focussing on 

neurological diseases) for phenotyping diseases by imaging techniques. We aim at: 

• providing the molecular basis underlying disease generation, progression, and therapies (including 

stem cell strategies) 

• providing adequate experimental animal models that reproduce many or certain disturbancies 

associated with the diseases 

• phenotyping brain injury and neurodegenerative disorders by micro-PET and micro-SPECT (AD, 

PD, stroke, epilepsy, disorders involving neurotransmitter alterations) 

• identifying new molecular targets relevant to disease diagnostics 

• validating the use of new imaging tracers 

• together with P18: imaging the cardiovascular system (clinical) 

Objectives: 

The Barcelona Training Platform could offer training for scientists and students in various specialities: 

• cellular and molecular biology/biochemistry for undertanding the molecular mechanisms underlying 

brain diseases 

• development of strategies to interfer with disease progression 

• imaging: micro-PET and micro-SPECT imaging for phenotyping brain injury and neurodegeneration 

and gene and stem cell strategies 

• validation in animal models of the use of new diagnostic PET tracers 

• together with P18: imaging the cardiovascular system (clinical) 



• biology laboratories for developing research in experimental animals and in cell cultures 

• access to radiochemistry laboratories, micro- and clinical PET camera, microSPECT applications 

b) specific training packages 

These are one-week teaching packages: 

• Development of specific animal models for neurological diseases (1 week) 

• Development of neural cell models in vitro for tracer validation (1 week) 

• Imaging cerebral alterations in animals by micro-PET (1 week) 

• Imaging the Cardiovascular System (1 week) 



specific studies with micro-PET, 

• participation in weekly research meetings and selected lectures from the IDIBAPS 

(http://www.idibaps.ub.es/) and its MD/PhD programmes 

Deliverables 

The training will be performed in groups of max 6 trainees. Entire training takes 3 full man months. This 

involves both postdoc and engineer time.


DiMI-TTP6 

Milan Training Platform for Cell and Animal Engineering (P6+36) 

The Centre of Excellence on Neurodegenerative Diseases which will host the training platform in animal and 

cell engineering is a multidisciplinary research center composed by a network of laboratories working at the 

University of Milan. The Center has generated two major core facilities dedicated to: 

1. “Genetic, cell and animal engineering” 

2. “Functional imaging”. 

3. The mission of the core facilities are the development of novel technologies, maintenance of 

innovative techniques, and training of younger scientists to facilitate the technology transfer among 

the different groups composing the Center. 

4. Moreover, it joins with P36 for PET/MR imaging applications in neurosciences 

Objectives: 

Training will be performed in modules on the selected topics reporter below. The trainees will follow small 

theoretical courses and will mostly practice by performing experiments. The training will be performed on a 

maximum of two students/module. Two weeks time will be required for each module. Training courses are 

suitable for Master and Ph.D. students and for post-doctoral fellows. The content of each training can be 

tailored according to the necessities of the trainees. 

The topics of the different modules will be: 

Module 1: Principles in vector design 

Module 2: Cell Engineering 

Module 3: Animal Engineering 

Module 4: PET/MR Brain Imaging (clinical, experimental) 



• Laboratory for cell biology fully equipped for cell growth, maintenance and engineering by means of 

quantitative microinjection, transfection by electroporation or adsorption and viral infection. The 

laboratory is also well equipped with instrumentation for light microscopy and video microscopy and 

image enhancement. Cellular dynamics can be monitored by fluorescence and interference 

techniques; fluorescence photobleaching, imaging of calcium efflux. Two confocal microscopes are 

available. 

• Laboratory for molecular biology fully equipped for manipulation of nucleic acids, DNA 

sequencing, DNA expression analysis by conventional molecular biology techniques and real time 

PCR. The laboratory has CCD camera units for in vivo imaging by bioluminescence. Animal 

facilities supervised by Veterinarians with expertise in mouse genetics are part of the laboratory. 

• PET/MRI laboratory 

• 

b) Teachers 

Surpervisor and course director: Adriana Maggi 

Molecular biology training: Paolo Ciana (Ph.D. in Molecular Genetics) with the technical help of Monica 

Rebecchi 

Cell biology training: Elisabetta Vegeto (Ph.D. in Chemistry and Pharmacology) with technical help of Clara 

Meda 

Oocyte injection and animal engineering: Giulia Chiesa (Ph.D. in Chemistry and Pharmacology) and Cinzia 

Parolini (Ph.D. in Chemistry and Pharmacology)


Animal Facilities: Paolo Sparaciari M.Vet. with the technical help of Samanta Oldoni 

PET/MR imaging in neurosciences: Daniela Perani 


Module 1: 

• Principles in vector design 

• Principles in reporter selection 

• Gene targeting 

• Analysis of reporter expression 

o Molecular biology-based methods 

o Biochemical methods 

o In vivo imaging 

o Cell sorting 

• Generation of recombinant plasmids 

• Recombinant virus 

o lentivirus 

o adenovirus 

Module 2 

• Cell Engineering 

o Immortalized cells 

o Cells in primary culture 

o Organ stem cells 

Module 3 

• Animal Engineering 

o Classical transgenesis 

o Gene targeting 

o Principle of nuclear transfer 

o Oocyte injection and implantation 

o Principles of genotyping 

o Animal colony generation and maitenance 

o Sperm and embryo banks 

o Ethics of animal handling 

o In vivo imaging by bioluminescence 

Module 4 

• PET/MR imaging in various applications in neuroscience 

Deliverables 

The training will be performed in groups of max 6 trainees.


DiMI-TTP7 

Copenhagen Training Platform for Image Analysis and Kinetic Modelling (P7) 

The Copenhagen Training Platform will cover data- and image analysis including kinetic modelling for data 

retrieved within the Network of Excellence. The tools to be provided for clinical and experimental studies 

through this platform will include 

• definition of human brain atlases in the normal and the diseased brain using MR 

• extraction of functional time brain data series from PET/SPECT and MR 

• statistical analysis of molecular imaging data 

• kinetic modelling of neuroreceptor systems from PET 

Objectives: 

The Copenhagen Training Platform will offer training for scientists and students with varying backgrounds. 

The topics include 

• imaging I: estimation parameters in kinetic models of, e.g., neuroreceptors 

• imaging II: visualisation and interpretation of data from kinetic models 

• kinetic modelling and validation of new tracers 

• physics and informatics I: atlas definition/transformation 

• physics and informatics II: methods for comparing and testing models and results 


a) available training infrastructure 

• data-analysis laboratory with computers and programs for analysis of imaging data 

o software developed in Copenhagen as well as public software for: co-registration of different 

image modalities, atlas definition, extraction of data, modelling data including testing 

models and other results 

o 

o 

hardware including a cluster of image processing workstations 

staff includes engineers, physicians, pharmacists, physicist, and technologists who will guide 

through all steps in the data-handling process 

• web-based access to computer cluster with software for analysis of kinetic image data will be 

established to enable access to software through the internet from other laboratories in the Network 

of Excellence 

• close collaboration with the Intelligent Signal Processing group at Informatics and Mathematical 

Modelling, Technical University of Denmark that has expertise in building and testing data models 

b) specific training packages 

Full week training courses for in-depth training: 

• basic kinetic modelling applied to MR and PET images (1 week) 

• extended kinetic modelling course (held in collaboration with Partner 29) (1 week) 

• use of Internet based service for handling and analysis of dynamic image data and neuroinformatics 

(1 week) 



data- and image handling of MR and PET images, extraction of data for analysis 

• participation in weekly research meetings and selected lectures at the Neurobiology Research Unit 

(NRU; http://www.nru.dk/) and its MD/PhD programme 

Deliverables 

The training will be performed in groups of max 6 trainees. Entire training takes 3 full man months per 

year. This involves both postdoc and engineer time.


DiMI-TTP8 

Antwerp Training Platform for Neuro Imaging: microscopy and macroscopy (P8) 

The Antwerp Training Platform will cover the imaging facilities hosted by Partner 8 which are related to 

neuro macroscopy (microMRI) and neuro microscopy (fluorescence, confocal, Two photon, FRET/FRAP 

techniques, life cell imaging (Ca++-imaging)) 

They are directed towards 

• phenotyping neurodegenerative diseases by MRI (experimental) 

• imaging neuronal networks by MRI (experimental) 

• imaging brain activity (experimental) 

• in vivo tract tracing (experimental) 

• Fluorescence, Confocal, Two photon, FRET/FRAP techniques, life cell imaging (Ca++-imaging) of 

neurons 

Objectives: 

1) to obtain both insight and experience in different MRI techniques using animals and microMRI 

instrumentation 

2) to learn what information (anatomical, physiological, cellular, molecular) these images provide 

3) insight and experience in the required image and data processing techniques to process the data 

4) to obtain both insight and experience in CT using animals and microCT instrumentation 

5) to learn what information these images can provide 

6) insight and experience in the required image and data processing techniques to process the data 

7) getting insight and practical experience in modern microscopical imaging techniques 

8) getting insight and practical experience in neuro applications of these microscopical techniques 



Macroscopy: 

The University of Antwerp can provide training access to a 7T microMRI systems and one in vivo microCT 

system (SkyScan, Belgium) for experimental in vivo small animal work (rats and mice). The Antwerp 

platform will also be a demonstration site for the SMEs MRRS and SkyScan which might get involved in the 

DiMI network along the line. The SME’s will ensure the state of the art condition of the platform in terms of 

providing the latest soft and hardware release in collaboration with the platform. 

Microscopy: 

We can provide training in all microscopical techniques, starting from classical light microscopy, confocal 

microscopy, two-photon microscopy, life cell imaging, protein trafficking, fret/frap techniques, stereological 

and morphometric techniques to classical TEM and SEM including ultracryomicrotomy 


MRI training: 

The training is considered as an integrated practical course in which different aspects of animal 

neurobiology, relevant for DiMI, are tackled using different MRI techniques. The students will be allowed 

to perform experiments, involving animal handling, MR imaging, image and data processing. They will end 

up with a set of data drawn from the MRI experiments.


1. General theoretical course on MRI and introduction to instrumentation (2 days, including 1 day on 

the instrument) 

2. Training on animal handling, restraining, catheterization, contrast applications, stereotactical 

injections, physiological monitoring and this for any MRI and CT setup (1 day, 0.5 days on the 

instrument) 

3. In depth training in different current MRI applications and the customized image processing relevant 

for the EMIL network (1.5 day per application, including theoretical background, instrument 

practice, processing of the obtained images). 

4. Perfusion-weighted MRI to measure Cerebral Blood Flow, angiography, functional MRI, diffusion 

weighted MRI, contrast applications in MRI including manganese enhanced MRI (total 7. 5 days) 

microCT training: 

Theoretical and practical course on basics of CT and introduction to the use / and use of the microCT 

instrument (2 days) 

Image Processing training: 

Matlab, practical training (2 days) 

Microscopy training: 

• Basic introduction in microscopical techniques (2 days) 

• Hands on conventional light microscopy (including phase-contrast/DIC/Dark-field) and electron 

microscopy (SEM+TEM) (1day) 

• Hands on fluorescence microscopy (0.5 days) 

• Hands on confocal microscopy (1 day) 

• Hands on Two photon microscopy (1 day) 

• Hands on FRET/FRAP techniques + life cell imaging (Ca++-imaging) (1 day) 

Deliverables 

In terms of instrument occupancy, the training could be done with groups of max 4 trainees. Groups will be 

split and the training duplicated if there are more applicants. We could go up to 8 trainees (two groups) for 

in depth training. Trainees should be master students in biomedical, medical, veterinary, dental, 

pharmaceutical sciences, bio, industrial, and civil engineering, physics, mathematics and informatics. 

people involved in training: 

MRI: 

MicroCT: 

Image processing Antwerp: 

Microscopy: 

Prof. A. Van der Linden, Dr. Marleen Verhoye (physicist), Ing. Johan van 

Audekerke, last years PhD student (Greet Vanhoutte), last years PhD 

student (Nadja Van Camp) 

Prof. N. De Clerck, Dr. Andrea Postnov (physicist) 

Prof. Paul Schuenders, Dr. Jan Sijbers (physicist), Dr. Steve De Backer 

(physicist) 

Prof. Dr. J.-P Timmermans, Prof. Dr. D. Adriaensen, Prof. Dr. F. Van 

Meir, Dr. L. Van Nassauw (zoologist), Dr. I. Brouns (Biomedical scientist)


DiMI-TTP9 

Bordeaux Training Platform for Molecular and Functional Imaging (P9) 

The Bordeaux Training Platform will cover the imaging facilities hosted by Partner 9 (Laboratory for 

Molecular and Functional Imaging) and the specific Molecular Imaging technologies developed. They are 

directed towards 

• control of gene expression based on local heat in combination with a heat-sensitive promoter 

• MRI guided Focused Ultrasound 

• research dedicated state-of-the-art 1.5T MRI system equipped with prototype Focused Ultrasound 

devices (including 256 element phased array technologies) 

• imaging gene and stem cell strategies by MRI 

• imaging macrophage activity 

• MR imaging of biomarkers (perfusion, diffusion, flow) 

Objectives: 

The Bordeaux Training Platform offers training for scientists and students in various specialities: 

• imaging I: MRI imaging for stem cell imaging 

• imaging II: MRI for assessment of macrophage activity in selected animal models 

• imaging III: MRI guided Focused ultrasound (imaging of temperature, motion correction) 

• imaging IV: MRI biomarkers (perfusion MRI, diffusion MRI, flow mapping permeability mapping, 

magnetic susceptibility mapping, cardiovascular functional imaging) 

• molecular biology/biochemistry: development of combination of new marker gene /heat-shockprotein 

promoter combinations for control of gene expression and quantification thereof 

• physics and informatics: image processing, motion correction, feedback control systems based on 

real-time image processing 



• 1.5 T Philips Intera MRI 

• laboratory for development of vectors, stem cells, cell transfection; 

• image processing facilities 

• laboratories for MRI-guided Focused Ultrasound hardware development 



• Vector, macrophage and stem cell applications in animal models in vivo including animal handling, 

anaesthesia, stereotactic application (1 week) 

• Imaging stem cell trafficking by MRI 

• Local hyperthermia using MRI guided Focused Ultrasound (1 week) 

• MR imaging biomarkers (1 week) 



hard- and software handling of cell tracking, control of transgene expression 

• participation in weekly research meetings and selected lectures at the Laboratory for Molecular and 

Functional Imaging 

Deliverables 




DiMI-TTP10 

Munich Training Platform for Cardiovascular Radionuclide Imaging (P10) 

The Munich Training Platform covers a broad spectrum of imaging facilities for cardiovascular investigation 

with a focus on radionuclide techniques and their ex vivo validation. Those include conventional 

scintigraphy, SPECT, PET, hybrid PET/CT, small animal micro PET, but also magnetic resonance and 

optical imaging. They are directed towards 

• Multi-modality in vivo characterization of myocardial metabolism, perfusion and viability 

(experimental, clinical) 

• Molecular imaging of cardiovascular gene expression and stem cell transplantation (experimental) 

• Radionuclide assessment of the cardiovascular autonomic nervous system (experimental, clinical) 

• Identification and validation of novel biomarkers for disease-specific imaging and therapy 

monitoring in coronary artery disease and heart failure (experimental, clinical) 

Objectives: 

The Munich Training Platform could offer training for scientists and students in various specialities: 

• imaging I: SPECT, PET and micro-PET imaging for phenotyping cardiovascular disease and 

monitoring of gene and stem cell strategies 

• imaging II: MRI imaging of myocardial function, perfusion and viability as well as coronary vessels 

in humans and experimental animals; correlation with nuclear imaging techniques 


for cardiovascular imaging; application of ex vivo validation techniques for experimental 

cardiovascular imaging 

• radiochemistry: development of new diagnostic tracers for PET and SPECT, refinement of existing 

labelling technologies 

• physics and informatics: software-based algorithms for 4D data display, quantitative image analysis, 

and multimodality image fusion; development of imaging detector hardware 



• various imaging laboratories for SPECT, PET, micro-PET, MRI, optical imaging 

• radiochemistry laboratory for the development of improved PET and SPECT tracers 

• radioactive S2-animal laboratory and surgery room for animal instrumentation, as well as application 

of vectors, stem cells and radiotracers in vivo 

• workstation network including custom-made multimodal image analysis software 

b)specific training packages 


• Handling of viral vectors and stem cells for applications in vitro and in animal models in vivo, 

including animal handling and anaesthesia (1 week) 

• Imaging cardiac gene expression by SPECT, PET, microPET and optical imaging (1 week) 


• Radiochemical synthesis of PET and SPECT probes (1 week) 

• Efficient software development and handling for multimodal image visualization and quantification 

(1 week) 

• SPECT and PET imaging of patients with cardiovascular diseases including coronary artery disease, 

myocardial infraction and heart failure (1 week)


• Clinical and experimental MRI imaging of cardiovascular function and morphology (1 week) 


• direct involvement in ongoing research projects with daily discussions on progress and problems 

• participation in weekly research meetings and selected lectures 

Deliverables 


3 months of instrument time per year. This involves both postdoc and engineer time. 

DiMI-TTP11 

Oslo Training Platform for optical imaging in transgenic reporter mice (P11) 

The Oslo Training Platform will cover the laboratory and imaging facilities hosted by Partner 11 (optical 

imaging, laboratories, animal facility) and Partner 43 (optical imaging) institutions. They are directed 

towards 

• Generation and validation of transgenic reporter mice (experimental) 

• molecular imaging in transgenic reporter mice (luciferase) 

• molecular imaging and assessment of disease in animal models of inflammation 

Objectives: 

The Oslo Training Platform will offer training for scientists and students in various specialities: 

• imaging: optical imaging in animal models 


for imaging transcriptional regulation 

• validation of optical imaging probes in vivo 



• animal laboratory for application of imaging in vivo; 

• Xenogen IVIS-100 apparatus for bioluminescence and fluorescence 


These are one-week teaching packages which can be extended to longer stays for individual scientists when 

appropriate: 

• One week seminar in optical imaging: 

o Theoretical background 

o Hands on/demonstration of in vivo imaging of luciferase, fluorescence in mice 



optical imaging camera 

• participation in weekly research meetings 

Deliverables 




DiMI-TTP12 

CEA Training Platform for Multimodal Molecular Imaging (P12+23) 

The CEA Training Platform will cover the imaging facilities hosted by Partner’s 12 (microPET, HRRT-PET, 

SPECT, MRI, optical imaging (OI), fluorescence microscopy, autoradiography) and Partner’s 23 [rodent and 

primate L2 and L3 biosafety security level animal facilities, rodent and primate models of neurodegenerative 

diseases (phenotypic, genetic and transgenic models), gene transfer techniques (lentiviral and adenoviral 

vectors), MRS, behavioural testing in rodents and primates (motor and cognitive tests), quantitative video 

movement analysis, organisation and completion of clinical trials (cellular transplantation, gene transfer, 

imaging) in HD or PD patients. They are directed towards 

• Behavioural phenotyping and molecular imaging in animal models of neurodegenerative diseases 

(AD, PD, HD) 

• PET and MRI/MRS monitoring in PD/HD patients undergoing experimental therapies (intracerebral 

cell transplantation and gene transfer) 

• development of generic methods for imaging in drug development and target identification using 

biopolymers (oligonucleotides, peptides) 

• imaging gene therapy and stem cell strategies by MRS, MRI, PET and OI (experimental) 

Objectives: 

The CEA Training Platform could offer training for neurologists, scientists and students in various 

specialities: 

• imaging I: microPET and HRRT-PET imaging for phenotyping neurodegenerative diseases and gene 

and stem cell therapies 

• imaging II: high-resolution MRI and MRS in animal models and stem cell strategies 


for imaging transcriptional regulation ; gene transfer by viral vectorisation (lentivirus technology) 

• radiochemistry: development of new diagnostic PET tracers 

• physics and informatics: image co-registration in multimodal imaging (in vivo/in vivo ; in vivo/postmortem 

; post-mortem/post-mortem 



• radiochemistry laboratory for the development of improved PET tracers; 

• radioactive P3-animal laboratory (rodents and non human primates) for application of vectors, stem 

cells and PET marker substrates in vivo; 

• radioactive PET laboratory for imaging animals harboring one dedicated high-resolution LSO-PETscanner 

(Siemens ECAT HRRT), a microPET (Concord FOCUS), a dedicated small animal SPECT 

(Gamma-Imager BIOSPACE) and an optical imaging camera (BIOSPACE); several implantable 

beta-microprobe systems (beta-microprobe BIOSPACE) 

• Physiology laboratories fully equipped for the optimal monitoring of physiological constants during 

imaging/ prolonged surgery (rodents and non-human primates) 

• MRI/MRS laboratory harboring a 3.0 T-MRI. 



• Vector and stem cell applications in animal models in vivo including animal handling, anaesthesia, 

stereotactic application and convection-enhanced delivery (1 week)


• Imaging gene expression by microPET, OI and MRI (1 week) 


• Radiochemical synthesis of F-18 and C-11 probes (1 week) 

• Efficient software development for image coregistration (1 week) 

• PET imaging of animal models with neurological diseases including Huntington, AD and PD (1 

week) 

• Quantitative video movement analysis of motor deficits in rodent and primate models of PD or HD 

(3 days) 



hard- and software handling of microPET, optical imaging camera, 3T MRI 

• participation in weekly research meetings and selected lectures from the Service hospitalier Frédéric 

Joliot and its MD/PhD programmes. 

Deliverables 




9.B Joint Research Activities 

9.2 Planning and time table & 9.3 Graphical presentation of WPs 

9.B 1.1 Multimodal integrated Imaging Technologies 

The major long-term goals of the jointly executed research activities of the imaging technologies programme 

within DiMI are: 

• to develop or adapt key imaging equipment to the mouse brain and heart, 

• to associate such equipment into multimodal imaging protocols, 

• to improve the performance of existing equipment in terms of quantitation by such protocols as well 

as other techniques 

The programme will put special emphasis on single photon tomography at extremely high resolutions that 

cannot be reached by other quantitative techniques, on optical imaging and on the coupling of MRI with 

PET. 

Below, the objectives, milestones, deliverables and planning for the first 18 months are summarized for 

the two specific WPs1+2 in the imaging technologies field: 

WP1: Ultra-high cerebral and heart imaging and quantitation with Single-Photon emitters 

Objectives: to demonstrate single-photon emitter tomographic imaging and quantitation of the rodent brain 

and heart at mm imaging resolution. 

Milestones: 

Milestone 

N° 

Milestone title 

WP 

N° 

Partner N° 

Delivery/ 

Achieved 

date 

Nature Disseminatio 

n Level 

M1.1 TOHR test on rat brain imaging 1 P4: Guilloteau 

P13: Meynadier 

12 mo R PP 

P30:Mastrippolito 

M1.2 TOHR test on cardiac mouse imaging 1 P10: Bengel 

P13: Meynadier 

18 mo R PP 

P30:Mastrippolito 

M1.3 multipinhole microSPECT design 1 P41:van Laere 12mo R PP 

M1.4 demonstration of registration accuracy of 

intermodality registration 

M1.5 demonstration of A-MAP reconstruction 

for MicroSPECT/microMRI data 

Deliverables: 

Deliver 

ables 

N° 

Deliverable title 

1 8:vdLinden 

P41:van Laere 

1 8:vdLinden 

P41:van Laere 

WP 

N° 

Partner N° 

12 mo R PP 

18 mo R PP 

Delivery/ 

Achieved 

date 

Nature 

Disseminati 

on Level 

D1.1 Validation of TOHR imaging on rat brain 1 4:Guilloteau 6,12,18 R PP


models 

D1.2 Validation of TOHR imaging on rat brain 

models 

D1.3 Validation of TOHR imaging on mouse 

heart models 

D1.4 Hardware multipinhole SPECT collimator 

prototype 

D1.5 Software for multipinhole SPECT 

reconstruction 

D1.6 Software for registration of MicroSPECT 

data with structural data 

D1.7 annual reporting on the relevant and 

applicable regulations of ethical issues 

13:Meynadier 

30:Mastrippolito 

1 10:Bengel 

13:Meynadier 


1 10:Bengel 

13:Meynadier 


1 8:vd Linden 

41:van Laer 

mo 

12,18 mo R PP 

6,12,18 

mo 

6,12,18 

mo 

R PP 

1 8:vd Linden 6,12,18 R PP 

41:van Laere 

mo 

1 8:vd Linden 6,12,18 R PP 

41:van Laere 

mo 

1 all 12 mo R PP 

R 

PP 

Planning for the first 18 months: 

Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 

Task N° Title of Task Partners N° 

1 validation of TOHR imaging on rat brain models 4,13,30 

2 validation of TOHR imaging on rat heart models 10,13,30 

3 validation of TOHR imaging on mouse heart models 10,13,30 

4 Hardware multipinhole SPECT collimator prototype 41 

5 Software for multipinhole SPECT reconstruction 8,41 

6 Software for registration of MicroSPECT data with structural data 

8,41 

Deliverables 1,5,6 2,3,4 

Milestones 1,5 2,3,4 

Internal Reporting R1 R2 R3 R4 

EC Reporting 

WP2: Quantitative microPET and multi-modality (PET/MR, OT/MR) scanner development 

Objectives: 

1. to develop the full range of data corrections (e.g. scatter, transmission , dead time and normalisation) 

required to achieve truly quan titative microPET image data. 

2. To construct an MRI micro imager based upon a novel split coil MR magnet and use this for 

simultaneous PET/MRI or Optical tomography/MRI Scanner. 

Milestones: 

Milestone 

N° 


WP 

N° 

Partner N° 

Delivery/ 

Achieved 

date 

Nature 

Disseminati 

on Le vel 

M2.0 Common meeting of partners 2 (Clark) 

1 (Jacobs) 

1 mo R PP 

5 (Planas) 

12 (Tavitian) 

M2.1 Monte Carlo model of microPET 2.1 2 (Clark) 6,12 mo R PP 

M2.2 Fast 3D FBP image reconstuction of 2.2 2 (Clark) 6,12 mo R PP 

microPET data 

M2.3 Optimise transmission scanning for 

microPET 

2.3 2 (Clark) 12,18 mo R PP 

M2.4 Verify microPET data corrections and 

image reconstruction software 

2.4 2 (Clark) 

1 (Jacobs) 

5 (Planas) 

12 (Tavitian) 

18 mo R PP


M2.5 Characterise imaging properties of split 

coil magnet MR imager 

M2.6 Assess performance of microPET block 

detector operating in MR imager 

M2.7 Produce initial design of combined 

optimal/MR imager 

2.5 2 (Clark) 6,12 mo R PP 

2.5 2 (Clark) 12,18 mo R PP 

2. 6 2 (Clark) 18 mo R PP 

Deliverables: 

Delivera 

bles N° 


Meeting with WP2 members for final 

WP 

N° 

Partner N° 

D2.0 2 (Clark) 

1 (Jacobs) 

agreement and initiation of work plan 

5 (Planas) 

12 (Tavitian) 

D2.1 Adapt Monte Carlo code 

(SimSET+GEANT4) to model microPET 

D2.2 Implement PROMIS 3D image 

reconstruction algorithm on PC-cluster 

D2.3 Implement singles and windowed 

coincidence mode transmission scanning 

on microPET, and implement iterative 

reconstruction of this data 

D2.4 Verification of microPET data corrections 

and image reconstruction 

Delivery/ 

Achieved 

date 

Nature 

Disseminati 

on L evel 

1 mo R PP 

2.1 2 (Clark) 6,12 mo R PP 

2.2 2 (Clark) 6,12 mo R PP 

2.3 2 (Clark) 12 ,18 mo R PP 

2.4 

2 (Clark) 

1 (Jacobs) 

5 (Planas) 

12 (Tavitian) 

18 mo R PP 

D2.5 Measure and assess magnetic field 2.5 2 (Clark) 6,12 mo R PP 

properties of 1T split pair magnet 

D2.6 Demonstrate the spatial and temporal 2.5 2 (Clark) 6,12 mo R PP 

resolution of the MR imager 

D2.7 Design and build split coil active shield 2.5 2 (Clark) 12,18 mo R PP 

gradients 

D2.8 Investigate the performance of a PET 2.5 2 (Clark) 12,18 mo R PP 

detector block operating in the MR 

imager 

D2.9 Produce an initial design of a combined 

optical/MR imager 

2.6 2 (Clark) 18 mo R PP 


Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


0 Meeting and detailed project planning 2,1,5,12 

1 Adapt Monte Carlo code (SimSET+GEANT4) to model microPET 2 

2 Implement 3D reconstruction on a PC-cluster 2 

3 Implement transmission scanning and iterative reconstruction 2 

4 Measure and assess field profile of 1T split pair magnet 2 

5 Demonstrate the spatial and temporal resolution of MR imager 2 

6 Design and build split coil active shield gradients 2 

7 Investigate performance of PET block detector in MR imager 2 

8 Verify microPET data corrections and image reconstruction 2,1,5,12 

9 Produce initial design of combined optical/MR imager 2 

Deliverables 0 1,4,5 2,6 3 7,8,9 

Milestones 0 1,2,5 3,4,6,7 


EC Reporting


9B 1.2 Diagnostic Molecular Imaging Probes 

The major long-term goal of the jointly executed research activities of the Imaging Probes programme within 

DiMI is to develop (design, synthesis, characterization) probes (a “library” of probes) for relevant targets for 

a given cardiovascular or neurodegenerative disease and for monitoring of gene expression using different 

modalities: 

• PET, SPECT 

• MRI 

• Optical Imaging 


the three specific WPs 3, 4.1 and 4.2 in the Imaging Probes field: 

WP3: Development of radiopharmaceutical probes for neurodegenerative disease 

Objectives: 

1. Development of new probes for PET/SPECT molecular imaging of targets involved in frequent 

neurodegenerative disorders (AD, PD). 

2. Development of fluorine-18 labelled PET probes derived from existing iodine-123 labelled SPET 

probes. 

3. Make available known probes ([ 123 I, [ 18 F], [ 11 C]) for in vivo studies in animal models and clinical 

investigations. 

4. Development of in vivo quantification methods suitable for each PET/SPECT probe. 

Milestones: 

Milestone 


N° 

M 3.1 Common meeting of partners for 

initiation of activities and agreement on 

tasks 

M 3.2 

M 3.3 

M 3.4 

M 3.5 

Development of one step radiolabelling 

with fluorine-18 or carbon-11 of tracer 

agents for dopamine transporter (DAT) 

Characterization of 18 F or 11 C labelled 

tracer agents for dopamine transporter in 

vitro and in vivo in animal models 

Modelling software for in vivo 

quantification of dopamine transporter 

using developed 18 F or 11 C labelled tracer 

agents 

Development of tracer agents, labelled 

with carbon-11 or fluorine-18, for noninvasive 

visualisation of amyloid plaques 

in brain 

WP 

N° 

Partner N° 

3 4 (Guilloteau) 

22(Halldin) 

29(Leenders/Vaalburg) 

7 (Knudsen) 

41(Verbruggen) 

1 (Jacobs) 

3.1 4 (Guilloteau) 

22(Halldin) 


3.2 4(Guilloteau) 

22(Halldin) 


7 (Knudsen) 


1 (Jacobs) 

3.3 7(Knudsen) 

4(Guilloteau) 

22(Halldin) 



1 (Jacobs) 


22(Halldin) 


Delivery/ 

Achieved 

date 

Nature Disseminati 

on Level 

1 mo R PP 

12 mo R PP 

18 mo R PP 

18 mo R PP 

18 mo R PP


M 3.6 

M 3.7 

Characterization of developed tracer 

agents for amyloid plaques in vitro and in 

vivo in animal models 

Meeting of all partners for discussion of 

results and further work plan 


22(Halldin) 


7 (Knudsen) 


1 (Jacobs) 

3 4(Guilloteau) 

22(Halldin) 


7 (Knudsen) 


1 (Jacobs) 

18 

mo 

12 mo 

R 

PP 

Deliverables: 

Deliver 


ables 

N° 

D3.0 Report of meeting with WP 3 members for 

final agreement and initiation of work 

plan 

D3.1 Precursors for radiolabelling with 

fluorine-18 or carbon-11 of tracer agents 

for dopamine transporter (DAT) 

D3.2 Written instructions for radiolabelling 



using deliverable D3.1 

D3.3 Software for quantification of dopamine 

transporter in vivo using developed 18 F or 

11 C labelled tracer agent and positron 

emission tomography 

D3.4 Results of evaluation in vitro and in vivo 

in animals of fluorine-18 or carbon-11 

labelled tracer agents for dopamine 

transporter 

D3.5 Precursors for radiolabelling with 

fluorine-18 or carbon-11of tracer agents 

for in vivo visualisation of amyloid 

plaques in brain 

D3.6 Written instructions for radiolabelling 


agents for in vivo visualisation of amyloid 


D3.7 Results of evaluation in vitro of fluorine- 

18 or carbon-11 labelled tracer agents for 



discussion of 1 st year results and further 

work plan 



WP 

N° 

Partner N° 

4 (Guilloteau) 

22(Halldin) 


7 (Knudsen) 


1 (Jacobs) 


22(Halldin) 



22(Halldin) 


3.2 7 (Knudsen)4 

(Guilloteau) 

22(Halldin) 



1 (Jacobs)) 


22(Halldin) 


7 (Knudsen) 


1 (Jacobs) 


22(Halldin) 



22(Halldin) 



22(Halldin) 


7 (Knudsen) 


1 (Jacobs) 


22(Halldin) 


7 (Knudsen) 


1 (Jacobs) 

Delivery/ 

Achieved 

date 


on Level 

1 mo R PP 

9 mo R PP 

12 mo R PP 

18 mo R PP 

18 mo R PP 

12 mo R PP 

18 mo R PP 

18 mo R PP 

13 mo R PP 

1 all 12 mo R PP



Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


0 Meeting and detailed project planning 1,4,7,22,29,41 

1 Development of precursors for F-18 and C-11 DAT tracers 4,22,41 

2 Design of 1-step labelling method of F-18 and C-11 DAT tracers 4,22,41 

3 Development of software for quantification of DAT 1,4,7,22,29,41 

4 on in vitro and in vivo (animals) of F-18 or C-11 labelled DAT tracers 1,4,7,22,29,41 

5 Development of precursors for F-18 and C-11 amyloid plaque tracers 4,22,41 

6 Design of labelling method for F-18 and C-11 amyloid plaque tracers 4,22,41 

7 Evaluation in vitro of F-18 and C-11 amyloid plaque tracers 1,4,7,22,29,41 

8 Meeting for follow-up and further planning 1,4,7,22,29,41 

Deliverables 0 0 0,1 0,1,2,5 0,1,2,5, 8 ,1,2,3,4,5,6,7,8 

Milestones 0 0 0 0,1,6 0, 1,6 0,1,2,3,4,5,6 

Internal Reporting R1 R2 R3 

EC Reporting 

WP4.1: Development of innovative MRI Probes and “in vitro” cellular labelling 

Objectives: 

1. Development of libraries of MRI-Gd(III) based probes endowed with high sensitivity and targeting 

capabilities. 

2. Development of libraries of high sensitivity MRI-CEST agents endowed with responsive properties to 

parameters characterising the tissutal microenvironment. 

3. Development of improved methods for “in vitro” cellular labelling with MRI probes. 

4. Deve lopment of libraries of MRI probes for assessing the vulnerability of atherosclero tic plaques. 

5. Set-up of improved MRI protocols for an optimised matching between image acquisition procedures 

and the characteristics of the Imaging ProbeDevelopment of libraries of MRI Probes endowed with 

responsive properties to parameters characterising the micro-environment. 

Milestones: 

Mile 

stone N° 


WP 

N° 

Partner N° 

M4.1.1 Meeting among WP partners 4.1 3: Aime 

M4.1.2 

M4.1.3 

9 : Moonen 

25: Hoehn 

35: Parker 

41: Verbruggen 

46: Benderbous 

50: Lukes 

Optimisation of MRI protocols for 4.1 3: Aime 

molecular imaging experiments using 

Gd(III)-based and CEST Imaging Probes 

Assessment of the relationships among 

chemical structure, cellular uptake, and 

contrastographic ability for the developed 

Imaging Probes 

9: Moonen 

25: Hoehn 

35: Parker 



50: Lukes 

4.1 3: Aime 

25: Hoehn 

35:Parker 

50: Lukes 

Delivery/ 

Achieved 

date 

Nature 

Disseminati 

on Level 

12 mo R PP 

18 mo R PP 

12 mo R PP


M4.1.4 

Set-up of MRI protocols for the 

visualisation of atherosclerotic plaques by 

using properly designed Imaging Probes 

4.1 

3: Aime 

9: Moonen 

25: Hoehn 

35: Parker 

41 : Verbruggen 

46 : Benderbous 

50: Lukes 

18 mo R PP 

Deliverables: 

Delivera 

bles N° 


WP 

N° 

Partner N° 

Delivery/ 

Achieved 

date 

Nature 

Disseminati 

on Level 

D4.1.1 Identification of high sensitive Gd(III)- 4.1 3: Aime, 12 mo R PP 

35: Parker 

based Imaging Probes endowed with 

50: Lukes 

specific targeting ability. 

D4.1.2 Identification of high sensitive 

4.1 3:Aime 6 mo R PP 

50: Lukes 

paramagnetic CEST agents responsive 

towards pH and temperature 

D4.1.3 Report on meeting among WP members 4.1 3:Aime 12 mo R PP 

D4.1.4 

D4.1.5 

D4.1.6 

D4.1.7 

Optimised procedures for cell-labelling 

using soluble Gd(III)-based and CEST 

Imaging Probes ( pynocitosis and 

electroporation) or insoluble Gd(III)-based 

bio-degradable particles (for labelling 

macrophages) 

Identification of Imaging Probes (Gd(III)- 

based and CEST agents) for targeting 

vulnerable plaques 

Set-up of MRI protocols “in vivo” for 

evaluating and optimising the diagnostic 

properties of the developed Imaging 

Probes 

annual reporting on the relevant and 


9: Moonen 

25: Hoehn 

35: Parker 



50: Lukes 

3: Aime 

25:Hoehn 

35:Parker 

4.1 12 mo R PP 

4.1 3: Aime 

50: Lukes 

4.1 3: Aime 

9: Moonen 

41:Verbruggen 


18 mo R PP 

18 mo R PP 



Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


1 Identification of high sensitive Gd(III)-based probes 3, 35, 50 

2 Identification of high sensitive CEST probes 3, 50 

3 Report on meeting among WP members 3, 9, 25, 35, 41, 46, 50 

4 Optimisation of cell-labelling procedures 3, 25, 35 

5 Identification of MRI Imaging Probes for visualising plaques 3, 50 

6 Set-up of "in vivo" MRI protocols 3, 9, 41, 46 

Deliverables 2 1,3,4 5,6 

Milestones 1,3 2,4 


EC Reporting


WP4.2: Development of optical and combined imaging probes 

Objectives : 

1. Synthesis and evaluation of luminescent metal-complex probes: from analytical applications in cell 

biology to their development for diagnostic applications in vivo. 

2. Correlation of behaviour of MR/radiotracer and Optical probes based on similarity of underlying 

chemistry of lanthanide systems 

3. Synthesis and evaluation of a novel class of “dual” Imaging Probes exploiting the superb anatomical 

resolution of MRI and the outstanding sensitivity of Optical and Nuclear Imaging Probes. 

Milestones: 

Milestone 

N° 


WP 

N° 

M4.2.1 Meeting among the WP members 

4.2 

M4.2.2 

M4.2.3 

Optimisation of the energy transfer 

between a lanthanide-based luminescent 

probe and a given chromophore 

Assessment of the determinants of the cell 

internalisation process, relating complex 

structure to cellular uptake/distribution 

Partner N° 

3: Aime 

9: Moonen 

35: Parker 



50:Lukes 

4.2 3: Aime 

35: Parker 


50:Lukes 

4.2 3: Aime 

9: Moonen 

35:Parker 


Delivery/ 

A chieved 

date 


on Level 

12 mo R PP 

12 mo R PP 

18 mo R PP 

M4.2.4 

Assessment of the determinants of the 

permeability of the cell nucleus with 

respect to the structure of the optical 

probes 

4.2 

3: Aime 

9: Moonen 

35: Parker 



18 mo R PP 

M4.2.5 

Optimisation of combined probes using 

MRI or PET with optical imaging 

4.2 3: Aime 

9: Moonen 

35: Parker 



50: Lukes 

18 mo R PP 

Deliverables: 

Deliverab 

les N° 


WP 

N° 

Partner N° Delivery/ 

A chieved 


on Level 

date 

D4.2.1 Lanthanide-based Optical Probes 4.2 3: Aime 18 mo R PP 

35: Parker 

responsive to intracellular analytes. 

D4.2.2 Report on 2 nd meeting among WP members 4.2 

50: Lukes 

3: Aime 

9: Moonen 

35: Parker 



50: Lukes 

12 mo R PP


D4.2.3 A lanthanide based Optical Probe for 4.2 

DNA-targeting. 

3: Aime 

9: Moonen 

35: Parker 


50: Lukes 

D4.2.4 Long-lived Optical Probes based on an 4.2 35: Parker 

50: Lukes 

efficient energy transfer between a 

Lanthanide metal complex and a 

Selected chromophore. 

D4.2.5 Combined Probes containing several 

chelating moieties (10-50) mostly charged 

with Gd(III) ions (for MRI visualisation) 

D4.2.6 

and containing one or few sites occupied 

by luminescent lanthanide ions or by 

lanthanide radioisotopes endowed with 

suitable emitting properties for Optical 

Imaging and PET detection, respectively. 



4.2 3: Aime 

9: Moonen 

35: Parker 


12 mo R PP 

9 mo R PP 

18 mo R PP 



Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


1 Lanthanide-based Optical probes responsive to intracellualr analytes 3, 35, 50 

2 Identification of an Optical probe for DNA targeting 3, 9, 35, 41, 50 

3 Identification of long-lived optical probes with efficient energy transfer 35, 50 

4 Development of combined probes 3, 9, 35, 46 

Deliverables 4 2,3 1,5 

Milestones 1 2.3,4 


EC Reporting 

task 1 months 3-18; task 2: 1-12; task 3 1-9; task 4 3-18


9.B 1.3 Animal Models 

The main goal in this topic is the creation of an “animal model library” for image validation in the three 

respective main topics (neuroscience, cardiovascular, inflammation) of this proposal. We expect, promote 

and encourage a bidirectional knowledge transfer from basic to imaging (a) and viceversa (b): 

a) from basic to imaging laboratories will promote the identification of molecular targets for 

diagnostic imaging and the input for chemical probe development; 

b) from imaging to basic research laboratories will enable us to translate the diagnostic objectives and 

application benefits, accounting for the technical constrains and study limitations of imaging for 

clinical diagnosis. 

It should be pointed out again, that at the current stage of molecular imaging, ex-vivo to in vivo correlations 

are of utmost importance. While in vivo imaging develops fast, it has to be taken into account, that 

molecular characterization is still based on in situ markers (histopathology, immunohistochemistry, etc.). 

Therefore, all imaging parameters obtained in vivo will be validated in situ by the appropriate techniques. 


the two specific WPs 5 and 6 in the Animal Models field: 

WP5: Animal library for diagnostic molecular imaging in neuroscience & cardiovascular 

Objectives: 

1. To establish a library of experimental animal models of human neurological diseases in order to validate and 

test the use of molecular imaging probes as markers of disease hallmarks for diagnostic purposes and for the 

study of disease progression. 

2. The same aim as in 1. for cardiovascular diseases. 

3. Generation of new animal models for neurodegenerative and cardiovascular diseases. 

4. Apply combinations of new and existing molecular imaging probes to generate complementary information for 

disease diagnostics 

5. Exchange relevant models/knowledge to members of the consortium. Tight interaction with animal libraries 

for inflammation research within the network. 

Milestones: 

Milestone 

N° 


M5.0 Common meeting of partners for the 

organization of the specific workplan 

and establishment of detailed 

interactions between partners 

M5.1 Coordination of the exchange between 

partners, and setting a) described and b) 

new animal models 

WP 

N° 

Partner N° 

5 (Planas) 

1(Jacobs) 

6(Maggi) 

25(Hoehn) 

8(vdLinden) 

42 (Vivien) 

14(Baekelandt) 

23(Hantraye) 

P7(Knudsen) 

P34(Auricchio) 

21 (Fleischmann) 

40(Schäfers) 

32(Nicolay) 

5.1 5 (Planas) 

6(Maggi) 

25(Hoehn) 

Delivery/ 

Achieved 

date 

Nature 

Disseminati 

on Level 

1 mo R PP 

a) 6 mo 

b) 12 mo 

R 

PP


M5.2 Characterization of pathological 

disturbances in specific diseases 

M5.3 Characterization of molecular 

disturbances in specific diseases (18 mo) 

5.2.1A3 

5.2.1B 

5.2.2A 

5.2.3B 

5.2.3C 

5.2.4 

5.2.6A 

5.2.1A1 

5.2.1A2 

5.2.1A4 

5.2.2B 

5.2.3A 

5.2.5A 

5.2.6B 

8(vdLinden) 

42 (Vivien) 


23(Hantraye) 

P7(Knudsen) 



40(Schäfers) 

5 (Planas) 

6(Maggi) 

25(Hoehn) 

42 (Vivien) 

23(Hantraye) 



40(Schäfers) 

32(Nicolay) 

5 (Planas) 

25(Hoehn) 

42 (Vivien) 

6(Maggi) 

23(Hantraye 

8(vdLinden) 



32(Nicolay) 

12 

18 

12 

18 

18 

18 

12 mo 

12 

12 

12 

18 

18 

12 

18 mo 

R 

R 

PP 

PP 

M5.4 Characterization of disease hallmarks (in 

the selected animal models) that can be 

studied by imaging, and characterization 

of histopathological, behavioural and 

molecular correlates of imaging 

alterations Links with WP6, WP7, WP9, 

WP11.1, WP11.2, and WP12 

M5.5 Characterization of disease hallmarks 

and gene transfer (in the selected animal 

models) that can be studied by imaging. 

Links with WPs, as above. (18 mo) 

M5.6 Integration of findings obtained with 

invasive methods and data from the 

different imaging modalities for each 

experimental model. Links to related 

WPs 

M5.7 Identification of molecular targets for 

the development of imaging markers. 

Integration of all studies for each 

disease. Links to related WPs. 

5.2.6.C 

5.3 

5 (Planas) 

1(Jacobs) 

6(Maggi) 

25(Hoehn) 

8(vdLinden) 

42 (Vivien) 


23(Hantraye) 

P7(Knudsen) 



40(Schäfers) 

32(Nicolay) 

5(Planas) 


18 

18 mo 

R 

PP 

18 mo R PP 

5.4 As in M5.0 18 mo R PP 

5.5 As in M5.0 18 mo R PP 

Deliverables: 

Delivera 

bles N° 


D5.0 Meeting with WP5 members for final 


WP 

N° 

Partner N° 

5 (Planas) 

1(Jacobs) 

6(Maggi) 

25(Hoehn) 

8(vdLinden) 

42 (Vivien) 


23(Hantraye) 

7(Knudsen) 

Delivery/ 

Achieved 

date 

Nature Disseminatio 

n Level 

1 mo R PP


D5.1 Characterisation of hallmarks of disease 

in the pre-established (a) animal 

models, and in (b) new animal models 

with invasive methods 

D5.2 Characterisation of biochemical, 

molecular and histopathological 

alterations in the different experimental 

models and characterization of viralmediated 

gene transfer in the selected 

animal models of disease. 

D5.3 Characterization of the glial and 

inflammatory reaction in models of 

stroke, PD, and AD. 

D5.4 Integrating imaging with 

neuropathological and molecular 

alterations in stroke, PD, AD, and HD; 

and non-invasive imaging of viralmediated 

gene transfer in HSP. 

Connection with related WPs. 



alterations in the ischemic heart, and 

biological characterization of 

atherosclerotic plaques 

D5.6 Labelling of progenitor and/or stem 

cells and evaluation of the biological 

effects in vitro for cardiovascular 

research. 

D5.7 Integrating imaging with pathological 

and molecular alterations in each model 

of cardiovascular diseases; reidentification 

of stem cells after 

transplantation into the injured mouse 

heart Connection with related WPs. 

D5.8 Integration of the resulting data for each 

disease. Exchange of animal models 

within the network. Links to other WPs. 



34b(Auricchio) 


32(Nicolay) 

40(Schäfers) 

5.1 5(Planas) 

25(Hoehn) 

42(Vivien) 

23(Hantraye) 

6(Maggi) 

14(Baekelandt) 21 

(Fleischmann) 

32(Nicolay) 

5.2.1A 

5.2.2B 

5.2.3A 

5.2.5 

5.2.1B 

5.2.2A 

5.2.3B 

5.2.1 

5.2.3C 

5.3 

5.4 

5.5 

5(Planas) 

42(Vivien) 

25(Hoehn) 


23(Hantraye) 

25(Hoehn) 


32(Nicolay) 

8(vdLinden) 

40(Schäfers) 

5(Planas) 

42(Vivien) 

25(Hoehn) 

5(Planas) 

42(Vivien) 


23(Hantraye) 

25(Hoehn) 

6(Maggi) 


8(vdLinden) 

7(Knudsen) 

32(Nicolay) 

40(Schäfers) 

6 mo 

18 mo 

R 

PP 

18 mo R PP 

12 mo R PP 

18 mo R PP 

12 mo R PP 

21(Fleischmann) 6 mo R PP 

21(Fleischmann) 

32(Nicolay) 

40(Schäfers) 


18 mo R PP 

As in 5.0 18 mo R PP 


Planning for the first 18 months:


Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


0 Meeting and detailed project planning 5,1,25,23,42,8,7,6,14,41,34b,21,32,40 

1 Setting pre-established animal models of diseases 5, 23, 25, 42, 34b, 21, 32, 40 

2 Developing new experimental models of diseases 23, 6 

3 Molecular and histological validation for neurological diseases 5, 6, 23, 14, 25, 42, 34b 

4 Molecular and histological validation for cardiovascular diseases 21, 32, 40 

5 Identification of imaging targets 8, 6, 23, 14, 25, 42, 5 

6 Integration of biological and imaging data for each model 5,1,25,23,42,8,7,6,14,41,34b,21,32,40 

Deliverables 0 1, 6 3, 5 1, 2, 4, 7 

Milestones 0 1 1, 2,3 2, 3, 4, 5, 6 


EC Reporting 

WP6: 

Evaluation of the role of estrogen and estrogen receptors in a mouse model of Alzheimer’s 

disease and generation of novel reporter systems 

Objectives: 

1. Understanding the relevance of inflammatory processes in the progression of neurodegenerative 

diseases 

2. Generating novel models for in vivo imaging of intracellular processes 

3. To evaluate the role of estrogen and estrogenic drugs on the inflammatory reaction in Alzheimer’s 

Disease (AD) 

4. To analyse the molecular mechanism of estrogen anti-inflammatory activity 

Milestones: 

Milestone 

N° 


WP 

N° 

Partner N° 

M6.0 Common meeting of partners 6 1(Jacobs) 

6(Maggi) 

11(Carlson) 

12 (Tavitian) 

Delivery/ 

Achieved 

date 

Nature 

Disseminati 

on Level 

1 mo R PP 

M6.1 assessment of the effect of estrogen 

chronic treatment on microglia 

activation in AD brain 

M6.2 elucidation of the molecular mechanism 

of anti-inflammatory action of estrogen 

in monocytes 

6 6 (Maggi) 12 R PP 


M6.3 assessment of the effect of the chronic 

treatment with SERMs on microglia 

activation in AD brain 

M6.4 Vectors genetically engineered to 

express luciferase and D2 receptor 

(lucIRESD2; and d2IREStk39 ) 

M6.5 Stably transfected cells with the 

lucIRESD2 and d2IREStk39 reporter 

M6.6 Assessment of ratio of expression of the 

two reporter in vivo (12 mo) 

6 6 (Maggi) 

1 (Jacobs) 

6 6 (Maggi) 

1 (Jacobs) 

6 6 (Maggi) 

1 (Jacobs) 

18 R PP 

6 R PP 

12 R PP 


M6.7 Common data for the detection 

sensitivity of cells expressing 

lucIRESD2 reporter by optical imaging 

and PET 

6 6 (Maggi) 

1 (Jacobs) 

12 (Tavitian) 

18 R PP


Deliverables: 

Delivera 

bles N° 


WP 

N° 

Partner N° 

Delivery/ 

Achieved 

date 


on Level 

D 6.0 Common meeting of partners 6 1 (Jacobs) 1 mo R PP 

D6.1 Assessment of the pharmacological 

activity of estrogen and selected ER 

mediators (SERMs) on brain 

inflammation 

D6.2 Identification of the mechanisms 

involved in estrogen anti-inflammatory 

activity 

D6.3 Vectors genetically engineered to express 

luciferase and D2 receptor (lucIRESD2 

and d2IREStk39) 

D 6.4 Stably transfected cells with the 

lucIRESD2 and d2IREStk39reporter 

D 6.5 Assessment of ratio of expression of the 

two reporter in vivo 

D 6.6 Common data for the detection 

sensitivity of cells expressing lucIRESD2 

reporter by optical imaging and PET 

6 (Maggi) 

11 (Carlson 

12 (Tavitian) 

6 6 (Maggi) 

1 (Jacobs) 

18 R PP 


6 6 (Maggi) 

1 (Jacobs) 

6 6 (Maggi) 

1 (Jacobs) 

6 R PP 

12 R PP 


6 6 (Maggi) 

12 (Tavitian) 

18 R PP 





Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


0 Meeting and detailed project planning 1,6,12,11 

1 Methodologies to study brain inflammatory processes 1,6,11,12 

2 Analysis of estrogen effects on brain inflammation 1,6 

3 molecular mechaisms of E2receptor anti-inflammtory action 6 

4 Generation of multimodalitiy imaging vectors 1,6 

5 methodologies to study multimodality imging vectors in vivo 1,6,11,12 

Deliverables 0 3 4 2 2 1,6 

Milestones 0 4 0 1,5,6 2 3 

Internal Reporting R! R2 R3 R4 

EC Reporting


9B 2.1 Neuroscience 

The major long-term goals of the jointly executed research activities of the neuroscience programme within 

DiMI are: 

• to establish a molecular imaging toolbox of new non-invasive diagnostic tests for in vivo 

phenotyping neurodegenerative diseases; 

• to develop molecular imaging approaches for non-invasive monitoring of novel molecular therapies 

for neurodegenerative diseases; 

• to use these molecular imaging tools for translational research from animal models to clinical 

application for early disease detection, follow-up disease progression and the effectiveness of 

therapeutic intervention. 

Current areas of major development in neuroscience are included in the DiMI programme, and comprise 

1. phenotyping and early detection of neurodegeneration by multimodal imaging; 

2. identification of new surrogate (imaging) markers; 

3. imaging neuroinflammation and the potential of stem cells for activation or transplantation and their 

specific actions (proliferation, migration, differentiation) in terms of targeted repair. Especially this 

last topic serves for integration and horizontal links to =>Topic 2.2 (cardio) and =>Topic 2.3 

(inflammation). 


the five specific WPs 7-10 in the neuroscience field: 

WP7: Non-invasive phenotyping of animal models for neurodegenerative diseases 

Objectives: To validate a novel library of diagnostic molecular imaging markers in vivo in defined mouse 

models for neurodegenerative diseases. The imaging partners of DiMI will integrate with those partners who 

construct new animal models by providing tools and expertise to validate their models, i.e. to study how well 

the models mimic the human pathology using (miniaturized or similar) clinical diagnostic tools. 

Milestones: 

Milestone 

N° 


WP 

N° 

Partner N° 

M7.0 Common meeting of partners 1(Jacobs) 

3(Aime) 

5(Planas) 

6(Maggi) 

8(Van der Linden) 


23(Hantraye) 

M7.1 Multimodality Phenotyping of 6- 

0HDA PD rat model 

2(1,3,4) 

3 

4 

41 (VanLaere) 

1(Jacobs) 

5(Planas) 

8(Van der Linden 


41 (VanLaere) 

Delivery/ 

Achieved 

date 

Nature 

Dissemina 

tion Level 

1 month R PP 

9 R PP 

M7.2 Multimodality Phenotyping of 

lentiviral PD rat model: 

2(1,3,4) 

3 

4 

1(Jacobs) 

5(Planas) 



41 (VanLaere) 

12 R PP


M7.3 Optical imaging Phenotyping of 

lentiviral PD mouse model: 

M 7.4 

Multimodality Phenotyping of 

chronic 3NP HD rat model: 

M 7.5 MRI phenotyping of different ALS 

genotype mice: 

M7.6 Multimodality Phenotyping of 

lentiviral HD rat model 

M7.7 Multimodality Phenotyping of a 

lesional model of Huntington's 

disease in rats 

M7.8 Implementation of animal brain 

atlases for automatic VOI definitions 

in rodents 

2.4 1(Jacobs) 

6(Maggi) 


41 (VanLaere) 


2(1,3,4) 

3 

4 

5(Planas) 

23 (Hantraye) 

2.1 8(Van der Linden) 

3(Aime) 

2(1,3,4) 

3 

4 

2.3 

2.4 

3 

4 

5(Planas) 

23 (Hantraye) 

5(Planas) 

41 (VanLaere) 

3(Aime) 

4 1(Jacobs) 

41 (VanLaere) 


18 R PP 

18 R PP 

6 R PP 

18 R PP 

12 

18 R PP 

Deliverables: 

Deliverables 

N° 


WP 

N° 

Partner N° 

D7.0 Common meeting of partners 7 1(Jacobs) 

3(Aime) 

5(Planas) 



23(Hantraye) 

34(Pappata) 

41 (VanLaere) 

D7.1 Multimodality Phenotyping of 6- 

0HDA PD rat model 

7 1(Jacobs) 



41 (VanLaere) 

Delivery/ 

Achieved 

date 

Nature Dissemination 

Level 

1 mo R PP 

9 R PP 

D7.2 Multimodality Phenotyping of 

lentiviral PD rat model: 

7 1(Jacobs) 



41 (VanLaere) 

18 R PP 

D7.3 Optical imaging Phenotyping of 


D 7.4 Multimodality Phenotyping of 

chronic 3NP HD rat model: 

D 7.5 MRI phenotyping of different ALS 



lentiviral HD rat model. 

D7.7 Multimodality Phenotyping of a 

lesional model of Huntington's 

disease in rats 

7 1(Jacobs) 


41 (VanLaere) 


18 R PP 

7 23 (Hantraye) 18 R PP 

7 8(Van der Linden) 6 R PP 

7 23 (Hantraye) 18 R PP 

7 41 (VanLaere) 12 R PP 

D7.8 Implementation of animal brain 

atlases for automatic VOI 

definitions 

7 1(Jacobs) 

41 (VanLaere) 


23 (Hantraye) 

18 R PP


D7.9 


applicable regulations of ethical 

issues 



Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


0 Meeting and detailed project planning 1, 3, 5, 6, 8, 14, 23, 41 

1 Multimodality Phenotyping of 6-0HDA PD rat model 1, 5, 8, 14, 41 

2 Multimodality Phenotyping of lentiviral PD rat model: 1, 5, 8, 14, 41 

3 Optical imaging Phenotyping of lentiviral PD mouse model 1, 6, 14, 41, 8 

4 Multimodality Phenotyping of chronic 3NP HD rat model 5, 23 

5 MRI phenotyping of different ALS genotype mice 3, 8 

6 Multimodality Phenotyping of lentiviral HD rat model. 5, 25 

7 Multimodality Phenotyping of a lesional model of Huntington's disease in rats 3, 5, 41 

8 Implementation of animal brain atlases for automatic VOI definitions 1, 8, 23, 41 

9 

Multimodality Phenotyping of HD (chronic 3NP lesion) models in non-human 

primates 3, 23 

10 Multimodality Phenotyping of PD (chronic MPTP lesion) models in non-human 23 

Deliverables 0 5 1 2. 3,6,7,8,9,10 

Milestones 0 5 1 2 3,6,7,8,9,10 


EC Reporting * 

WP8.1: 

Identification of novel neuroimaging targets in neurodegenerative disease 

Objectives: Identification of novel targets for the future development of neuroimaging ligands in 

neurodegenerative disease including Alzheimer’s disease and related dementias. Whole genome microarray 

gene expression profiling will be performed in patients showing extensive pathology, elderly normal 

individuals with no cognitive impairment or neuropathology, and where possible individuals with no 

cognitive/motor impairment but with early stage pathology. 

Milestones: 

Milestone 

N° 


WP 

N° 

Partner N° 

Delivery/ 

Achieved 

date 

Nature 

Dissemina 

tion Level 

M8.1.0 Meeting with other partners 8.1 31 (Morris) 

1 (Jacobs) 

1 mo M PP 

3 (Aime) 


8 (vdLinden) 

M8.1.1 Sectioning of tissues for laser 8.1 31 (Morris) 4,9 mo R PP 

capture 

M8.1.2 Extraction and quality control of 8.1 31 (Morris) 7-12 mo R PP 

RNA 

M8.1.3 Amplification and array 

8.1 31(Morris) 10,15 mo R PP 

hybridisation 

M8.1.4 Western blot based validation of 

targets 

8.1 31(Morris) 13,18 mo R PP 

M8.1.5 

Discussion and selection of imaging 

targets 

8.1 31(Morris) 

1 (Jacobs) 

3 (Aime) 


8 (vdLinden) 

17,18mo R PP 

Deliverables: 

Deliverables 

N° 


WP 

N° 

Partner N° 

Delivery/ 

Achieved 

date 

Nature 

Dissemination 

Level


D8.1.0 

D8.1.1 

D8.1.2 

D8.1.3 

D8.1.4 

D8.1.5 

D8.1.6 

Meeting with DiMI partners for 

agreement and initiation of work 

plan 

Sectioning of tissues for laser 

capture 

Extraction and quality control of 

RNA 

Amplification and array 

hybridisation 

Western blot based validation of 

targets 

Discussion and selection of 

imaging targets 

reporting on the relevant and 


issues 

31(Morris) 

1 (Jacobs) 

3 (Aime) 


8 (vdLinden) 

1 mo R PP 

8.1 31(Morris) 4 mo R PP 

8.1 31(Morris) 7-12 mo R PP 

8.1 31(Morris) 10,15 mo R PP 

8.1 31(Morris) 13,18 mo R PP 

8.1 all 12,18mo R PP 



Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


0 Meeting and detailed project planning 31 

1 Sectioning of tissues for laser capture 31 

2 Extraction and quality control of RNA 31 

3 Amplification and array hybridisation 31 

4 Western blot based validation of targets 31 

5 Discussion and selection of imaging targets 

31 

Deliverables 0 

Milestones 0 D1 D2 D3 D4,D5 

Internal Reporting 

R1 R2 R3 

EC Reporting 

WP8.2 

Early diagnosis of neurodegenerative diseases 

Objectives: The aims of this workpackage are: 

• in a large scale study to map and follow the functional status of relevant neuroreceptor systems or 

other biomarkers in patients with neurodegenerative disorders and in a normal ageing population 

with the best methods currently available, 

• to validate currently used methods for PET or SPECT data analysis and to explore new approaches 

towards comparisons between normal and diseased brains taking brain atrophy into account, 

• to relate the findings from molecular imaging with progression ra tes and over-all prognosis, 

• on the basis of these results, to establish the diagnostic value of neuroreceptor imaging tools for a 

nosological classification in the elderly patient with memory disturban ces or parkinsonism, 

• on the basis of the obtained results to point to new areas for potential drug development. 

Milestones: 

Milestone 

N° 

M8.2.0 


Meeting with WP8.2 members for 

final agreement and initiation of 

work plan 

WP 

N° 

Partner N° 

8.2.1-8.2.8 1(Herholz) 

7(Knudsen) 

10(Bengel) 

17(Brooks) 

20(Ebmeier) 

Delivery/ 

Achieved 

date 

Nature 

Disseminati 

on Level 

1 mo R PP


M8.2.1 

M8.2.2 

M8.2.3 

Definition of coordinated and 

detailed study protocols for 

submission to ethics committees 

Start of clinical studies after 

approval by ethics committees (14 

mo) 

Recruitment of first patients and 

controls 

29(Leenders) 

34(Pappata) 

36(Perani) 

39(Salmon) 

45(Masdeu) 

33(Nordberg) 

8.2.1-8.2.8 1(Herholz) 

7(Knudsen) 

10(Bengel) 

17(Brooks) 

20(Ebmeier) 

29(Leenders) 

34(Pappata) 

36(Perani) 

39(Salmon) 

45(Masdeu) 

33(Nordberg 

8.2.1-8.2.8 1(Herholz) 

7(Knudsen) 

10(Bengel) 

17(Brooks) 

20(Ebmeier) 

29(Leenders) 

34(Pappata) 

36(Perani) 

39(Salmon) 

45(Masdeu) 

33(Nordberg 

8.2.1-8.2.8 1(Herholz) 

7(Knudsen) 

10(Bengel) 

17(Brooks) 

20(Ebmeier) 

29(Leenders) 

34(Pappata) 

36(Perani) 

39(Salmon) 

45(Masdeu) 

33(Nordberg 

6 mo R PP 

14 mo R PP 

18 mo R PP 

Deliverables: 

Deliverables 

N° 

D8.2.0 

D8.2.1 

D8.2.2 




work plan 

Protocol drafts to perform 

standardized and coordinated 

baseline studies 

Approvals from local ethics 

committees 

WP 

N° 

Partner N° 

Delivery/ 

Achieved 

date 

Nature 

Disseminati 

on Level 

8.2.1-8.2.8 1(Herholz) 1 mo R PP 

7(Knudsen) 

10(Bengel) 

17(Brooks) 

20(Ebmeier) 

29(Leenders) 

34(Pappata) 

36(Perani) 

39(Salmon) 

45(Masdeu) 

33(Nordberg) 

8.2.1-8.2.8 1(Herholz) 6 mo R PP 

7(Knudsen) 

10(Bengel) 

17(Brooks) 

20(Ebmeier) 

29(Leenders) 

34(Pappata) 

36(Perani) 

39(Salmon) 

45(Masdeu) 

33(Nordberg) 

8.2.1-8.2.8 1(Herholz) 

7(Knudsen) 

10(Bengel) 

17(Brooks) 

20(Ebmeier) 

12 mo R PP


D8.2.3 

Approval by the respective ethics 

committees will be presented to the 

EC before start of subject 

recruitment 

29(Leenders) 

34(Pappata) 

36(Perani) 

39(Salmon) 

45(Masdeu) 

33(Nordberg) 

8.2.1-8.2.8 1(Herholz) 

7(Knudsen) 

13 mo R PP 

D8.2.4 

Presentation of molecular 

techniques to be used in this 

protocol to other participants and to 

other interested parties, in particular 

pharmaceutical industry 

8.2.1-8.2.8 1(Herholz) 12,18 

7(Knudsen) 

mo 

R 

PP 

D8.2.5 Start of studies with inclusion of 8.2.1-8.2.8 

first patients and controls 

D8.2.6 

reporting on the relevant and 


issues 

1(Herholz) 

7(Knudsen) 

10(Bengel) 

17(Brooks) 

20(Ebmeier) 

29(Leenders) 

34(Pappata) 

36(Perani) 

39(Salmon) 

45(Masdeu) 

33(Nordberg) 

18 mo R PP 



Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


0 h WP10 members for final agreement and initiation of work plan 1,7,10,17,20,29,34,36,39,41,45,33 

1 Protocol drafts to perform baseline studies 1,7,10,17,20,29,34,36,39,41,45,33 

2 Approvals from local ethics committees 1,7,10,17,20,29,34,36,39,45,41,33 

3 Approval will be presented to the EC 1,7 

4 Presentation of techniques to other participants and industry 1,7 

5 Start of studies with inclusion of first patients and controls 1,7,10,17,20,29,34,36,39,41,45,33 

Deliverables 0 1 2 3 4,5 

Milestones 0 1 2 3 


EC Reporting 

WP9: Neuroinflammation 

Objectives: 

1. To develop and validate new methodology using established and new molecular imaging probes for 

MR and PET and investigate their ability to accurately reflect inflammation as compared to 

histological examinations. 

2. To investigate the involvement and time c ourse o f gliosis in relation to disease s everity or – 

progression, as revealed by molecular imaging. 

3. To relate gene expression profiling to the propagation and perpetuation of neuronal degeneration.


4. To determine whether blood-derived tissue plasminogen activator (tPA) can influence neuronal 

damage after cerebral ischemia. 

Milestones: 

Milestone 

N° 

M9.1 

Milestone title WP 

N° 

Partner N° Delivery/ 

A chieved 

date 

Nature Disseminat 

ion Level 

Q-space methodology implemented at 3T 9 

12 mo R PU 

MR-scanner and evaluated in healthy 

7, 1, 34 

subjects 

M9.2 Q-space MR-studies conducted in patients 

with multiple sclerosis 

9 7, 1, 34 

18 mo R PU 

M9.3 Blood-brain barrier integrity investigated in 9 7, 1, 34 18 mo R PU 

patients with multiple sclerosis by 3T MRI 

using bolus contrast agent administration 

M9.4 t-PAstop labelled with 11 C 9 42 6 mo R PP 

M9.5 Brain tissue distribution and metabolism of 9 9 mo R PU 

11 C-tPAstop-tPA complexes after 

42 

intravenous injection in control rats 

M9.6 Paramagnetically labeled tPA synthesized 9 42 9 mo R PP 

M9.7 Paramagnetically labeled tPA evaluated 9 42, 7 18 mo R PU 

after intravenous injection in control rats 

M9.8 Development of new PET radioligands for 9 36 12 mo R PP 

in vivo studies of microglia activation 

M9.9 New PET radioligands evaluated in healthy 9 36 18 mo R PU 

and in QA injected rats 

M9.10 Specificity and sensitivity of [ 11 C]PK11195 9 36, 5 18 mo R PU 

binding to identify microglial activation in 

QA rats through histological gold-standard 

evaluation 

M9.11 [ 11 C]PK11195 PET binding assessments in 

a rat stroke model 

9 5 18 mo R PU 

M9.12 Cross-sectional study in patients with 9 

18 mo R PU 

idiopathic and atypical Parkinsons disease 

with [ 

C](R) –PK11195 and [ 18 F]-dopa 

PET is completed 

17 

M9.13 Cross-sectional study in patients with MCI 9 

18 mo R PU 

and AD with [ 11 C]PIB and [ 11 C]deprenyl is 

completed 

33 

M9.14 Cross-sectional study in patients with 

multiple sclerosis and healthy control 

subjects with MR and [ 18 F]FDG is 

completed 

9 

1, 34,7 

18 mo R PU 

M9.15 Cross-sectional study in patients with mild 

cognitive impairment, Alzheimer’s disease, 

prion protein disease, or Huntington’s 

disease with [ 11 C](R) –PK11195 is 

completed 

9 

36 

18 mo R PU 

M9.16 Study of correlations between MR methods 

and standard invasive histopathology and 

autoradiography/in situ hybridisation in rats 

with and without meningitis completed 

9 

7,5,42 

18 mo R PU 

M9.17 Microarray techniques and proteomics in 9 18 mo R PU


patients with multiple sclerosis are 

compared to MR imaging methods 

7 

Deliverables: 

Deliverables 

N° 


WP Partner N° Delivery/ 

N° 

Achieved 

date 

D9.1 Establishment of in- and exclusion 9 7,1,17,33,34,36 3 mo R PP 

criteria for all patient groups 

D9.2 Specification of ethical aspects with 

particular emphasis on patients with 

degenerative brain disorders and 

dementia and national regulations 

D9.3 Specification of ethical aspects in 

animal models with particular 

emphasis on national regulations 

11 

Establishmen 

in other DiMI laboratories 

BBB, mic 

probes validated 

D9.6 Establishment of the ability of tPA 

and tPAstop-tPA complexes to cross 

the blood-brain barrier and tissue 

distribution 

Implemen 

imaging 

Initial histopatholo 

current neuroimaging markers of 

inflammation 

Initial blood-brain barrier integrity 

studies in patients with multiple 

sclerosis 

Initial in-vivo studies in mo 

cerebral ischemia 

D9.11 Cross-sectional MR and/or PET in 

patients with MS, parkinsonism, 

memory dysfunction, HD, and prion 

disease 

D9.12 Paramagnetically labeled tPA made 

available to other partners 

D9.13 Biochemical inflammatory markers, 

gene expression, and proteomics in 

patients 



issues 


Level 

9 7,1,17,33,34,36 

3 mo R PU 

9 7, 5,36,42 

3 mo R PU 

D9.4 t of [ C](R)-PK11195 9 7,5, 17,36 6 mo R PP 

D9.5 roglial probes or tPA 9 7,5,36,42 9 mo R PU 

9 42,5 6 mo R PU 

D9.7 tation of protocols for MR- 9 7,1,34 6 mo R PP 

D9.8 gical validation of 9 7,5 18 mo R PU 

D9.9 9 7,1,34 18 mo R PU 

D9.10 dels of 9 5 12 mo R PU 


9 7,1,17,33,34,36 18 mo R PU 

9 42,7,5 15 mo R PP 

9 7 12 mo R PU 

1 all 12 mo R PP


Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 

Task N° 

0 

1 

Title of Task 

Meeting and detailed project planning 

Implementation of MR-sequences and probes in other labs 

Partners N° 

7,1,5,17,33,34,36,42 

7,1,5, 34 

2 Developement and testing of probes for inflammation 7,36,42 

3 Testing animal models against histological examinations 

7,5,36,42 

4 Microarray and proteomics 

7,1,34 

5 Patient studies 7,1,17,33,34,36 

Deliverables 1,2,3 4,6,7 5, 12 8,10 9,11,13 

Milestones 4 5,6 1,8, 

2,3,7,9-17 

Internal Reporting R1 R2 

EC Reporting 

R3 

 

R4 

WP10: Stem cell trafficking in the CNS 

Objectives: Molecular imaging techniques open up new possibilities in our ability to study aspects of graft 

integration into the host brain circuitry with regard to several aspec ts: 

1. induction of NPC in vivo. 

2. tracking of labelled stem cells in vivo during their migration toward s the target site thus understanding 

the dynamics of survival and migration. 

3. monitoring the differentiation in normal host environment in vivo. 

4. possibility to provide image-guided control of differentiation due to expression of specific (trans)genes 

(cytokines, others). 

5. guiding the use of stem cells as vectors in gene therapy. 

Milestones: 

Milestone 

N° 


WP 

N° 

Partner N° 

M10.0 Common meeting of partners 10 1 (Jacobs) 

15(Kirik) 

25(Hoehn) 

8(vdLinden) 

M10.1 Improved techniques for labelling of 10.1 

NPC/NSC 10.2 

M10.2 Improved techniques for multimodal, 

high-resolution, sensitive 

imaging of NPC/NSC 

10.1 

10.2 

10.3 

10.5 

10.6 

10(Bengel) 

17( Brooks) 

26(Hofstra) 

9(Moonen) 


52(Sykova) 

1 (Jacobs) 

15(Kirik) 

25(Hoehn) 

10(Bengel) 

9(Moonen) 


52(Sykova) 

1 (Jacobs) 

15(Kirik) 

25(Hoehn) 

8(vdLinden) 

10(Bengel) 


9(Moonen) 


52(Sykova) 

Delivery/ 

Achieved 

date 

Nature 

Dissemination 

Level 

1 mo R PP 

6,12,18 R PP 

mo 

12,18 mo 

R PP 

M10.3 In vivo tran sduction of NPC using 10.5 8(vdLinden) 6,12 mo R PP 


LV vectors in mouse brain 

10.6 

M10.4 

Induction of proliferation and 10.5 8(vdLinden) 12,18 mo R 

PP 


differentiation after LV transduction 

10.6 

of NPC 

M10.5 Vectors serving controlled 

10.4 1 (Jacobs) 12,18 R PP


expression of imaging genes and 

cytokines 

M10.6 Recruitment of transduced NPC into 10.3 

regions of ischemia and/or 

10.5 

neurodegeneration 

10.6 

M10.7 Correlation of stem cell behaviour in 

vivo with metabolism and function 

10.3 

10.5 

10.6 

10.7 

10.5 15(Kirik) 

10(Bengel) 

mo 


9(Moonen) 


1 (Jacobs) 

15(Kirik) 

25(Hoehn) 


8(vdLinden) 


1 (Jacobs) 

15(Kirik) 

25(Hoehn) 

8(vdLinden) 

17(Brooks) 


12,18 R PP 

mo 

12,18 R PP 

mo 

Deliverables: 

Deliverables 

N° 


D10.0 Meeting with WP10 members for 


work plan 

D10.1 Common protocol for improved 

labelling of NP/NSC with MRI 

contrast agents and in vitro 

assessment of sensitivity of MRI 

detection of labelled cells. 

D10.2 Common protocol for magnetoliposomes 

targeting specifically 

NPC 

D10.3 Genetically engineered NPC/NSC 

expressing tkIRESluc 

D10.4 Detection of tkIRESluc expressing 

NPC/NSC using PET and optical 

imaging (12, 18 mo) 

D10.5 Common data for the detection 

sensitivity of NPC/NSC by MRI, 

PET and optical imaging 

D10.6 Assessment of behaviour of 

native/modified NPC/NSC with 

respect to toxicity due to labelling 

procedure, differentiation 

capabilities and homing potential 

D10.7 Vectors for controlled and specific 

tkIRESluc marker gene expression 

WP 

N° 

Partner N° 

10 1 (Jacobs) 

15(Kirik) 

25(Hoehn) 

8(vdLinden) 

10(Bengel) 

17(Brooks) 


9(Moonen) 


52(Sykova) 

Delivery/ 

Achieved 

date 

Nature 

Dissemination 

Level 

1 mo R PP 

10.1 15(Kirik) 6,12,18 mo R PP 

25(Hoehn) 

9(Moonen) 

52(Sykova) 

10.5 8(vdLinden) 


10.2 1 (Jacobs) 

15(Kirik) 

6(Maggi) 

10(Bengel) 


9(Moonen) 


10.3 

12,18 mo R PP 

6,12,18 

mo 

1 (Jacobs) 6, 12,18 

15(Kirik) 

mo 

25(Hoehn) 


10(Bengel) 

10.1 1 (Jacobs) 

6,12,18 R PP 

10.3 

mo 

10.5 

10.1 

10.3 

10.5 

25(Hoehn) 

8(vdLinden) 

10(Bengel) 


9(Moonen) 


52(Sykova) 

15(Kirik) 

25(Hoehn) 

8(vdLinden) 


10.4 1 (Jacobs) 

15(Kirik) 

6,12,18 

mo 

12,18 

mo 

R 

R 

R 

R 

PP 

PP 

PP 

PP


in NP/NSC 

D10.8 Multi-tracer 

microPET/microSPECT in the 

assessment of metabolism and 

function after NPC/NSC 

transplantation 



issues 

10(Bengel) 


9(Moonen) 


10.6 1 (Jacobs) 

17(Brooks) 

18 

mo 


R 

PP 


Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


0 Meeting and detailed project planning 1,15,25,8,6,10,17,26,9,14,23,52 

1 Labelling of NP/NSC with MRI contrast agents 15,25,8,9,52 

2 Genetic engineering NP/NSC for detection by PET and BLI 1,15,6,10,26,9,14 

3 Testing modified NP/NSC with respect to toxicity and homing 1,15,25,8,14,23,52 

4 Controlled expression of imaging marker and cytokine genes 1,15,6,10,26,9,14 

5 Induction and guidance of endogenous NPC by LV 8,14 

6 Imaging endogenous gene expression in response to NP/NSC 1,17,14,23 

Deliverables 0 1, 3, 4, 5, 6 1,2,3,4,5,6,7 1,2,3,4,5,6,7,8 

Milestones 0 1, 3 1,2,3,4,5,6,7 1,2,4,5,6,7 


EC Reporting


9B 2.2 Cardiovascular 

The major long-term goals of the jointly executed research activities of the cardiovascular programme within 

DiMI are: 

• to establish a molecular imaging toolbox of new noninvasive diagnostic tests for in vivo 

identification of various precursors and early biologic changes of cardiovascular diseases; 

• to develop molecular imaging approaches for non-invasive monitoring of novel molecular therapies 

for cardiovascular disease; 

• to use these molecular imaging tools for translational research from animal models to clinical 

application to increase possibilities and effectiveness of cardiovascular therapy, and finally; 

• to use these molecular imaging tools for monitoring of disease progression, risk stratification and 

assessment of therapeutic efficacy in the clinical setting. 

Current areas of major development in cardiovascular disease are included in the DiMI programme, and 

comprise 

1. biologic characterization of atherosclerotic plaques; 

2. myocardial ischemia and angiogenesis as a pathobiologic and therapeutic target; 

3. the usage of cell transplantation for preservation and restitution of myocardial and vascular integrity. 


the three specific WPs in the cardiovascular field: 

WP11.1 Multimodalitiy characterization of atherosclerotic plaques 

Objectives: 

1. To characterize the molecular activity of arteriosclerotic plaques developing in animal models 

(ApoE -/- mice without and with carotid ligation and rabbits under hypercholesterolemic diet) by 

animal-PET, animal-SPECT, optical imaging and PET/CT. 

2. To non-invasively characterize carotid plaques in patients using molecular imaging of apoptosis. 

Milestones: 

Milestone 

N° 


WP 

N° 

Partner N° 

M11.1.0 Common meeting of partners 11.1 40a (Schäfers) 

40b (Bremer) 

26 (Hofstra) 

2 (Clark) 

10 (Bengel) 

32 (Nicolay) 

37 (Poelmann) 

18 (Carrio) 

9 (Moonen) 

27 (Horn) 

28 (Laugier) 

M11.1.1 

M11.1.2 

Correlation of molecular imaging 

results in different plaque stages and 

animal strains 

Correlation of morphological and 

molecular imaging results in 

different plaque stages and animal 

strains 

11.1 40a (Schäfers) 

40b (Bremer) 


2 (Clark) 

10 (Bengel) 


40b (Bremer) 26 

(Hofstra) 

2 (Clark) 

10 (Bengel) 

18 (Carrio) 

32 (Nicolay) 

37 (Poelmann) 

9 (Moonen) 

Delivery/ 

Achieved 

date 

Nature 

Disseminati 

on Level 

1 mo R PP 

12,18 mo R PP 

12,18 mo R PP


M11.1.3 

M11.1.4 

Correlation of molecular imaging 

results with ex vivo 

histology/immuno-histochemistry 

Non-invasive assessment of 

apoptosis in human plaques and 

response to therapy 

27 (Horn) 

28 (Laugier) 


40b (Bremer) 26 

(Hofstra) 

2 (Clark) 

10 (Bengel) 

18 (Carrio) 

32 (Nicolay) 

37 (Poelmann) 

9 (Moonen) 

27 (Horn) 

28 (Laugier) 

12,18 mo R PP 

11.1 26 (Hofstra) 18 mo R PP 

Deliverables: 

Deliverables 

N° 

D11.1.0 

D11.1.1 

D11.1.2 

D11.1.3 

D11.1.4 




work plan 

Common data for glucose 

consumption (PET) in different 

plaque stages in ApoE -/- mice and 

rabbits 

Common data for MMP activity 

(PET, optical) in different plaque 

stages in ApoE -/- mice 

Common data for apoptosis in 

different plaque stages in ApoE -/- 

mice 

Common data for αvβ3 integrin 

expression (PET) in different plaque 


WP 

N° 

Partner N° 


40b (Bremer) 


2 (Clark) 

10 (Bengel) 

32 (Nicolay) 

37 (Poelmann) 

18 (Carrio) 

9 (Moonen) 

27 (Horn) 

28 (Laugier) 


2 (Clark) 

10 (Bengel) 


40b (Bremer) 

11.1 26 (Hofstra) 

40a (Schäfers) 


10(Bengel) 

Delivery/ 

Achieved 

date 


Level 

1 mo R PP 

6, 12 mo R PP 

12,18 mo R PP 

12,18 mo R PP 

18 mo R PP 

D11.1.5 

D11.1.6 

D11.1.7 

D11.1.8 

Common data for smooth muscle 

proliferation in different plaque 


Data for morphological 

characterization in different plaque 


Data for non-invasive detection of 

apoptosis in different plaque stages 

and effect of treatment in human 

carotid plaques 



issues 

11.1 18 (Carrio) 

40a (Schäfers) 

11.1 32 (Nicolay) 

37 (Poelmann) 

18 mo R PP 

18 mo R PP 

11.1 26 (Hofstra) 18 mo R PP 

11.1 all 12 mo R PP



Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


0 Meeting and detailed project planning 40a,40b,26,2,10,32,37,18,9,27,28 

1 Production of animal models (ApoE-/- and rabbits) 40a,26,2 

2 Animal-PET studies 40a,2,10,26,18 

3 Optical imaging of animals 

40b,26 

4 MRI of animals 

32,37,9 

5 human SPECT 26 

6 Correlation imaging & ex vivo 40a,40b,26,2,10,32,37,18,9,27,28 

Deliverables 0 1,2,3,4,5 1,2,3,4,5,6,7 

Milestones 0 1,2,3 1,2,3,4 

Internal Reporting R1 R2 

EC Reporting 

R3 

WP11.2 

Characterization of myocardial angiogenesis 

Objectives: 

1. to design vectors for tissue specific overexpression of reporter genes and proangiogenetic genes; 

2. to design vectors for monitoring of specific endogenous myocardial genes; 

3. to evaluate the feasibility of the aforementioned vectors for noninvasive in vivo imaging; 

4. to establish molecular imaging approaches for visualization of the expression of angiogenesis-related 

proteins; 

5. to determine the time course of integrin and MMP expression in ischemically damaged my ocardium; 

6. to characterize the relationship between gene expression, expression of related proteins, 

and 

functional/physiologic effects following angiogenesis induction in the heart; 

7. to establish tools for future specific monitoring of clinical myocardial angiogenesis therapy. 

Milestone s: 

Milestone 

N° 

M11.2.1 


Improved techniques for monitoring of 

myocardial gene expression 

WP 

N° 

M11.2.2 In vivo imaging of reporter genes using 11.2 

weak, specific promoters in the 

myocardium 

M11.2.3 

Improved techniques for imaging of 

myocardial expression of angiogenesisrelated 

genes and proteins 

M11.2.4 Baseline characterization of vectormediated 

11.2 

angiogenesis in 

myocardium 

M11.2.5 

Correlation of the expression of 

exogenous and endogenous genes in 

myocardium with other noninvasively 

determined biologic characteristics 

(contractile function, perfusion, 

Partner N° 

11.2 10(Bengel) 

9(Moonen) 

21( Fleischmann) 

1(Jacobs) 

41(van Laere) 

10(Bengel) 

9(Moonen) 

21( Fleischmann) 

1(Jacobs) 

41(van Laere) 

11.2 10(Bengel) 

9(Moonen) 

40(Schäfers) 

9(Moonen) 

32(Nicolay) 

37(Poelmann) 


10(Bengel) 

9(Moonen) 

40(Schäfers) 

9(Moonen) 

32(Nicolay) 

37(Poelmann) 


28(Laugier) 

11.2 10(Bengel) 

9(Moonen) 

40(Schäfers) 

9(Moonen) 

32(Nicolay) 

37(Poelmann) 

Delivery/ 

Achieved 

date 

Nature 

Disseminati 

on Level 

12 mo R PP 

12 mo R PP 

12 mo R PP 

18 mo R PP 

18 mo R PP


metabolism, apoptosis, integrin 

expression, MMP expression) 


28(Laugier) 

Deliverables: 

Deliverab Deliverable title 

les N° 

D11.2.1 

D11.2.2 

D11.2.3 

D11.2.4 

D11.2.5 

D11.2.6 

D11.2.7 

D11.2.8 

D11.2.9 

Vectors for induction and in vivo 

monitoring of angiogenesis gene 

therapy 

Vectors for monitoring of endogenous 

cardiovascular genes 

Meeting of WP participants for 

discussion and coordination of in vivo 

studies 

Common protocol for in vivo imaging 

of reporter gene expression 

Common protocol for in vivo imaging 

of integrin expression using MRI and 

PET 

Detection of myocardial MMP 

expression using PET and optical 

imaging 

Time course of expression of 

angiogenesis-related proteins in 

myocardial ischemia 

Repeatable non-invasive imaging 

approach for detection of endogenous 

cardiovascular gene expression 



WP 

N° 

Partner N° 

11.2 10(Bengel) 

9(Moonen) 


1(Jacobs) 

11.2 10(Bengel) 

9(Moonen) 


1(Jacobs) 

11.2 10(Bengel) 

9(Moonen) 


40(Schäfers) 

37(Poelmann) 

32(Nicolay) 

28(Laugier) 


1(Jacobs) 

41(van Laere) 

11.2 10(Bengel) 

9(Moonen) 

40(Schäfers) 


1(Jacobs) 

41(van Laere) 

11.2 10(Bengel) 

9(Moonen) 

40(Schäfers) 

37(Poelmann) 

32(Nicolay) 


11.2 40(Schäfers) 

10(Bengel) 


11.2 10(Bengel) 

9(Moonen) 

40(Schäfers) 

37(Poelmann) 

32(Nicolay) 

28(Laugier) 


11.2 10(Bengel) 

9(Moonen) 

41(van Laere) 

Delivery/ 

Achieved 

date 


on Level 

6 mo R PP 

6,12 mo R PP 

6 mo R PP 

6,12 mo R PP 

12 mo R PP 

12 mo R PP 

12,18 mo R PP 

18 mo R PP 

11.2 all 12 mo R PP 


Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


1 Development of vectors and in vitro evaluation 10,9,21,1 

2 Coordination and establishment of in vivo models and probes 10,9,40,37,32,28,26,41 

3 Meeting for planning of in vivo imaging studies 10,9,21,40,37,32,28,26,1,41 

4 In vivo imaging of protein expression in myocardial ischemia 10,9,40,37,32,28,26 

5 In vivo imaging of gene expression using novel vectors 10,9,40,41 

6 Multi-modality imaging of myocardial angiogenesis 10,9,40,37,32,28,26,41 

Deliverables 1,2,3,4 2,4,5,6,7 7,8,9 

Milestones 


EC Reporting


WP12: Stem cell therapy monitored by molecular imaging 

Objectives: 

1. To further develop methods for labelling stem cells and progenitor cells for visualization by optical, 

nuclear and MRI methods; 

2. To monitor longitudinally stem cell migration in vivo and their homing towards diseased tissues; 

3. To develop molecular imaging markers for non-invasive assessment of stem cell differentiation; 

4. To develop MI methods to track labelled stem cells as vectors for gene therapy. 

Milestones: 

Milestone 

N° 


M12.1 Multi-modality, sensitive, tracking of 

stem cells 

M12.2 Controlled expression of marker and 

therapeutic genes in transplanted stem 

cells in animal models 

M12.3 Administration of labelled stem cells: 

image-guided intracardiac injection, 

local intravascular injection, systemic 

intravascular injection 

M12.4 Non-invasive assessment of stem cell 

differentiation in vivo 

WP 

N° 

Partner N° 

12 9:Moonen, 

3:Aime, 

32:Nicolay, 

21: Fleischmann, 

37:Poelmann 

26:Hofstra, 

10:Bengel, 

18:Carrio 

1: Jacobs 

12 9:Moonen, 

10:Bengel 

12 9:Moonen, 

10:Bengel, 

21:Fleischmann 

12 21:Fleischmann, 

10:Bengel, 


9:Moonen 

37:Poelmann 

Delivery/ 

Achieved 

date 

Nature 

Disseminati 

on Level 

9 mo R PP 

18 mo R PP 

12 mo R PP 

18 mo R PP 

Deliverables: 

Delivera 

bles N° 


D12.1 Improved labelling of cardiac stem 

cells with MRI contrast agent and in 

vitro assessment of sensitivity of MRI 

detection of labelled cells 

D12.2 Transfection of cardiac stem cells with 

marker genes (e.g. luciferase, TK) that 

allow visualization using optical and 

PET/SPECT methods 

D12.3 Detection of modified stem cells 

using optical and PET/SPECT 

methods and evaluation of detection 

sensitivity 

D12.4 Assessment of viability of native and 

modified stem cells with respect to 

toxicity due to the labelling procedure, 

differentiation capabilities and homing 

WP 

N° 

Partner N° 

12 9:Moonen, 

3:Aime, 

32:Nicolay, 

21: Fleischmann, 

37:Poelmann 

12 26:Hofstra, 

10:Bengel, 

18:Carrio 

1:Jacobs 

12 37:Poelmann, 

26:Hofstra 

1:Jacobs 

12 9:Moonen, 

37:Poelmann 

Delivery/ 

Achieved 

date 

Nature 

Disseminati 

on Level 

6 mo R PP 

9 mo R PP 

9 mo R PP 

12 mo R PP


potential 

D12.5 Development of different 

administration approaches for labelled 

stem cells: image-guided intracardiac 

injection, local intravascular injection, 


D12.6 Assessment of stem cell homing and 

migration an established mouse model 

of cardiac 

D12.7 Development of target gene markers 

for identification of differentiation 

and demonstration in vitro 

D12.8 Transfection of stem cells with marker 

genes under control of the hsp70 

promoter or tissue-specific promoters 

and demonstration of image-guided 

expression control in vitro and in vivo 



12 9:Moonen, 

10:Bengel, 

21:Fleischmann 

12 21:Fleischmann 

26:Hofstra 

32:Nicolay 

1:Jacobs 

12 21:Fleischmann, 

10:Bengel, 


9:Moonen 

12 9:Moonen, 

10:Bengel 

12 mo R PP 

18 mo R PP 

18 mo R PP 

18 mo R PP 



Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


1 Labeling of stem cells with SPIOs. MR relaxivity measurements. 3,9,21,32,37 

2 Transfection with marker genes for PET/SPECT and optical imaging 1, 10,18,26 

3 Detection of modified stem cells using optical and PET/SPECT 1,23,26,37 

4 In vitro viability, differentiation and homing tests of stem cells 9,37 

5 Transplantation studies on animals under image guidance 10,9,21 

6 Analysis of suitable phenotype markers for differentiation studies 9,10,21,26 

7 Studies on image-guided expression control in vitro and in vivo 9,1 

8 Stem cell homing in a mouse model of cardiac ischemia 21, 1, 26, 32 

Deliverables 1 2,3 4,5 6,7,8 

Milestones 1 3 2,4 


EC Reporting


9B 2.3 Inflammation & Regeneration 

Our main goal in the five year period of this proposal is to visualize crucial events in the inflammatory 

process as follows: 

• investigate the role of gene regulation in models of inflammatory disease using bioluminescence 

imaging in transgenic reporter models; 

• develop novel transgenic reporter models for gene regulation and intracellular signalling; 

• establish novel and existing imaging probes specific for inflammation such as complement 

activation, immune cells and reactive oxygen species in animal models of inflammation; 

• develop technology for fluorescence imaging in deeper tissues; 

• clinical assessment of immune cell activation in patients with lung inflammatory disease. 


the specific WP13 in the field of inflammation: 

WP13 Molecular imaging of NF-κB activation and imaging chronic inflammation using optical probes 

Objectives: 

1. To test whether NF-κB, as assessed by molecular imaging reflect the disease states in mouse models 

of chronic inflammation disease using luciferase (bioluminescence). 

2. To cross-breed the Ncf1 mutation, the arthritis susceptible Aq gene in the Balb/c genetic 

background. 

3. Employ existing optical imaging probes (NIRF activated by cathepsin B and H, Annexin-5 in mouse 

inflammation models using fluorescence imaging. 

4. Seek to devise fluorescent probes sensitive to ROS for in vivo imaging. 

5. Devise novel near infrared probes for detection of complement activation. 

6. Validate targeted fluorescent probes to site of inflammation (αβ integrins) 

7. Assess utility of novel lanthanide based imaging probes in cell cultures for detection of ROS. 

8. Correlate various imaging probes in combination with imaging NF-κB activity during the onset and 

progression of autoimmune disease. 

9. Seek to devise fluorescence lifetime imaging, or time resolved imaging, or to influence the design of 

imaging systems so that they match the optical properties of the new probes. 

10. Macrophages play a pivotal role in inflammation. Using the ligand PK11195, which binds with high 

affinity to macrophages, we can monitor macrophage kinetics in vivo. PET scanning has been 

carried out using the 11C-labelled ligand and demonstrated an increased signal in response to 

inflammatory challenge in animal models. These studies have been extended to humans and shown 

that the pulmonary signals are affected by lung disease and by cigarette smoking. Initial validations 

using cellular resolution autoradiography of the tritiated analogue of the ligand show localisation to 

monocyte lineage cells. We now have access to PK 11195 labeled with a fluorescent marker and 

plan to use this in to validate the signal further and to define the phenotype of the cells responsible 

for the signal obtained by PET scanning, using FACS analysis. Using this fluorescent analogue we 

plan to carry out ex vivo and in vitro studies in animal models of inflammation. 

11. Make and validate new DNA constructs for generating new transgenic reporter mice with coexpression 

of reporter genes (co-expression cassettes of lucIREStk39gfp/dsred) controlled by NFκB. 

12. Exchange relevant models/knowledge to members of the consortium for validation using other 

imaging modalities.


Milestones: 

Milestone 

N° 


WP 

N° 

Partner N° 

M13.0 Meeting with partners. 13 43(Carlsen) 

11(Blomhoff) 

16(Holmdahl) 

40b(Bremer) 

17b(Jones) 

35(Parker) 

1(Jacobs) 

38(Rizo) 


M13.1 Imaging NF-κB dependent luciferase 

acitivity in two inflammation models 

M13.2 Imaging of cathepsin B and H, and 

Annexin 5 in autoimmune disease models. 

M13.3 Validating fluorescent macrophage ligand 

PK 11195 in vitro and in inflammation 

models (12, 18 mo). 

M13.4 Development of utility of optical imaging 

probes for complement activation and 

ROS detection. 

M13.5 Development of targeted probes (α β 

integrins) and validation in vitro and in 

inflammation models (18 mo) 

M13.6 Multimodal imaging of NF-κB activity in 

cell culture studies. 

13 43 (Carlsen) 


16(Holmdahl) 



40b(Bremer) 




17b(Jones) 

13 35(Parker) 

17b(Bremer) 

43(Carlsen) 


13 40b(Bremer) 

43(Carlsen) 


13 1(Jacobs) 

43 (Carlsen) 


Delivery/ 

Achieved 

date 


on Level 

3 mo R PP 

18 mo R PP 

18 mo R PP 

6,18 mo R PP 

18 mo P PP 

18 mo R 

12 mo R PP 

Deliverables: 

Deliverables 

N° 


D13.0 Meeting with WP13 members for 

initiation of work plan. 

D13.1 Imaging NF-κB dependent luciferase 

acitivity in transgenic autoimmune 

disease model. 

D13.2 Imaging cathepsin B and H, and 

Annexin 5 in inflammation model. 

D13.3 Validating fluorescent macrophage 

ligand PK 11195 in cell cultures and in 

inflammation models. 

D13.4 Development of utility of optical 

imaging probes for complement 

activation and ROS detection. 

D13.5 Establishment of a new mouse strain 

with spontaneous development of 

arthritis (with the Ncf1 mutation, a 

WP 

N° 

Partner N° 

13 43(Carlsen) 


16(Holmdahl) 

40b(Bremer) 

17b(Jones) 

35(Parker) 

1(Jacobs) 

38(Rizo) 






40b(Bremer) 




17b(Jones) 

13 35(Parker) 

17b(Bremer) 

43(Carlsen) 


13 16(Holmdahl) 

43 (Carlsen) 


Delivery/ 

Achieved 

date 


Level 

3 mo R PP 

12 mo R PP 

18 mo R PP 

6, 18 mo R PP 

18 mo P PP 

18 mo R PP


susceptible MHC class II gene on the 

Balb/c background) expressing the 

NF-κB luc transgene useful for image 

analysis of arthritis. 

D13.6 Development of targeted probes (α β 

integrins) and validation in vitro. 

D13.7 Establishment of DNA construct with 

NF-κB dependent expression of luc, tk 

and GFP/DsRed. Validation in cell 

cultures. 



13 40b(Bremer) 18 mo R PP 

13 1(Jacobs) 

43 (Carlsen) 


12 mo R 



Months 1-2-3 4-5-6 7-8-9 10-11-12 13-14-15 16-17-18 


0 Meeting and detailed project planning 43,11,16,17b,26,35,38,40b 

1 Imaging NF-kB activity in model of autoimmune disease 43,11 

2 Imaging fluorescent probes in model of autoimmune disease 43,11,40b 

3 Validating PK 11195 in model of autoimmune disease 43,11,17b 

4 Dev. of utility of optical probes of ROS and complement 38,43,11,17b 

5 Establishing new inflammation model for arthritis 16,43,11 

6 Dev. of targeted NIR probes 17b 

7 Prod. and valid. of new DNA construct for multimodal imaging 1,43,11 

Deliverables 0 3,4,5,6,7 1,2,3,4,5,6,7 1,2,3,4,5,6,7 2,3,4,5,6 2,3,4,5,6 

Milestones 0 1, 3 1,2,3,4,5,6,7 1,2,4,5,6,7 


EC Reporting 

WP10 + WP12 

Stem cell technology for the CNS and heart 

Please find both stem cell WPs under the respective section in Neuroscience and Cardiovascular Research. 

9.C Joint Activities to spread Excellence 

The activities for training, dissemination and communication will be managed by two Boards (BOT, 

BODIC), and their activities for the first 18 months are given in the respective WPs (=>WP15.1 and 

WP15.2). With respect to educational training courses, these will be established primarily by the DiMI- 

TTPs (an example is given on the next page for DiMI-TTP-8).


Antwerp Education Platform for Neuro-Imaging (microscopy and macroscopy) 

The University of Antwerp organizes a post academic one year course: European Higher Education Area: 

Advanced Academic Studies: Master in Biomedical Imaging 

Started: This academic year (2003) 

Number of students: 10 

Responsible: 

Prof. Dr. Annemie Van der Linden: macroscopic- and neuro imaging 

Prof. Dr. Frans Van Meir: microscopic imaging 

Applications: 

Master students in biomedical, medical, veterinary, dental, pharmaceutical sciences, Physiotherapy, bio, 

industrial, and civil engineering, physics, mathematics and informatics 

Content of the one year Master: 

The course provides advanced education in macroscopic, microscopic, the latest molecular imaging 

techniques and image processing for biomedical purposes. It is also an excellent preparation for a PhD in 

Biomedical Imaging. 

The Master program is modular and starts with a bridge program, either ‘Applied mathematics, System 

Theory and Signal Processing’ or ‘Structure and Function of the Human Body’. This depends on the 

background of the student. 

The student has to choose one of the following three options: 

1. Macroscopic Imaging: clinical and experimental, organ centered modules on CT, MRI, PET, 

SPECT, optical imaging, contrast agents, image processing, master thesis 

2. Microscopic Imaging: clinical and experimental, organ centered modules on LM, Fluorescence and 

confocal Microscopy, Atomic Force, EM, Stereology, image analysis master thesis. 

3. Neuro Imaging: clinical and experimental Macroscopic and Microscopic Imaging of the central 

nervous system, image analysis master thesis. 

Detailed content, focusing on the option Neuro Imaging: 

1. Biomedical imaging techniques including computer tomography (CT), magnetic resonance imaging 

(MRI), ultrasound, nuclear imaging (PET/SPECT) and endoscopy (6stp) 

2. Radio pharmacy and contrast agents (3 stp) 

3. Imaging of the central nervous system (6 stp) 

4. Microscopic techniques including light microscopy, fluorescence and confocal microscopy, electron 

microscopy, stereology and image analysis (6stp) 

5. Tracers and fluorescent probes (3 stp) 

6. Microscopy of the central nervous system (3 stp) 

7. The thesis focuses on research of the central nervous system using imaging techniques (15 stp)


9.4 Work package list Joint programme of activities (18 months 

period month 0 - 18) 

Work 

package 

No 

Work package title 

Lead 

contrac 

tor 

No 

Personmonths 

Start 

month 

End 

month 

Deliverable 

No 


WP1 

WP2 

Imaging technologies: ultra-high cerebral and 

heart imaging and quantitation with singlephoton 

emitters 

Quantitative microPET and multi-modality 

(PET/MR, OT/MR) scanner development 

13 89 0 18 D1.0-D1.9 

2 72 0 18 D2.0-D2.9 


WP3 

WP4.1 

Development of radiopharmaceutical probes for 

neurodegenerative diseases 

Development of library of innovative MRI 

Probes and improved methods for “in vivo” 

cellular labelling 

4 39 0 18 D3.0-D3.5 

3 117 0 18 D4.1.1-D4.1.6 

WP4.2 Development of Optical and Combined 


3 99 0 18 D4.2.1-D4.2.6 

Topic 1.3 Library of Animal Models 

WP5 Animal library for diagnostic molecular 

imaging in neuroscience & cardiovascular 

5 274 0 18 D5.0-D5.9 

WP6 

Evaluation of the role of estrogen and estrogen 

receptors in mouse model of Alzheimer disease 

and generation of novel reporter systems 

6 72 0 18 D6.1-D6.7 


WP7 

WP8.1 

Non-invasive phenotyping of animal models 

for neurodegenerative diseases 

Identification of novel neuroimaging targets in 

neurodegenerative disease 

8 93 0 18 D7.1-D7.10 

1 72 0 18 D8.1.0-D8.1.5 

WP8.2 Early diagnosis of neurodegenerative disease 1 85 0 18 D8.2.0- D8.2.2 

WP9 Neuroinflammation 7 138 0 18 D9.1- D9.14 

WP10 Stem cell trafficking in the CNS 1 165 0 18 D10.0- D10.9



WP11.1 

Multimodality characterization of 


10 75 0 18 D11.1.0-D11.1.8 

WP11.2 Characterization of myocardial angiogenesis 10 120 0 18 D11.2.1- 

D11.2.10 

WP 12 

Cardiac stem cell therapy monitored by 

Molecular Imaging 

9 141 0 18 D12.1-D12.9 


WP 13 

Molecular imaging of NF-κB activation and 

imaging chronic inflammation using optical 

probes 

11 78 0 18 D13.0-D13.8 

WP10 see topic 2.1 

WP12 see topic 2.2 

Integration, Training, Dissemination 

WP 14 Integrating activities 13 29 0 18 D14.1-D14.6 

WP 15.1 Activities of the Board for Training (BOT) 12 36 0 18 D15.1.1-D15.1.4 

WP 15.2 

Activities of the Board for Dissemination and 

Communication (BODIC) 

12 29 0 18 D15.2.1-D15.2.2 

Management 

WP16 Management Activities 1 80 0 18 D16.0-D16.7 

20 TOTAL 1920


9.5 Deliverables list 

Joint programme of activities (18 months period, month 00 - 18) 

Del. 

Deliverable name WP 

no. 1 no. 

Lead 

partic 

ipant 

Estimated 

indicative 

person 

months 

Nature 2 

Dissemin 

ation 

level 3 

Delivery 

date 4 

(proj. 

month) 


D1.1 Validation of TOHR imaging on rat 1 P13 24 R PP 6,12,18 mo 

brain models 

D1.2 Validation of TOHR imaging on rat heart 1 P13 20 R PP 6,12,18 mo 

models 

D1.3 Validation of TOHR imaging on mouse 1 P13 9 R PP 12,18 mo 

heart models 

D1.4 Hardware multipinhole SPECT 1 P13 9 R PP 6,12,18 mo 

collimator prototype 

D1.5 Software for multipinhole SPECT 1 P13 13 R PP 6,12,18 mo 


D1.6 Software for registration of MicroSPECT 1 P13 14 R PP 6,12,18 mo 

data with structural data 

D1.7 annual reporting on the relevant and 1 P13 0 R PP 12 mo 


D2.0 Meeting with WP2 members for final 2 P2 0 R PP 1 mo 


D2.1 Adapt Monte Carlo code 2 P2 6 R PP 6,12 mo 

(SimSET+GEANT4) to model 

microPET 

D2.2 Implement PROMIS 3D image 2 P2 6 R PP 6,12 mo 

reconstruction algorithm on PC-cluster 

D2.3 Implement singles and windowed 2 P2 6 R PP 12,18 mo 

coincidence mode transmission scanning 

on microPET, and implement iterative 

reconstruction of this data 

D2.4 Verification of microPET data 2 P2 21 R PP 18 mo 

corrections and image reconstruction 

D2.5 Measure and assess magnetic field 2 P2 3 R PP 6,12 mo 

properties of 1T split pair magnet 

D2.6 Demonstrate the spatial and temporal 2 P2 3 R PP 6,12 mo 


D2.7 Design and build split coil active shield 2 P2 6 R PP 12,18 mo 

gradients 

D2.8 Investigate the performance of a PET 2 P2 6 R PP 12,18 mo 

1 Deliverable numbers in order of delivery dates: D1 – Dn 

2 Please indicate the nature of the deliverable using one of the following codes: 

R = Report 

P = Prototype 

D = Demonstrator 

O = Other 

3 Please indicate the dissemination level using one of the following codes: 

PU = Public 

PP = Restricted to other programme participants (including the Commission Services). 

RE = Restricted to a group specified by the consortium (including the Commission Services). 

CO = Confidential, only for members of the consortium (including the Commission Services). 

4 Month in which the deliverables will be available. Month 1 marking the start of the project, and all delivery dates 

being relative to this start date.


detector block operating in the MR 

imager 



2 P2 6 R PP 18 mo 


D3.0 Report of meeting with WP 3 members 

P4 0 R PP 1 mo 

for final agreement and initiation of work 

plan 

D3.1 Precursors for radiolabelling with 3 P4 36 R PP 9 mo 

fluorine-18 or carbon-11 of tracer agents 

for dopamine transporter (DAT) 

D3.2 Written instructions for radiolabelling 3 P4 0 R PP 12 mo 



using deliverable D3.1 

D3.3 Software for quantification of dopamine 3 P4 3 R PP 18 mo 

transporter in vivo using developed 18 F 

or 11 C labelled tracer agent and positron 

emission tomography 

D3.4 Results of evaluation in vitro and in vivo 3 P4 0 R PP 18 mo 

in animals of fluorine-18 or carbon-11 

labelled tracer agents for dopamine 

transporter 

D3.5 Precursors for radiolabelling with 3 P4 36 R PP 12 mo 

fluorine-18 or carbon-11of tracer agents 

for in vivo visualisation of amyloid 


D3.6 Written instructions for radiolabelling 3 P4 0 R PP 18mo 


agents for in vivo visualisation of 

amyloid plaques in brain 

D3.7 Results of evaluation in vitro of fluorine- 3 P4 0 R PP 18 mo 

18 or carbon-11 labelled tracer agents for 


D3.8 Report of meeting with WP 3 members 

for discussion of 1 st year results and 

3 P4 0 R PP 13 mo 

further work plan 



D4.1.1 Identification of high sensitive Gd(III)- 4.1 P3 30 R PP 12 mo 

based Imaging Probes endowed with 

specific targeting ability. 

D4.1.2 Identification of high sensitive 4.1 P3 12. R PP 6 mo 

paramagnetic CEST agents responsive 

towards pH and temperature 

D4.1.3 Report on meeting amongst WP4.1 4.1 P3 0 R PP 12 mo 

members 

D4.1.4 Optimised procedures for cell-labelling 4.1 P3 0 R PP 9 mo 

using soluble Gd(III)-based and CEST 

Imaging Probes ( pynocitosis and 

electroporation) or insoluble Gd(III)- 

based bio-degradable particles (for 

labelling macrophages) 

D4.1.5 Identification of Imaging Probes 4.1 P3 24 R PP 18 mo 

(Gd(III)-based and CEST agents) for 

targeting vulnerable plaques 

D4.1.6 Set-up of MRI protocols “in vivo” for 4.1 P3 24 R PP 18 mo 

evaluating and optimising the diagnostic 

properties of the developed Imaging 

Probes 

D.4.1.7 annual reporting on the relevant and 4.1 P3 0 R PP 12 mo



D4.2.1 Lanthanide-based Optical Probes 

responsive to intracellular analytes. 

D4.2.2 Report on 2 nd meeting among WP 

members 

D4.2.3 A lanthanide based Optical Probe for 

DNA-targeting. 

D4.2.4 Long-lived Optical Probes based on an 

efficient energy transfer between a 

Lanthanide metal complex and a 

Selected chromophore. 

D4.2.5 Combined Probes containing several 

chelating moieties (10-50) mostly 

charged with Gd(III) ions (for MRI 

visualisation) and containing one or few 

sites occupied by luminescent lanthanide 

ions or by lanthanide radioisotopes 

endowed with suitable emitting 

properties for Optical Imaging and PET 

detection, respectively. 

D4.2.6 annual reporting on the relevant and 


4.2 P3 21 R PP 18 mo 

4.2 P3 0 R PP 12 mo 

4.2 P3 27 R PP 12 mo 

4.2 P3 21 R PP 9 mo 

4.2 P3 30 R PP 18 mo 

4.3 P3 0 R PP 12 mo 

Topic 1.3 Animal Models 




in the pre-established (a) animal models, 

5 P5 58 R PP 6 mo 

18 mo 

and in (b) new animal models with 

invasive methods 

D5.2 Characterisation of biochemical, 5 P5 80 R PP 18 mo 


alterations in the different experimental 

models and characterization of viralmediated 

gene transfer in the selected 

animal models of disease. 

D5.3 Characterization of the glial and 5 P5 30 R PP 12 mo 

inflammatory reaction in models of 

stroke, PD, and AD. 

D5.4 Integrating imaging with 5 P5 61 R PP 18 mo 

neuropathological and molecular 

alterations in stroke, PD, AD, and HD; 

and non-invasive imaging of viralmediated 

gene transfer in HSP. 

Connection with related WPs. 

D5.5 Characterisation of biochemical, 5 P5 15 R PP 12 mo 


alterations in the ischemic heart, and 

biological characterization of 


D5.6 Labelling of progenitor and/or stem cells 5 P5 12 R PP 6 mo 

and evaluation of the biological effects in 

vitro for cardiovascular research. 

D5.7 Integrating imaging with pathological 5 P5 30 R PP 18 mo 

and molecular alterations in each model 

of cardiovascular diseases; reidentification 

of stem cells after 

transplantation into the injured mouse 

heart Connection with related WPs. 


disease. Exchange of animal models 

within the network. Links to other WPs. 

5 P5 26 R PP 18 mo




D6.0 Common meeting of partners 6 P6 0 R PP 1 mo 

D6.1 Assessment of the pharmacological 6 P6 18 R PP 18 mo 

activity of estrogen and selected ER 

mediators (SERMs) on brain 

inflammation 

D6.2 Identification of the mechanisms 6 P6 24 R PP 15 mo 

involved in estrogen anti-inflammatory 

activity 

D6.3 Vectors genetically engineered to 6 P6 4 R PP 6 mo 

express luciferase and D2 receptor 

(lucIRESD2) 

D 6.4 Stably transfected cells with the 6 P6 4 R PP 12 mo 

lucIRESD2 reporter 

D 6.5 Assessment of ratio of expression of the 6 P6 10 R PP 12 mo 

two reporter in vivo 

D 6.6 Common data for the detection 6 P6 12 R PP 18 mo 

sensitivity of cells expressing 

lucIRESD2 reporter by optical imaging 

and PET 



6 P6 0 R PP 12 mo 


D7.0 Common meeting of partners 7 P8 0 R PP 1 mo 

D7.1 Multimodality Phenotyping of 6-0HDA 7 P8 16 R PP 9 mo 

PD rat model 

D7.2 Multimodality Phenotyping of lentiviral 

PD rat model: 

7 P8 22 R PP 18 mo 

D7.3 Optical imaging Phenotyping of 


D7.4 Multimodality Phenotyping of chronic 

3NP HD rat model: 

D7.5 MRI phenotyping of different ALS 



lentiviral HD rat model. 

D7.7 Multimodality Phenotyping of a 

lesional model of Huntington's disease 

in rats 

D7.8 Implementation of animal brain atlases 

for automatic VOI definitions 

7 P8 20 R PP 18 mo 

7 P8 6 R PP 18 mo 

7 P8 4 R PP 6 mo 

7 P8 6 R PP 18 mo 

7 P8 4 R PP 12 mo 

7 P8 12 R PP 18 mo 



D8.1.0 Meeting with DiMI members for 

P31 0 R PP 1 mo 


D8.1.1 Sectioning of tissues for laser capture 8.1 P31 18 R PP 4 mo 

D8.1.2 Extraction and quality control of RNA 8.1 P31 18 R PP 7-12 mo 

D8.1.3 Amplification and array hybridisation 8.1 P31 18 R PP 10,15 mo 

D8.1.4 Western blot based validation of targets 8.1 P31 18 R PP 13,18 mo 

D8.1.5 Discussion and selection of imaging 8.1 P31 0 R PP 12,18 mo 

targets 

D8.1.6 annual reporting on the relevant and 8.1 P31 0 R PP 12 mo



D8.2.0 Meeting with WP8.2 members for final 8.2 P1 0 R PP 1 mo 


D8.2.1 Protocol drafts to perform standardized 8.2 P1 6,5 R PP 6 mo 

and coordinated baseline studies 

D8.2.2 Approvals from local ethics committees 8.2 P1 0 R PP 12 mo 

D8.2.3 Approval by the respective ethics 8.2 P1 0 R PP 13 mo 

committees will be presented to the EC 

before start of subject recruitment 

D8.2.4 Presentation of molecular techniques to 8.2 P1 0 R PP 12,18mo 

be used in this protocol to other 

participants and to other interested 

parties, in particular pharmaceutical 

industry 

D8.2.5 Start of studies with inclusion of first 8.2 P1 16 R PP 18 mo 

patients and controls 

D8.2.6 reporting on the relevant and applicable 8.2 P1 0 R PP 12 mo 

regulations of ethical issues 

D9.1 Establishment of in- and exclusion 9 P7 0 R PP 3 mo 

criteria for all patient groups 

D9.2 Specification of ethical aspects with 9 P7 0 R PU 3 mo 

particular emphasis on patients with 

degenerative brain disorders and 

dementia and national regulations 

D9.3 Specification of ethical aspects in 9 P7 0 R PU 3 mo 

animal models with particular emphasis 

on national regulations 

D9.4 Establishment of [ 11 C](R)-PK11195 in 9 P7 4 R PP 6 mo 

other DiMI laboratories 

D9.5 BBB, microglial probes or tPA probes 9 P7 20 R PU 9 mo 

validated 

D9.6 Establishment of the ability of tPA and 9 P7 7 R PU 6 mo 

tPAstop-tPA complexes to cross the 

blood-brain barrier and tissue 

distribution 

D9.7 Implementation of protocols for MRimaging 

9 P7 3 R PP 6 mo 

D9.8 Initial histopathological validation of 9 P7 4 R PU 18 mo 

current neuroimaging markers of 

inflammation 

D9.9 Initial blood-brain barrier integrity 9 P7 9 R PU 18 mo 

studies in patients with multiple 

sclerosis 

D9.10 Initial in-vivo studies in models of 9 P7 8 R PU 12 mo 


D9.11 Cross-sectional MR and/or PET in 9 P7 70 R PU 18 mo 

patients with MS, parkinsonism, 

memory dysfunction, HD, and prion 

disease 

D9.12 Paramagnetically labeled tPA made 9 P7 8 R PP 15 mo 

available to other partners 

D9.13 Biochemical inflammatory markers, 9 P7 6 R PU 12 mo 

gene expression, and proteomics in 

patients 

D9.14 reporting on the relevant and applicable 9 P7 0 R PP 12 mo 

regulations of ethical issues 



D10.1 Common protocol for improved 10 P1 18 R PP 6,12,18 mo 

labelling of NP/NSC with MRI contrast 

agents and in vitro assessment of


sensitivity of MRI detection of labelled 

cells. 

D10.2 Common protocol for magnetoliposomes 

targeting specifically NPC 

D10.3 Genetically engineered NPC/NSC 

expressing tkIRESluc 

D10.4 Detection of tkIRESluc expressing 

NPC/NSC using PET and optical 

imaging (12, 18 mo) 

D10.5 Common data for the detection 

sensitivity of NPC/NSC by MRI, PET 

and optical imaging 

D10.6 Assessment of behaviour of 

native/modified NPC/NSC with respect 

to toxicity due to labelling procedure, 


potential 

D10.7 Vectors for controlled and specific 

tkIRESluc marker gene expression in 

NP/NSC 

D10.8 Multi-tracer microPET/microSPECT in 

the assessment of metabolism and 

function after NPC/NSC transplantation 



10 P1 12 R PP 12,18 mo 

10 P1 40 R PP 6,12,18 mo 

10 P1 18 R PP 6,12,18 mo 

10 P1 6 R PP 6,12,18 mo 

10 P1 48 R PP 6,12,18 mo 

10 P1 18 R PP 12,18 mo 

10 P1 18 R PP 18 mo 

10 P1 0 R PP 12 mo 


D11.1.0 Meeting with WP11.1 members for 11.1 P40a 0 R PP 1 mo 

final agreement and initiation of work 

plan 

D11.1.1 Common data for glucose consumption 11.1 P40a 3 R PP 6, 12 mo 

(PET) in different plaque stages in 

ApoE -/- mice and rabbits 

D11.1.2 Common data for MMP activity (PET, 11.1 P40a 15 R PP 12,18 mo 

optical) in different plaque stages in 

ApoE -/- mice 

D11.1.3 Common data for apoptosis in different 11.1 P40a 0 R PP 12,18 mo 

plaque stages in ApoE -/- mice 

D11.1.4 Common data for αvβ3 integrin 11.1 P40a 0 R PP 18 mo 

expression (PET) in different plaque 


D11.1.5 Common data for smooth muscle 

proliferation in different plaque stages 

in ApoE -/- mice 

D11.1.6 Data for morphological characterization 

in different plaque stages in ApoE -/- 

mice 

D11.1.7 Data for non-invasive detection of 

apoptosis in different plaque stages and 

effect of treatment in human carotid 

plaques 

D11.1.8 annual reporting on the relevant and 


D11.2.1 Vectors for induction and in vivo 

monitoring of angiogenesis gene 

therapy 

D11.2.2 Vectors for monitoring of endogenous 


D11.2.3 Meeting of WP participants for 

discussion and coordination of in vivo 

studies 

11.1 P40a 0 R PP 18 mo 

11.1 P40a 0 R PP 18 mo 

11.1 P40a 9 R PP 18 mo 

11.1 P40a 0 R PP 12 mo 

11.2 P10 6 R PP 6 mo 

11.2 P10 12 R PP 6,12 mo 

11.2 P10 0 R PP 6 mo


D11.2.4 Common protocol for in vivo imaging 11.2 P10 12 R PP 6,12 mo 

of reporter gene expression 

D11.2.5 Common protocol for in vivo imaging 11.2 P10 18 R PP 12 mo 

of integrin expression using MRI and 

PET 

D11.2.6 Detection of myocardial MMP 11.2 P10 12 R PP 12 mo 

expression using PET and optical 

imaging 

D11.2.7 Time course of expression of 11.2 P10 42 R PP 12,18 mo 

angiogenesis-related proteins in 

myocardial ischemia 

D11.2.8 Repeatable non-invasive imaging 11.2 P10 18 R PP 18 mo 

approach for detection of endogenous 

cardiovascular gene expression 

D11.2.9 annual reporting on the relevant and 11.2 P10 0 R PP 12 mo 


D12.1 Improved labelling of cardiac stem cells 12 P9 27 R PP 6 mo 

with MRI contrast agent and in vitro 

assessment of sensitivity of MRI 

detection of labelled cells 

D12.2 Transfection of cardiac stem cells with 12 P9 24 R PP 9 mo 

marker genes (e.g. luciferase, TK) that 

allow visualization using optical and 

PET/SPECT methods 

D12.3 Detection of modified stem cells using 12 P9 0 R PP 9 mo 

optical and PET/SPECT methods and 

evaluation of detection sensitivity 

D12.4 Assessment of viability of native and 12 P9 12 R PP 12 mo 

modified stem cells with respect to 

toxicity due to the labelling procedure, 


potential 

D12.5 Development of different administration 12 P9 12 R PP 12 mo 

approaches for labelled stem cells: 

image-guided intracardiac injection, 

local intravascular injection, systemic 

intravascular injection 

D12.6 Assessment of stem cell homing and 12 P9 24 R PP 18 mo 

migration an established mouse model 

of cardiac 

D12.7 Development of target gene markers for 12 P9 24 R PP 18 mo 

identification of differentiation and 

demonstration in vitro 

D12.8 Transfection of stem cells with marker 12 P9 18 R PP 18 mo 

genes under control of the hsp70 

promoter or tissue-specific promoters 

and demonstration of image-guided 

expression control in vitro and in vivo 




D13.0 Meeting with WP13 members for 13 P11 0 R PP 3 mo 

initiation of work plan. 

D13.1 Imaging NF-κB dependent luciferase 13 P11 15 R PP 12 mo 

acitivity in transgenic autoimmune 

disease model. 

D13.2 Imaging cathepsin B and H, and 13 P11 9,5 R PP 18 mo 

Annexin 5 in inflammation model. 

D13.3 Validating fluorescent macrophage 13 P11 4,5 R PP 6, 18 mo 

ligand PK 11195 in cell cultures and in


inflammation models. 

D13.4 Development of utility of optical 

imaging probes for complement 

activation and ROS detection. 

D13.5 Establishment of a new mouse strain with 

spontaneous development of arthritis (with 

the Ncf1 mutation, a susceptible MHC class 

II gene on the Balb/c background) 

expressing the NF-κB luc transgene useful 

for image analysis of arthritis. 

D13.6 Development of targeted probes (α β 

integrins) and validation in vitro. 

D13.7 Establishment of DNA construct with 

NF-κB dependent expression of luc, tk 

and GFP/DsRed. Validation in cell 

cultures. 



D10.0-8 Please, see Topic 2.1 Neuroscience 

D12.1-8 Please, see Topic 2.2 Cardiovascular 

13 P11 18,5 P PP 18 mo 

13 P11 15 R PP 18 mo 

13 P11 6 R PP 18 mo 

13 P11 9,5 R 12 mo 

13 P11 0 R PP 12 mo 

Integration, Training & Dissemination 

D14.1 Electronic tools for an easy website 14 P13 7 R PU 6 mo 

update of the integration levels 

D14.2 Measureables for integration by JPRA 14 P13 5 R PU 12 mo 

D14.3 Measureables of performance of DiMI- 14 P13 5 R PU 12 mo 

TTPs 

D14.4 Measureables of successful exchange 14 P13 5 R PU 12 mo 

and mobility 

D14.5 Measureables for successful integration 14 P13 4 R PU 12 mo 

of SMEs 

D14.6 Measureables for integration through 14 P13 3 R PU 12 mo 

specific integrative tools 

D15.1.1 Exchange and mobility of researchers 15.1 P12 10 R PU 3,6,18 mo 

and students 

D15.1.2 Organisation of short and medium-term 15.1 P12 10 R PU 3,6,18 mo 

training 

D15.1.3 Organisation of European courses for 15.1 P12 10 R PU 3,6,18 mo 

doctoral students in Diagnostic 

Molecular Imaging and Annual Meeting 

D15.1.4 Raising of awareness 15.1 P12 6 R PU 3,6,12 mo 

D15.2.1 Organisation of the web site 15.2 P12 5 R PU 3,6,10,12,18 

mo 

D15.2.2 APDAC 15.2 P12 4 R 3,6,12 mo 

D16.1.0 Meeting with WP16 participants to 16 P1 0 R 1 

define tasks & scheduling 

D16.1.1 Organisational chart with all contacts by 16 P1 8 R 3 

partner (scientific, legal, financial, 

administrative) 

D16.1.2 Organisational chart with all 16 P1 6 R 3 

Governance Bodies and members 

D16.1.3 Setting –up of reporting procedures 16 P1 12 R 3 

(between partners and Scientific 

Administrators 

D16.1.4 Setting –up of financial and accounting 16 P1 12 R 3 

reporting procedure of the consortium 

resources 

D16.1.5 EC Annual report 16 P1 18 R 12 

D16.1.6 Financial report including audit 16 P1 18 R 12 

certificates 

D16.1.7 Preparation of JPA for the next period 16 P1 6 R 6-12; 18-24.. 

TOTAL 

1920

P 


9.6 Work Package Description 

WP1: Ultra-high resolution cerebral and heart imaging and quantitation with single-photon 

emitters 

Workpackage number WP1 Start date or starting event: Start of program 

Activity Type Other Specific Activities 

Participant id P13:Meynadier P4:Guilloteau P10: Bengel P30:Mastrippolito P41:vLaere P8: vdLinden 

Person-months 

per participant 

P13: 12 P4: 6 P10: 6 P30: 18 P41: 42 P8: 5 

Objectives 

1. to demonstrate single-photon emitter tomographic imaging and quantitation of the rodent brain and heart, at 

sub-0.5 mm imaging resolution. 

2. to validate dedicated protocols for gated cardiac imaging of the mouse heart 

3. to validate dedicated protocols for neurodegenerative studies in the rat brain 

4. to combine high resolution scintigraphic images with other modalities, i.e. (micro)MRI and (micro)CT. 

5. to analyze the count rate to resolution trade-off will be analyzed in relation with the administered radioligand 

activity currently possible for brain and heart imaging. 

Description of subprojects 

The work package consists of two applications of developments in high-resolution single-photon scintigraphy (SPECT) 

dedicated to animal imaging, in particular mouse and rat imaging. 

1. TOHR is a high-energy photon counter associated with an original high resolution, high efficiency focussing 

collimator (Valda Ochoa et al, 97). The principle of operation is based on the sequential acquisition of individual voxels 

which size is defined by the geometrical properties of several (20) tungsten collimators all focussed on the same spot. In 

order to achieve a very good signal to noise ratio, another originality is to use radiolabelled tracers that emits two 

photons with no angular correlation at each decay ( 125 I, 123 I, 111 In...). The selection of detected events is made at the 

same time by the coincidence of the two photons and by the spatial selection made by the collimator around the focal 

point. The image is then made sequentially by moving the animal in the detector and the scanned region can be adjusted 

to the region of interest. A system with a spatial resolution of 0.4 mm (0.7 mm in the single photon mode) is under 

development. Its performance is adapted to the imaging of small volumes, such as the brain or heart of mice. The WP 

will assess the relevance of the technique for those two applications, which are poorly imaged by conventional isotope 

imaging such as SPECT or PET. 

1.1 Validation and use for cerebral imaging : Cerebral imaging will be validated in the normal rat and then will be 

applied to rat models of neurodegenerative disorders (Parkinson’s disease). In vivo quantification of the dopamine 

123 

transporter localized on the dopaminergic nerve endings with the specific tracer P 

PI-PE2I (Chalon et al., 1999) or 

123 

PI-FPCIT (Booij et al, 1999) will allow to follow in vivo the evolution of degeneration and in a second phase the 

effects of new neuroprotective/neurorepairing strategies. 

1.2 Validation and use for cardio imaging : For cardiac imaging, gated acquisition is possible using the high 

temporal resolution of the equipment. Such gating will be tested and dedicated protocols will be developed for this 

specific application. Perfusion and function studies will be performed in normal rats and mice and in a mouse 

infarct model exhibiting global and regional impairments. Echocardiography and MRI are available for validation. 

2. A second, cost-effective approach will be investigated using a clinical gamma camera equipped with one or several


pinhole collimators of small aperture. Initially, comparative experiments will be carried out with the new microPET and 

a clinical gamma camera equipped with a single hole pinhole collimator with small aperture. At the same time, a multipinhole 

collimator will be designed with the aim of improving the system sensitivity. Software for calibration and 

reconstruction will be developed and a prototype collimator will be built, resulting in a high performance microSPECT 

scanner. Co-registration with other modalities, in particular MRI and CT scan, will be studied for both the TOHR and 

pinhole-microSPECT applications. Reconstruction techniques for pinhole SPECT with anatomically-based MAP 

reconstruction using MicroSPECT and microMRI data (with implicit partial volume correction) will be evaluated for 

the rat brain. 

Deliverables 

D1.1 validation of TOHR imaging on rat brain models (mo 12) 

D1.2 validation of TOHR imaging on rat heart models (mo 18) 

D1.3 validation of TOHR imaging on mouse heart models (mo 18) 

D1.4 Hardware multipinhole SPECT collimator prototype (mo 18) 

D1.5 Software for multipinhole SPECT reconstruction (mo12) 

D1.6 Software for registration of MicroSPECT data with structural data (mo 12) 

D1.7 reporting on the relevant and applicable regulations of ethical issues (mo 12) 

Milestones and expected results 

M1.1 TOHR test on rat brain imaging (12 mo) 

M1.2 TOHR test on cardiac mouse imaging (18 mo) 

M1.3 multipinhole microSPECT design (mo 12) 

M1.4 demonstration of registration accuracy of intermodality registration (mo 12) 

M1.5 demonstration of A-MAP reconstruction for MicroSPECT/microMRI data (mo 18) 

Ethical issues 

Countries were research is carried : France, Germany and Belgium 

Research on humans : none 

Research on genetically modified organisms: yes (Lentiviral-induced alpha-synuclein expression, studies currently 

performed in Leuven) 

Research on animals: rats (brain studies, heart studies: total of approximately 30 rats), mice (heart studies: total of 

approximately 10 mice) 

Literature and patents WP1 

1. Valda Ochoa A, Ploux L, Mastrippolito R, Charon Y, Lanièce P, Pinot L, Valentin L ; ‘An original Emission Tomograph for in vivo Brain Imaging 

of Small Animals’ ; IEEE Trans.Nucl.Sci. (1997), 44(4), p.1533-1537. 

2. R. Mastrippolito, Y. Charon, P. Lanièce, L. Ploux, L. Pinot, R. Siebert, H. Tricoire, A. Valda-Ochoa, L. Valentin. Brevet n°95 07345: 

"Tomographe haute résolution pour l'imagerie sur des petits animaux". 

3. R. Mastrippolito, Y. Charon, P. Lanièce, L. Ploux, L. Pinot, R. Siebert, H. Tricoire, A. Valda-Ochoa, L. Valentin. Brevet n°95 12508: 

"Collimateurs haute résolution". 

4. Chalon S, Garreau L, Emond P, Zimmer L, Vilar Mp, Besnard JC, Guilloteau D: Pharmacological characterization of (e)-N-(3-iodoprop-2-enyl)- 

2beta-carbomethoxy 3beta (4’ methylphenyl) nortropane or PE2I as a selective and potent inhibitor of the neuronal dopamine transporter. Journal 

of Pharmacology and Experimental Therapeutics, 1999, 291(2):648-654. 

5. Beque D, Nuyts J, Bormans G, Suetens P, Dupont P.T Characterization of pinhole SPECT acquisition geometry. TIEEE Trans Med Imaging. 2003 

May;22(5):599-612. 

6. Nuyts J, Bequé D, Dupont P, Mortelmans L. TA concave prior penalizing relative differences for maximum-a-posteriori reconstruction in emission 

tomography. TIEEE Trans Nucl Sci. 2002 Feb;49(1):56-60. 

7. K. Baete, J. Nuyts, W. Van Paesschen, P. Suetens, and P. Dupont, "Anatomical based FDG-PET reconstruction for the detection of hypo-metabolic 

regions in epilepsy" IEEE Transactions on Medical Imaging, 2003, in press. 

8. Booij J, Tissingh G, Winogrodzka A, van Royen EA. Imaging of the dopaminergic neurotransmission system using single- photon emission 

tomography and positron emission tomography in patients with parkinsonism. Eur J Nucl Med 1999; 26:171-182.


WP2: Quantitative microPET and multi-modality (PET/MR, OT/MR) scanner development 


Activity Type 

Other Specific Activities 

Participant id P2: Clark P1: Jacobs P5: Planas P12: Tavitian 

Person-months per 

participant 

P2: 54 P1: 6 P5: 6 P12: 6 

Objectives: 

1. Development of methods and software for fully quantitative microPET. 

Using software and hardware under development in the University of Cambridge, we will demonstrate the full range 

of data corrections (e.g. scatter, transmission, dead time and normalisation) required to achieve truly quantitative PET 

image data. The unique ability of PET to measure in vivo tracer binding can only be harnessed with a fully validated 

quantified PET scanner. 

2. To construct an MRI micro imager based upon a novel split coil MR magnet and use this for simultaneous 

PET/MRI or Optical tomography/MRI Scanner. 

Specific objectives: 

1. Monte Carlo modelling: 

We will adapt our SimSET + GEANT4 Monte Carlo code to model the geometry and materials of the microPET 

scanner. As well as scatter assessment and correction, the code will be used to examine normalisation, optimise the 

energy window for various tracers and animals, and help design shielding to limit the degrading influence of out of 

field activity. 

2. Image reconstruction of PET data on parallel computers: 

All scans acquired on our microPET are fully 3D, and to adequately sample the kinetic behaviour of the tracer, we 

typically split the data into a large number of time frames (up to 50). Consequently, reconstruction time for these 

datasets is an important issue. We will therefore implement a version of the PROMIS algorithm on a PC-cluster. The 

reconstruction time per frame will be reduced to < 1 minute. 

3. Transmission scanning: 

We will implement singles and windowed coincidence mode transmission scanning using a rotating Ge-68 source. 

The latter method will enable post-injection scanning, which is necessary for many microPET studies. We will 

implement parallel 2D and 3D Bayesian reconstructions of the transmission scan data to obtain high quality, low noise 

attenuation correction data. 

4. Verification of microPET data corrections and image reconstruction: 

We will conduct a multi-site verification of the microPET data corrections and image reconstruction given above. 

5. Split coil MRI magnet: 

The first phase of the project will be the accurate measurement of the magnets magnetic field profiles, both in the bore 

(to establish the field volume for imaging), and in the magnet gap, to optimise the location of the PET detector PMT's. 

Split active shield gradient coils will be designed using adaptations of the magnet design software, in combination 

with target field approaches. Initial imaging experiments to establish the spatial and temporal resolution that can be 

achieved with the system for target animals will be accomplished using a 9cm free bore active shielded gradient set. 

Using a pair of detector blocks, equivalent to those found on a FOCUS microPET, we will investigate the efficiency 

of the PET part of the scanner and establish the optimum position for the PMTs. Our Monte Carlo code will be used to 

investigate photon scatter from the MR magnet. 

6. Optical tomography: 

We will survey the hardware available for optical photon detection and produce a prototype design of a combined 

optical/MR imager.


Deliverables 

D2.0 Meeting with WP2 members for final agreement and initiation of work plan (1 mo) 

D2.1 Adapt Monte Carlo code (SimSET+GEANT4) to model microPET (6,12 mo) 

D2.2 Implement PROMIS 3D image reconstruction algorithm on PC-cluster (6,12 mo) 

D2.3 Implement singles and windowed coincidence mode transmission scanning on microPET, and implement 

iterative reconstruction of this data (12,18 mo) 

D2.4 Verification of microPET data corrections and image reconstruction (18 mo) 

D2.5 Measure and assess magnetic field properties of 1T split pair magnet (6,12 mo) 

D2.6 Demonstrate the spatial and temporal resolution of the MR imager (6,12 mo) 

D2.7 Design and build split coil active shield gradients (12,18 mo) 

D2.8 Investigate the performance of a PET detector block operating in the MR imager (12,18 mo) 

D2.9 Produce an initial design of a combined optical/MR imager (18 mo) 


M2.0 Common meeting of partners (1mo) 

M2.1 Monte Carlo model of microPET (6,12 mo) 

M2.2 Fast 3D FBP image reconstruction of microPET data (6,12 mo) 

M2.3 Optimise transmission scanning for microPET (12,18 mo) 

M2.4 Verify microPET data corrections and image reconstruction software (18 mo) 

M2.5 Characterise imaging properties of split coil magnet MR imager (6,12 mo) 

M2.6 Assess performance of microPET block detector operating in MR imager (12,18 mo) 

M2.7 Produce initial design of combined optimal/MR imager (18 mo) 


No human or animal studies will be performed.


WP3: Development of radiopharmaceutical probes for neurodegenerative diseases 

Workpackage number WP.3 Start date or starting event: Start of program 

Activity Type 


Participant id P4:Guilloteau P22:Halldin P29:Leenders 


participant 

P7:Knudsen P41:Verbruggen P1:Jacobs 

/Vaalburg 

P4: 12 P22: 12 P29: 0 P7: 3 P41: 12 P1: 0 

Objectives: 

1. to develop new probes for SPET/PET molecular imaging of targets involved in the most frequent 

neurodegenerative affections, i.e. Alzheimer’s and Parkinson’s disease. 

2. to develop fluorine-18 labelled PET probes derived from existing iodine-123 labelled SPET probes. 

3. to make available known probes ([ 123 I, [ 18 F], [ 11 C]) for in vivo studies in animal models and clinical 

investigations. 

4. to develop in vivo quantification methods suitable for each SPET/PET probe. 

Description of work 

1. PET probes for brain cholinergic function 

Reduced acetylcholine release from neuronal cells is a characteristic feature occurring at early stage of Alzheimer’s 

disease (AD) (Volkow et al, 2001). Hence, in vivo markers of acetylcholine neuronal integrity can be useful for the 

early diagnosis, follow-up and treatment of AD. In this project, several molecular targets of the cholinergic system 

involved in Alzheimer’s disease are proposed: vesicular acetylcholine transporter (VAChT), acetylcholinesterase 

activity (AChE), and acetylcholine receptors. The usefulness of each target will be evaluated for the early diagnosis, 

follow-up and treatment using SPET/PET radiotracers. 

VAChT: These transporters are localized in the cell terminals and carry acetylcholine from the cytoplasm into the 

vesicles. To date, (-)-5-[ 123 I]iodobenzovesamicol ([ 123 I]IBVM) has been developed and used to image in humans the 

transporter by SPET. In order to improve in vivo quantification of the VAChT, we propose to develop a PET tracer 

derived from the chemical structure of IBVM. Such a fluorinated derivative is currently being developed in our team, 

with very promising results (Zéa-Ponce et al, 2003). 

AChE: This enzyme catalyses the hydrolysis of acetylcholine and is consistently reduced in the brain of AD subjects. 

Its activity can be measured using labelled acetylcholine analogs or labelled enzyme inhibitors. We propose to 

investigate both approaches via the development of SPET/PET tracers. 

Acetylcholine receptors: Several PET tracers belonging to different chemical families have been developed for 

mapping M2 muscarinic and nicotinic (alpha 4 beta 2 and alpha 7 types) receptors. We propose to select the more 

relevant radioactive probes and to make them available for animal models and clinical investigations. 

2. SPET/PET probes for amyloid plaques 

Amyloid plaques and neurofibrillary tangles are an integral part of brain pathology in Alzheimer’s disease, but until 

recently could be detected only post-mortem. To date, a limited number of radiotracers has been proposed for 

radioisotopic visualisation of amyloid plaques (Agdeppa et al., 2001; Mathis et al., 2003; Vanderghinste et al. 2003a; 

Vanderghinste et al., 2003b; Verduyckt et al., 2003) but they are not yet in clinical use and further optimisation is 

required. Our aim is to extend the development of such tracers for PET and SPET which can have high relevance in 

the improvement of early diagnosis and evaluation of treatment of AD. 

3. PET probes for brain dopamine function 

The best index of neuronal degeneration of dopaminergic neurons in Parkinson’s disease is the dopamine transporter 

(DAT) localized on striatal nerve endings. The recent development and use of specific SPET radiotracers for the DAT 

are expected to improve early diagnosis and treatment (Prunier et al., 2003). Our aim is to obtain [ 18 F] or 11 C labelled 

PET tracers from the chemical structure of PE21, an iodinated derivative of cocaine which has very high specificity


for the DAT (Chalon et al., 1999; Halldin et al., 2003). Such derivatives labelled with fluorine-18 or carbon-11 are 

currently being developed in our team, with very promising results (Dollé et al, 2003) and would allow a better 

quantification and higher resolution images. 

4. SPET/PET probes for peripheral benzodiazepine receptors (PBR) 

PBR are a reliable tool for the evaluation of CNS inflammation which is a contributing factor of neurodegeneration. 

The SPET tracer [ 123 I]iodo-PK11195 has already been proposed for clinical evaluation of Alzheimer’s disease. Our 

aim is to develop a specific fluorine-18 labelled PET tracer in order to extend this type of investigation in Alzheimer’s 

and Parkinson’s disease. 

5. Mapping of Sigma receptors in the brain with PET 

The sigma receptor is involved in several diseases of the central nervous system (CNS), such as schizophrenia, 

depression, dementia and ischemia, as well as in peripheral nervous system diseases. In vitro studies on the 

postmortem human brain have shown a reduced density of the sigma receptors in the CA1 area of the hippocampus in 

Alzheimer’s disease and in the cerebral cortex and in the caudate of schizophrenic patients. The sigma receptor is 

classified into two subtypes, sigma1 and sigma2. To map sigma receptors, a lead compound 11 C-labelled SA4503 

([ 11 C]SA4503) was developed as a radioligand for positron emission tomography (PET). Receptor-specific uptake of 

[ 11 C]SA4503 was observed in the brain by tissue dissection and ex vivo autoradiography in rats and mice and by PET 

in a cat. The specific objectives are the development of [ 11 C]- and [ 18 F]-derivatives of e.g. [ 11 C]SA4503 to find the 

optimal radioligand for mapping sigma receptors in the human brain. [ 18 F]Fluorinated analogs of SA4503 will be 

developed to enable prolonged PET-protocols. Furthermore, [ 11 C]SA5845, a [ 11 C]SA4503 analog, and its 

[ 18 F]fluoroalkylated analog will be evaluated in rodents for its potency to measure sigma receptors. 

6. Validation and quantification of new tracers 

Once the selelective probes have been synthesised, their pharmacokinetics and binding characteristics will be 

investigated in rodents, mini-pigs, or monkeys. Appropriate modelling with state-of-the-art arterial input and brain 

tissue data sampling will be conducted along with validation and optimisation of methods for quantification of 

dynamic images (Pinborg et al, 2002) as well as, when feasible, steady-state infusion experiments (Pinborg et al, 

2002). Software developed for modelling and quantification within the network will be made freely available to all 

interested parties. 

In order to perform the biological evaluation of the newly developed fluorine-18 or carbon-11 labelled tracer agents 

for visualisation and quantification of the DAT transporter and for visualisation of amyloid plaques, we will use: 

- 55 mice (Partners 4 (15 mice) and 20 (80 mice)) for ex vivo biodistribution studies by activity counting or 

autoradiography in normal and MPTP treated mice. The animals will be injected with 10-100 µCi of one of the 

newly developed tracer agents under general anaesthesia and will be sacrificed while still under anaesthesia after 10 

min or 60 min by decapitation. Activity in dissected organs will be counted or visualised using autoradiography. To 

obtain statistically significant data, series of at least 4 mice per tested time point and product have to be used. 

- 55 rats (Partners 4 (25 rats), 7 (10 normal rats and 10 beta-amyloid injected rats) and 41 (10 rats) for assessment of 

passage of newly developed tracer agents over blood brain barrier and visualisation of intracerebral distribution of 

radioactivity. The animals will be injected with 30-300 µCi of one of the newly developed tracer agents under 

general anaesthesia and will be sacrificed while still under anaesthesia after 10 min or 60 min by decapitation. Brain 

and other selected organs will be dissected and their activity will be counted or the intracerebral distribution of 

radioactivity will be determined using autoradiography of brain slices. In 10 of the rats, micro-PET imaging will be 

performed between the injection of tracer agent and the moment of sacrifice under general anaesthesia. 

- 10 transgenic mice for Alzheimer’s models ((Partners 4 (5 mice) and 41 (5 mice)) for study of uptake of newly 

developed tracer agents in amyloid plaques. The animals will be injected with 10-100 µCi of one of the newly 

developed tracer agents under general anaesthesia and will be sacrificed while still under anaesthesia after 10 min or 

60 min by decapitation. Activity in the brain will be visualised using autoradiography on brain slices. 

- 6 mini-pigs ( Partner 7): the animals will be anaesthetized and PET-scanned after bolus injection of one of the tracer 

agents. Arterial and venous lines will be put in for determination of input 

curves. The outcome of these studies will be quantification of the tracers and dosimetry. Since this is a non invasive 

in vivo imaging method, the only manipulation the animals will be submitted to is anaesthesia and this is done to


increase the comfort of the animal by decreasing its restraining and manipulation stress. During anaesthesia the 

animals are accurately monitored to maintain optimal physiological parameters. After anaesthesia the animals are 

allowed to recover in an acclimitised recovery chamber. Animals are submitted to several imaging protocols and 

there is no reason to sacrifice them after the experiments. Since such imaging techniques are non invasive, the same 

animals can be followed over time thereby minimizing the number of experimental animals. 

All animal studies will be performed under the local and national guidelines summarized elsewhere in the project 

description. 

Deliverables 

D3.0 Report of meeting with WP 3 members for initiation of work plan (1 mo) 

D3.1 Precursors for radiolabelling with fluorine-18 or carbon-11 of tracer agents for dopamine transporter 

(DAT) (9 mo) 

D3.2 Written instructions for radiolabelling with fluorine-18 or carbon-11 of tracer agents for dopamine 

transporter (DAT) using deliverable D3.1 (12 mo) 

D3.3 Software for quantification of dopamine transporter in vivo using developed 18 F or 11 C labelled tracer 

agent and positron emission tomography (18 mo) 

D3.4 Results of evaluation in vitro and in vivo in animals of fluorine-18 or carbon-11 labelled tracer agents for 

dopamine transporter (18 mo) 

D3.5 Precursors for radiolabelling with fluorine-18 or carbon-11of tracer agents for in vivo visualisation of 

amyloid plaques in brain (12 mo) 

D3.6 Written instructions for radiolabelling with fluorine-18 or carbon-11 of tracer agents for in vivo 

visualisation of amyloid plaques in brain (18 mo) 

D3.7 Results of evaluation in vitro of fluorine-18 or carbon-11 labelled tracer agents for visualisation of 


D3.8 Report of meeting with WP 3 members for discussion of 1 st year results and further work plan. (13 mo) 

D3.9 Reporting on the relevant and applicable regulations of ethical issues (12mo) 

D3.10 Guidelines for preparation of SPET ([ 123 I]) and/or PET([ 18 F],[ 11 C]) radiopharmaceuticals with high in 

vivo selectivity for the vesicular acetylcholine transporter, acetylcholinesterase, acetylcholine receptors, 

peripheral benzodiazepine receptors, sigma receptors (later than 18 mo) 

D3.11 Modelling software for quantification of selected tracers mentioned under D3.6 and D3.9. (later than 18 

mo) 

D3.12 results of in vitro and in vivo (animals) evaluation of selected tracers mentioned under D3.9 (later than 18 

mo) 


M3.0 Common meeting of partners for initiation of activities and agreement on tasks (1 mo) 

M3.1 Development of one step radiolabelling with fluorine-18 or carbon-11 of tracer agents for dopamine 

transporter (DAT) (12 mo) 

M3.2 Characterization of 18 F or 11 C labelled tracer agents for dopamine transporter in vitro and in vivo in 

animal models (18 mo) 

M3.3 Modelling software for in vivo quantification of dopamine transporter using developed 18 F or 11 C labelled 

tracer agents (18 mo) 

M3.4 Development of tracer agents, labelled with carbon-11 or fluorine-18, for non-invasive visualisation of 


M3.5 Characterization of developed tracer agents for amyloid plaques in vitro and in vivo in animal models (18 

mo) 

M3.6 Meeting of all partners for discussion of results and planning of further work (12 mo) 

M3.7 Development of tracer agents, labelled with iodine-123, carbon-11 or fluorine-18, for non-invasive 

visualisation of: vesicular acetylcholine transporter, acetylcholinesterase, acetylcholine receptors, 

peripheral benzodiazepine receptors, sigma receptors (later than 18 mo) 

M3.8 Modelling software for in vivo quantification of selected tracer agents mentioned under M3.4 and M3.7 

(later than 18 mo) 

M3.9 Characterization of selected developed tracer agents mentioned under M3.4 and M3.7 in vitro and in vivo 

in animal models (later than 18 mo)


Ethical rules concerned with the use of laboratory animals 

Experimental procedures in animals are subjected to approval by the Local Ethics Committee, installed by the Local 

German Government Authorities in Cologne, Copenhagen, Stockholm and Tours. All animal experimentation will be 

conducted in accordance with the European current guidelines (86/609/CEE) as well the National Institutes of Health 

animal protection guidelines. All animals will be housed in an animal local which has agreement in respect to the 

European and national rules. Animals (rodents) are provided by an authorized supplier (CERJ, Le Genest St Isle or 

FranceCharles River, Lyon, France). 

The 3R principle for animal experimentation will strictly be followed. Animal experiments are designed to assure the 

minimum amount of animals needed. Further, we care for the welfare of laboratory animals: a) animals are maintained 

under standardized environmental conditions of temperature and humidity and a day/night light cycle; animals are 

kept in appropriate cages with no more than 4 animals per cage; animals are allowed free access to food and water; b) 

surgical interventions are always performed under general anesthesia (halothane or isoflurane; with N 2 O); after 

surgery, local anesthetics are applied to avoid animal suffering; c) animals are always sacrificed under general 

anesthesia. Finally, methods alternative to the use of animals, such as cell cultures, are employed where possible and 

applicable, and the assessments of biological actions of novel probes for imaging is always first carried out and 

validated in vitro, prior to animal studies. 

Handling and surgical procedures of animals for the experiments planned in WP3: 

The affinity, selectivity and cerebral distribution of new tracers will be determined on cerebral rat or mouse sections. 

These sections will be obtained after the euthanasia (pentobarbital overdose) of animals and removal of their brains. 

Few animals will be necessary as one serial sections of each brain will be used for several tracers. 

In vivo properties will be determined either by ex vivo autoradiography (injection of the tracer under isoflurane 

anesthesia, then euthanasia with pentobarbital overdose before brain removal), or by in vivo isotopic imaging method 

(alive animal under isoflurane anesthesia). 

One tracer (for the dopamine transporter) will be validated in a rat model of Parkinson’s disease obtained by 

intracerebral stereotaxic injection of 6-OHDA under isoflurane anaesthesia. This protocol (surgery and animal care 

after surgery) has already been approved by the Local Ethical Committee. After that, the tracer will be used in 

lesioned animals as described above. 

Literature 

1. Agdeppa ED, Kepe V, Liu J, Flores-Torres S, Satyamurthy N, Petric A, Cole GM, Small GW, Huang SC, Barrio JR. Binding characteristics 

of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid 

plaques in Alzheimer's disease. J Neurosci. 2001 Dec 15;21(24) 

2. Chalon S, Garreau L, Emond P, Zimmer L, Vilar Mp, Besnard Jc, Guilloteau D: Pharmacological characterization of (e)-N-(3-iodoprop-2- 

enyl)-2beta-carbomethoxy 3beta (4’ methylphenyl) nortropane or PE2I as a selective and potent inhibitor of the neuronal dopamine 

transporter. J Pharmacology and Experimental Therapeutics, 1999, 291(2):648-654 

3. Dolle F., Emond P., Saba W., Chalon S., Demphel S., Halldin C., Mavel S., Garreau L., Coulon C.,. Ottaviani M, Maziere B., Valette H., 

Bottlaender M., Guilloteau D. Radiosynthesis of [11C]LBT-999, a selective radioligand for the visualisation of the dopamine transporter with 

PET. J Labelled Compounds and Radiopharmaceuticals 2003, 46: s145 

4. Halldin C, Erixon-Lindroth N, Pauli S, Chou YH, Okubo Y, Karlsson P, Lundkvist C, Olsson H, Guilloteau D, Emond P, Farde L. 

[(11)C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain. Eur J Nucl Med 

Mol Imaging. 2003, 30(9):1220-30 

5. Mathis CA, Wang Y, Holt DP, Huang G-F, Shao L,Debnath ML, Klunk WER. Development of 18F-labelled thioflavin-T analogues as 

amyloid plaque imaging agents. J Labelled Compds Radiopharm 2003, 46, S62 

6. Pinborg LH, Videbæk C, Svarer C, Yndgaard S, Paulson OB, Knudsen GM: Quantification of [123I]PE2I binding to dopamine transporters 

with SPET. Eur J Nucl Med 2002;29:623-31 

7. Pinborg LH, Adams KH, Svarer C, Holm S, Hasselbalch SG, Haugbol S, Madsen J, Knudsen GM: Quantification of 5HT2A receptors in the 

human brain using [18F]altanserin-PET and the bolus/infusion approach. J Cereb Blood Flow Metabol 2003;23:985-96 

8. Prunier C, Payoux P, Guilloteau D, Chalon S, Giraudeau B, Majorel C, Tafani M, Mantzarides M, Bezard E, Besnard JC, Esquerre Jp, 

Baulieu JL.Quantification of the dopaine transporter by 123I-PE2I SPECT and non invasive logan graphical method in parkinson disease. J 

Nuclear Medicine, 2003, 44: 663-670 

9. Vanderghinste, D., Van Eeckhoudt, M., Cleynhens, B., de Groot, T., Bormans, G., and Verbruggen, A. C-11 and I-123 labelled 2- 

phenylbenzothiazoles and 2-phenylbenzoxazoles as potential tracers for Alzheimers disease. Eur.J.Nucl.Med.Mol.Imaging 30, S175. 2003. 

10. Vanderghinste, D., Van Eeckhoudt, M., Cleynhens, B., de Groot, T., Verbeke, K., Bormans, G., and Verbruggen, A. Synthesis and 

preliminary evaluation of 99mTc-BAT-thioflavine T derivatives for in vivo visualization of amyloid ß. Technetium, Rhenium and Other 

Metals in Chemistry and Nuclear Medicine [6], 463-465. 2003. 

11. Verduyckt, T., Serdons, K., Cleynhens, B., Vanderghinste, D., Bormans, G., and Verbruggen, A. Synthesis and evaluation of a Tc-99m- 

BATphenylbenzothiazole conjugate as a potential in vivo tracer for visualisation of amyloid . Eur.J.Nucl.Med.Mol.Imaging 30, S317. 2003. 

12. Volkow ND, Ding YS, Fowler JS, Gatley SJ. Imaging brain cholinergic activity with positron emission tomography: its role in the evaluation 

of cholinergic treatments in Alzheimer's dementia. Biol Psychiatry. 2001 Feb 1;49(3):211-20 

13. Zea-Ponce Y., Mavel S., Chalon S., Guilloteau D. Synthese of (e)-(-)-5-AOIBV and (-)-5-FPOBV, as potential SPECT/PET probes for the 

vesicular acetylcholine transporter. J Labelled Compounds and Radiopharmaceuticals 2003, 46: S167


WP4.1: Development of library of innovative MRI Probes and improved methods for “in 

vivo” cellular labelling 

Workpackage number WP4.1 Start date or starting event: Start of program 

Activity Type 


Participant id P3:Aime P9:Moonen P25:Hoehn P35: Parker P41: P46: 


participant 

P50:Lukes 

Verbruggen Benderbous 

P3: 54 P9: 3 P25: 9 P35: 18 P41: 3 P46: 12 P50: 18 

Objectives: 

1. Development of libraries of MRI-Gd(III) based probes endowed with high sensitivity and targeting 

capabilities. 

2. Development of libraries of high sensitivity MRI-CEST agents endowed with responsive properties to 

parameters characterising the tissutal microenvironment. 

3. Development of improved methods for “in vitro” cellular labelling with MRI probes. 

4. Development of libraries of MRI probes for assessing the vulnerability of atherosclerotic plaques. 

5. Set-up of improved MRI protocols for an optimised matching between image acquisition procedures and the 

characteristics of the Imaging Probe. 

Description of the work 

This WP will deal either with the development of novel MR Imaging Probes (high sensitivity Gd(III)-based 

agents and CEST agents) or the set-up of applications on cellular and animal models including the optimisation 

of image acquisition protocols for the best exploitation of the characteristics of the Imaging Probe. 

1. High sensitive Gd(III)-based agents 

Gd(III) chelates are the most used class of contrast agents in clinical applications. The currently available 

systems do not display the theoretically foreseen relaxation enhancement of water protons. Therefore, efforts 

will be devoted to pursue high relaxivity systems by optimising the parameters involved in the paramagnetic 

relaxation process (Aime, Lukes, Parker, Verbruggen). In this context it will be gained an in-depth understanding 

of the relationships between water dynamics and the structural/motional properties of the Gd(III) complexes by 

measuring 17 O- and 1 H-NMR relaxation times of water molecules. Structural control of the exchange lifetime 

and, possibly, inner rotation of the coordinated water will be pursued. Moreover, other routes to the attainment of 

high relaxivities will be tackled by synthesising di-aqua Gd(III) chelates using heptadentate ligands able of a 

strong coordination towards Lanthanide(III) ions. In order to deliver a sufficient number of Imaging Probes at 

the targeting sites, synthetic strategies will be set-up in order to have multimeric Gd-containing systems 

(dendrimeric structures, Lukes; supramolecular adducts, Aime and Parker). Finally, the Imaging Probe (or the 

multimeric construct) will be conjugated with the proper synthon in order to endow it the specific recognition 

ability required in a Molecular Imaging experiment. 

2. High sensitive CEST agents 

The recently reported novel class of MRI agents, the so-called CEST agents, act as negative agents via the 

transfer of saturated magnetisation to the water proton resonance. A CEST agent contains one or more sets of 

exchangeable protons that are selectively irradiated by means of a proper rf field. It differs from Gd(III) agents 

because its presence in a given district is detected only “at will”, i.e. upon switching on the proper irradiation 

frequency corresponding to the absorption frequency of its exchangeable pool of protons. In this project we will 

pursue the synthesis of systems endowed with improved sensitivity (Aime, Lukes). This goal will be pursued by 

increasing the number of exchangeable protons and by increasing their chemical shift separation from water 

resonance in order to exploit larger exchange rates which, in turn, is the main parameter responsible for the 

magnetisation transfer. Paramagnetic Lanthanide(III) complexes endowed with efficient Chemical Shift Reagent 

properties will be considered. The exchangeable protons could be located either on the ligand or on additional 

substrate able to form a supramolecular adduct with the Shift Reagent. Of course, highly shifted water molecules 

could also be exploited for this application. Next, attention will be focused on CEST agents responsive to 

parameters like pH or temperature in order to design diagnostic protocols based on such parameters. This target


will pursued by designing ligands containing a set of mobile protons whose exchange rate is made dependent 

upon the parameter of interest. 

3. Cellular labelling with MR Imaging Probes 

A number of applications can be envisaged for cells labelled with MRI probes. A particularly important field is 

represented by the Stem cells. Successful “in vivo” investigations requires the optimisation of “in vitro” 

procedures for cellular labelling. 

The following lines of research will be activated: 

• Labelling of stem cells and other cell lines with Gd(III) chelates by simple pinocytosis. The entrapment of 

the Imaging Probe will occur by internalisation of portions of extracellular fluid. Therefore, Gd(III)-based 

MRI agents will be selected on the basis of properties like high hydrophilicity, overall very low toxicity, 

very high thermodynamic stability, etc…The cellular localisation of Gd(III) chelates will be validated by the 

use of related Eu(III) chelates as the latter species display good fluorescent properties and may, therefore, 

visualised by confocal fluorescence microscopy (Aime, Parker). Analogous entrapment by electroporation 

will also be pursued. 

• Labelling of cells by means of bio-degradable Gd(III)-containing particles. MRI-visualisation of cells 

requires the internalisation of a high number of Imaging Probes and a straightforward solution should be 

represented by the entrapment of solid particles. However, to be effective, Gd(III) complexes need to be in 

the solution state. Therefore, the solid particles have to be solubilised once entrapped into the cells. The 

Gd(III) chelate will be engineered in order to pursue its solubilisation upon the action of a given enzyme 

(Aime, Hoehn). 

• Labelling of cells by means of CEST agents. This procedure will provide us with the unique opportunity of 

labelling, with different agents, different lines of cells. Each label corresponds to the peculiar absorption 

frequency of a pool of exchangeable protons. Therefore, once the cells will be transplanted on an animal 

model, their individual MR-visualisation is possible by “interrogating” the system with the proper 

irradiation frequency (Aime, Hoehn). 

4. MR-Imaging Probes targeting Atherosclerotic Plaques 

The visualisation of atherotic plaques (and the assessment of their vulnerability) is a target of primary 

importance in the diagnosis of cardiovascular diseases. To this regard, the following routes will be explored: 

• use of suitably functionalised Gd(III) chelates able to form stable micellar systems. These supramolecular 

adducts are characterised by a high relaxivity and should remain in the vasa vasorum system of the plaque 

for a time longer than their residence time main blood vessels. Moreover, the Gd(III) chelates may be 

actively targeted to the plaques by the use of LDL-based micelles (Aime) 

• use of labeled macrophages. We will pursue the labeling of macrophages either with Gd(III) chelates or with 

CEST agents. As it is well established that these cells are involved in the activation of the proceess that lead 

to the plaque rupture, the detection of an increased local activity of macrophages may be of high diagnostic 

value (Aime, Lukes). 

5. Set-up of improved MRI protocols for an optimised matching between image acquisition procedures 

and the characteristics of the Imaging Probe 

After the demonstration of the feasibility and optimization of the “in vitro” procedures, it is advisable to develop 

and validate the “in vivo” imaging protocols. The understanding of the different molecular and functional 

aspects that occur during desease development might allow the establishment of new therapeutic strategies. The 

involved methodology will be helpful to evaluate new targets for therapeutic strategies. 

• Thanks to the agents developed at the point, which are sensitive to physiological micro-environment 

changes, the MR-response sensitivity and the interest will be objectified. The temporal expression profiles 

of some key proteins belonging to either damaging or protective cell-pathways will be explored by MRspectroscopy, 

spectroscopic imaging, pH-MR imaging map, cerebral blood flow quantification and 

parametric mapping after image processing (Aime, Benderbous, Moonen). 

• To study the processes that occur in vivo in the developing brain subjected to transient ischemia and explore 

cell damage and/or recovery after brain hypoxia using pH-sensitive probe and cell labelled implantation. 

MR-imaging will be conducted on an experimental in utero fetal sheep or rat experimental model with 

altered cerebral oxygenation, induced ischemia or/and with angiogenesis inhibitors (Angiostatin and 

thrombospondin) (Aime, Benderbous, Moonen). 

Deliverables 

D4.1.1 Identification of high sensitive Gd(III)-based Imaging Probes endowed with specific targeting 

ability 

D4.1.2 Identification of high sensitive paramagnetic CEST agents responsive towards pH and temperature.


D4.1.3 Report on meeting of the WP members. 

D4.1.4 Optimised procedures for cell-labelling using soluble Gd(III)-based and CEST Imaging Probes ( 

pynocitosis and electroporation) or insoluble Gd(III)-based bio-degradable particles (for labelling 

macrophages) 

D4.1.5 Identification of Imaging Probes (Gd(III)-based and CEST agents) for targeting vulnerable plaques. 

D4.1.6 Set-up of MRI protocols “in vivo” for evaluating and optimising the diagnostic properties of the 

developed Imaging Probes. 

D4.1.7 Reporting on the relevant and applicable regulations of ethical issues (12 mo) 

Milestones 

M4.1.1 Meeting among WP partners 

M4.1.2 Optimisation of MRI protocols for molecular imaging experiments using Gd(III)-based and CEST 


M4.1.3 Assessment of the relationships among chemical structure, cellular uptake, and contrastographic 

ability for the developed Imaging Probes. 

M4.1.4 Set-up of MRI protocols for the visualisation of atherosclerotic plaques by using properly designed 



Since statistical significance needs at least a data set of 6 animals, we will choose 10 animals per experimental 

group to make sure we have included all extra tests that might seem necessary. 

A significant amount of the work in this workpackage will be carried out on cell cultures. However, since the 

aim of this network is to develop and evaluate Diagnostic Molecular Imaging tools it is obvious that work with 

animals is necessary in order to achieve our goals. Since MRI technique is non invasive, the same animals can be 

followed over time thereby minimising the number of experimental animals. 

All experiments will follow the guidelines of the Council Directive (86/609/EEC) and experienced personnel 

authorised by the ministry have been trained for animal care and handling. 

Since we are exclusively dealing with a non invasive in vivo imaging method, the only manipulation the animals 

will be submitted to is anaesthesia and administration of the contrast agent. During anaesthesia the animals will 

be very accurately monitored to maintain optimal physiological parameters (comparable with circumstances in a 

human operation theatre). After anaesthesia the animals are allowed to recover in an acclimatised recovery 

chamber. Animals are submitted to several imaging protocols and there is no reason to sacrifice them after the 

experiments, unless correlative histopathological data are required. 

Ethical rules concerned with the use of stem cells 

Only animal stem cells will be used in this workpackage. No human embryonic stem cells will be used. 

Therefore, ethical guidelines on the use of (embryonic) human stem cell do not apply here. 

Literature WP4.1 

1. Ward KM, Aletras AH, Balaban RS. (2000) A New Class of Contrast Agents for MRI Based on Proton Chemical Exchange Dependent 

Saturation Transfer (CEST). J Magn Res 143: 79-87. 

2. Zhang S, Winter P, Wu K, Sherry AD. (2001) A Novel Europium(III)-based MRI Contrast Agent. J Am Chem Soc 123: 1517-1518. 

3. Aime S, Barge A, Delli Castelli D, Fedeli F, Mortillaro A, Nielsen FU, Terreno E (2002) Paramagnetic lanthanide(III) complexes as 

pH-sensitive chemical exchange saturation transfer (CEST) contrast agents for MRI applications Magn Res Med, 4: 639-648. 

4. Aime S, Delli Castelli D, Fedeli F, Terreno E (2002) A paramagnetic MRI-CEST agent responsive to lactate concentration. J Am 

Chem Soc 124:9364-9365. 

5. Aime S, Delli Castelli D, Terreno E (2002) Novel pH-reporter MRI Contrast Agents. Angew. Chemie Int Ed 41: 4334-4336. 

6. Aime S, Delli Castelli D, Terreno E (2003) Supramolecular Adducts between Poly-L-arginine and [TmIIIdotp]: A Route to Sensitivity- 

Enhanced Magnetic Resonance Imaging-Chemical Exchange Saturation Transfer Agents. Angew. Chemie Int Ed 42: 4527-4529. 

7. Aime S, Cabella C, Colombatto S, Crich SG, Gianolio E, Maggioni F (2002) Insights into the use of paramagnetic Gd(III) complexes in 

MR-molecular imaging investigations JMRI 16:394-406 

8. Marchand B, Douek PC, Benderbous S, Corot C, Canet E (2000). Pilot MR evaluation of pharmacokinetics and relaxivity of specific 

blood pool agents for MR angiography. Invest Radiol 35(1):41-9. 

9. Berry I, Benderbous S, Ranjeva JP, Gracia-Meavilla D, Manelfe C, Le Bihan D (1996). Contribution of Sinerem used as blood-pool 

contrast agent: detection of cerebral blood volume changes during apnea in the rabbit. Magn Reson Med., 36 (3):415-9. 

10. Shah PK (2003) Mechanisms of Plaque Vulnerability and Rupture J Am Coll Cardiol 41: 15S-22S 

11. Stefanidis C, Toutouzas K, Tsiamis E, Stratos C, Vavuranakis M, Kallikazaros I, Panagiotakos D, Toutouzas P (2001) Increased Local 

Temperature in Human Coronary Atherosclerotic Plaques. J Am Coll Cardiol 37: 1277-1283.


WP 4.2: Development of Optical and Combined Imaging Probes 

Workpackage number 4.2 Start date or starting event: Start of Programme 

Activity Type 


Participant id P3 Aime P9: Moonen P35: Parker P41:Verbruggen P46: Benderbous P50:Lukes 


participant 

P3: 12 P9: 6 P35: 51 P41: 6 P46: 6 P50:18 

Objectives 

1. Synthesis and evaluation of luminescent metal-complex probes: from analytical applications in cell 

biology to their assessment for development in diagnostic applications in vivo. 

2. Correlation of behaviour of MR/radiotracer and optical probes based on the similarity of underlying 

chemistry of lanthanide systems. 

3. Synthesis and evaluation of a novel class of “dual” Imaging Probes exploiting the superb anatomical 

resolution of MRI and the outstanding sensitivity of Optical and Nuclear Imaging Probes. 


This workpackage will be organised in several research lines: 

1. Development of biomolecular Optical Probes responsive to intracellular analytes. Cell permeable lanthanide 

complexes will be devised that are able to signal changes in their local environment. New luminescent lanthanide 

complexes will be characterised for which the form, lifetime and polarisation of optical emission will be designed 

to be a defined function of the intracellular levels of pH, pX (e.g. X = chloride, hydrogencarbonate) pO 2 or even 

pM (e.g. M = zinc). By synthesising small libraries of metal complexes of defined surface charge, hydrophobicity 

and chirality, the factors determining the compartmentalisation of the complexes will be studied. This work will be 

carried forward using confocal fluorescence microscopy, allowing the spatio-temporal distribution of the 

complexes to be defined. For systems exhibiting organelle-selective localisation profiles, information on the 

biological role of the target bioactive ion will be revealed, e.g. changes in bicarbonate in mitochondria as a 

function of respiratory rate, environmental stress and its regulatory role in cyclic AMP release. Finally, 

luminescent probes that bind to protein phosphorylation sites will be examined, potentially allowing transient 

bursts of phosphorylation to be followed in real-time, live cell imaging studies. 

2. DNA targeted probes. Photoactivated agents are currently being used clinically in the laser treatment of skin 

melanoma and in the management of glaucoma following administration of dyes that exhibit some build-up at the 

desired site. New metal complex based systems will be studied that may be efficiently taken up by cells, enter the 

cell nucleus and reversibly bind to DNA. The main aims of this work-package are: 

a) to expand the range of complexes that are cell permeable and exhibit DNA binding, and to investigate the 

feasibility of two-photon excitation, by irradiating in the wavelength range 700-820 nm allowing maximal 

tissue penetration and the application of fibre-optic excitation protocols; 

b) to establish the means of targeting the metal complexes to the desired cell population, using covalently 

linked conjugates, such as peptide-based vectors; 

c) to monitor the time profile of the localisation process by microscopy and to correlate this behaviour to the 

complex biodistribution profile established by radiolabelling the complexes with appropriate positron or 

gamma-emitting lanthanide isotopes. 

3. Long-lived luminescent probes. Lanthanide probes and dye-conjugates for use in time-resolved immunoassays 

and for application to FRET analyses aimed at monitoring protein function have been developed by CIS-Bio 

(France), Amersham Biosciences (UK) and Wallac-Oy (Finland). As a result of tremendous advances in CCD 

photon detection systems, the detection of luminescence is now considered to be as sensitive as the measurement 

of radioactivity. In addition, many new light-emitting diodes (370, 430 nm) and low-cost lasers are available


allowing excitation at wavelengths appropriate to sensitised lanthanide luminescence. Moreover, the advent of two 

photon excitation microscopy allows the excitation of many systems with wavelengths in the range 710 to 840 nm, 

where tissue has its maximal transmittance. Such systems therefore, offer the potential to replace many assays 

based on the use of radioisotopes. However, improvements are still needed in the efficiency of the overall emission 

process and in extending the excitation wavelength towards the visible/near-IR region for single photon excitation 

processes. Therefore new families of highly emissive complexes will be prepared and characterised, incorporating 

chromophores that absorb one (or two) photons very strongly and transfer their excited state energy effectively to a 

proximate metal ion. These will be based on different types of lanthanide-binding ligands, including 8 and 9- 

coordinating macrocyclic systems. Furthermore, highly emissive systems (overall quantum yield >20% in water) 

will be derivatised with a suitably reactive electrophilic component, allowing selective linkage to proteins and 

antibody fragments or conjugation to low MW targeting vectors, e.g. for use in FRET assays. 

4. Development of combined probes. An inherent advantage of studying lanthanide based imaging systems is that 

the coordination chemistry of Gd(III) complexes used in MRI and of emissive lanthanide Eu(III)/Tb(III) complexes 

is nearly identical, thus allowing a direct correlation of information regarding cell uptake/retention profiles and 

tissue distribution to be safely inferred. Moreover, there are also certain lanthanide parent-daughter generator 

systemsavailable for the production of positron-emitting radioisotopes, e.g 134 -Ce/ 134 -La (half-life 3.2 days and 6.7 

min., respectively) and 140 -Nd/ 140 -Pr (half-life 3.4 days and 3.4 min, respectively), so that the advantages of 

radiotracers studies (e.g. precise quantitation of short-term uptake/localisation) can potentially be extended to the 

work on MRI and Optical Imaging Probes. As an example of this approach, its application to study the role of 

hypoxia in inflammation may be considered. In this research line systems containing several ligands for Ln(III) ions 

wil be synthesised. Most of the ligands will be coordinated to Gd(III) ion (MRI-active probe), whereas some will 

be coordinated to Eu(III) or Tb(III) (Optical-active probes) or to the radio-lanthanide of choice (PET-active probes). 

Furthermore, the “dual” Imaging Probe will be functionalised in order to accumulate at the targeting site. When the 

Imaging Probe is entrapped into cells the Optical-active synthon can be suitably endowed with responsive 

capabilities towards specific parameters characterising the intracellular microenvironment (see line 1). MRI and 

radioisotopes containing probes will be systems developed in the specific WP dealing with MRI probes (WP 4.1) 

and Nuclear probes (WPs.2.1 and 2.2), respectively. The validation of selected combined probes will be carried out 

mainly at cellular level and may be examined, in a later stage of the project, for the most interesting system, on 

animal models. 

Deliverables 

D4.2.1 Lanthanide-based Optical Probes responsive to intracellular analytes 

D4.2.2 Report on 2 nd meeting among WP members 

D4.2.3 A lanthanide based Optical Probe for DNA-targeting 

D4.2.4 Long-lived Optical Probes based on an efficient energy transfer between a Lanthanide metal complex 

and a Selected chromophore. 

D4.2.5 Combined Probes containing several chelating moieties (10-50) mostly charged with Gd(III) ions (for 

MRI Visualisation) and containing one or few sites occupied by luminescent lanthanide ions or by 

lanthanide; radioisotopes endowed with suitable emitting properties for Optical Imaging and PET 

detection, respectively 

D4.2.6 reporting on the relevant and applicable regulations of ethical issues (12 mo)


Milestones 

M4.2.1 

M4.2.2 

M4.2.3 

M4.2.4 

M4.2.5 

Meeting among WP partners. 

Optimisation of the energy transfer between a lanthanide-based luminescent probe and a given. 

Assessment of the determinants of the cell internalisation process and responsiveness to a defined 

intracellular parameter for Optical Probes. 

Assessment of the determinants of the permeability to cell nucleus for Optical Probes. 

Optimisation of the MRI, Optical and PET properties of Combined Probes 


All animal studies will be performed under permission of National Ethical Committees for Animal 

Experimentation and/or Local Animal Ethical Committees providing international standards for animal 

experimentation. For each animal experiment a written protocol describing in detail the aims and methods used to 

examine the hypothesis of a given study will be submitted and approved by the National Ethical Committees 

before experiments are initiated. Protocols will be accessible by local authorities at any time during the experiment 

and members of National Ethical Committees or local authorities are free to call for inspections at any time. In 

compliance with the rules of the National Ethical Committees a record is kept for each experiment. Experiments 

will be performed by highly skilled persons with long-lasting experience in performing science using animals and 

with all necessary certificates. Animal examination involving models using surgical experimentation and imaging 

of animals will be performed in anaesthetized animals and care will be taken to ensure that proper treatment with 

pain relieving drugs takes place if necessary. Every partner involved in animal research employs highly skilled 

technical personnel for animal care-taking. 

No experiments using using genetically modified organisms (GMOs) are foreseen. 

Experiments using animals are justified from the point of view that detailed physiological knowledge, the role of 

various genes and evaluation of therapeutic strategies in vivo cannot be obtained in models with lower biological 

analogy to humans such as cell cultures and yeast. The choice of animal models is carefully considered with 

regards to the specific diseases that will be studied. For examination of specific cellular processes, and for initial 

testing of imaging probes, appropriate cell culture studies will be performed. The animals will be housed in 

authorized animal facilities which are approved by National European Authorities. The welfare of animals is 

secured by highly skilled personnel, which are approved by the National European Authorities to serve as animal 

care-takers at research institutions. The mice will be monitored on a daily basis (inspection of symptoms and 

weighing). End points will be defined in accordance with the Local Ethical Committee. Mice will be sacrificed in 

compliance with humane methods approved by the National Ethical Committee. 


1. Parker D., Dickins RS, Puschmann H, Crossland C, Howard JAK (2002) Being excited by lanthanide coordination complexes. Aqua 

species, chirality, excited-state chemistry, and exchange dynamics. Chem. Rev. 102: 1977-2010. 

2. Bretonniere Y, Cann MJ, Parker D, Slater R (2002) Ratiometric probes for hydrogenocarbonate analysis in intracellular or extracellular 

environments using europium luminescence. Chem Comm 1930-1931. 

3. Bobba G, Frias JC, Parker D (2002) Highly emissive, nine-coordinate enantiopure lanthanide complxes incorporating 

tetraazatriphenylenes as probes for DNA Chem Comm 890-891. 

4. Caravan P, Ellison JJ, McMurry TJ, Lauffer RB (1999) Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics and 

Applications. Chem Rev 99: 2293-2352. 

5. Fatin-Rouge N, Toth E, Perret D, Backer RH, Merbach AE, Bunzli JCG (2000) Lanthanides podates with programmed intermolecular 

interactions: Luminescence enhancement through association with cyclodextrins and unusually large relaxivity of the gadolinium selfaggregates 

J Am Chem Soc 122: 10810-10820.


WP5: Animal library for diagnostic molecular imaging in neuroscience & cardiovascular 

Workpackage WP5 Start date or starting event: Start of Programme 

number 

Activity Type Other Specific Activities 

Participant id P5:Planas P8:vd Linden P6: Maggi P23: Hantraye P14:Baeckelandt P25: Hoehn 

P1:Jacobs P42: Vivien P7:Knudsen P34b:Auricchio P21:Fleischmann P32:Nicolay 

P41: van Laere P40:Schäfers 

Person-months P5: 35 P8: 16 P6: 24 P23: 0 P14: 16 P25: 38 

per participant 

P1: 6 P42: 29 P7: 3 P34b: 21 P21: 22 P32: 30 

P41: 30 P40: 15 

General Objectives 

1. To establish a library of experimental animal models of human neurological diseases in order to validate and test 

the use of molecular imaging probes as markers of disease hallmarks for diagnostic purposes and for the study of 

disease progression. 

2. The same aim as in 1. for cardiovascular diseases. 

3. Generation of new animal models for neurodegenerative and cardiovascular diseases. 

4. Apply combinations of new and existing molecular imaging probes to generate complementary information for 

disease diagnostics. 

5. Exchange relevant models/knowledge to members of the consortium. Tight interaction with animal libraries for 

inflammation research within the network. 


1. To identify imaging targets in particular animal models of neurological diseases (Stroke, Alzheimer’s, 

Huntington’s and Parkinson’s diseases, and Hereditary Spastic Paraplegia) with relevance for the diagnostic and 

for the study of disease progression. 

2. The same as 1. for cardiovascular diseases (Heart infarction, Ischemic heart disease, Atherosclerosis). 

3. To combine different imaging techniques to obtain additional and complementary information relevant for 

diagnostic purposes. 

4. To characterise by means of biochemical, molecular and histopathological techniques the pathological 

disturbances in tissue/cells targeted in the imaging studies. 

5. To correlate non-invasive imaging data with data obtained from the tissue/cells by means of invasive methods 

in animals and in vitro to better understand the molecular and pathological basis of imaging data. 

6. To identify, through molecular and biochemical studies, new potential targets for the development of imaging 

probes. 

7. To test new imaging markers (subjected to availability) to in vitro cell culture systems to validate its biological 

target. 


1. The Experimental Models: Selected animal models of diseases for the first 18 months of the study: 

Establishing a set of standardized, relevant and reproducible, animal models allowing multimodal imaging of 

hallmark disturbances in neurological (stroke, Alzheimer’s, Parkinson’s, and Huntington’s diseases, and 

Hereditary Spastic Paraplegia) and cardiovascular (Atherosclerotic models, Ischemic models) diseases. 

Animal models will have to be adapted to the particular necessities of imaging. When possible, in vitro


models in cell cultures will be used for certain specific issues to minimise the use of living animals. 

However, work with living animals is necessary in this WP in order to achieve the aims of the study (see 

above). 

1.1 Models of Stroke: The following models of focal cerebral ischemia in adult Sprague-Dawley and Wistar 

rats, and C57 Black and OF1 mice will be used: 

A) Transient cerebral ischemia: 1-hour MCA occlusion/reperfusion with an intraluminal method in rats: 

middle cerebral artery (MCA) occlusion/reperfusion in rats with an intraluminal method based on the 

insertion of a nylon microfilament in the external carotid artery through the internal carotid artery until 

the level where the MCA branches out under halothane or isoflurane anaesthesia (Justicia et al., 2000). 

The filament is removed after 1 hour to allow reperfusion (n=30 ischemic and controls using Sprague- 

Dawley rats, and n=10 Wistar rats). Also, 30 min MCA occlusion will be carried out in rats (Sprague- 

Dawley) and mice (OF1) (8 animals per group, control, sham-operated). 

B) Tromboembolic MCA occlusion in rats (n=10 animals per group: ischemic and control; in two groups 

using different rat strains: Sprague-Dawley and Wistar) by intracarotid injection of thrombin-induced 

clots under halothane anaesthesia, with a method modified in our laboratory that produces consistent 

MCA occlusion and that allows the use of thrombolytics to induce reperfusion. 

C) Permanent cerebral ischemia in rats and mice under isoflurane anaesthesia (8 animals per group 

control, sham-operated). 

D) In vitro models of excitotoxicity will be used to study the effect of the excitotoxic component of 

ischemia derived from glutamate release: NMDA lesion in neural cell cultures (pure neuronal and 

mixed neuronal and glial) from Sprague-Dawley rats. 

E) In vitro models of exposure to oxidative stress and pro-inflammatory cytokines to study the 

inflammatory component of ischemia: Exposure of cultured astrocytes from Sprague-Dawley rats to 

hydrogen peroxide, ING-γ, Interleukin-6. 

1.2 Models of Alzheimer’s Disease (AD): 

A) Continuous intracerebroventricular infusion of amyloid β peptide (Aβ) 1-42 for 15 days, 300 pmol/day, 

0.5ul/h dissolved in vehicle: 35% acetonitrile/0.1% trifluoroacetic acid under sodium pentobarbital (50 

mg/kg i.p.) anaesthesia. Control rats are injected with the vehicle This is an established animal model that 

reproduces some of the neuropathological alterations and cognitive impairment in AD (Frautschy et al., 

1996). Adult Sprague-Dawley rat will be used (n=8-10 rats per group). 

B) APP23 model of AD, a transgenic mouse (C57Black strain) generated by using a construct in which the 

Swedish mutation of APP aa670-671 has been is placed under the control of a neuron-specific promoter 

(murine TH1). The effect of oestrogen and drugs acting on oestrogen receptors will be studied in nonsham 

operated and ovariectomized mice. Mice will be sacrificed at 8, 12, 18 months of age (n= 8-10 per 

group). 

C) In vitro cell cultures: Certain effects of β-amyloid will be tested in cell cultures. 

i. Neurotoxin treatment of the human neuroblastoma cell line SH-SY5Y with the amyloid β 

peptide. 

ii. 

Primary cultures of neural cells (mixed glial, pure microglial, pure astrocyte cultures) from 

Bl/C57 mice will be treated with β-amyloid (1-42 fragment). 

1.3 Models of Parkinson’s Disease (PD): 

A) Progressive neurodegeneration model of PD: Striatal 6-hydroxydopamine (6-OHDA) administration 

induces a slow and progressive dopaminergic neuronal death (Sauer and Oertel, 1994) that mimics the 

degenerative process in PD. Unilateral stereotaxic administration of 6-OHDA (20µg in 4µl) in the 

striatum of adult Sprague-Dawley rats (n=25 lessened rats and n=25 rats administered with vehicle, i.e.


saline solution containing 0.2 mg/ml ascorbic acid). The 6-OHDA model for PD will also be carried 

out in Wistar rats (n= 10 diseased versus n=10 controls) 

B) Optimization and characterization of a novel in vivo model for synucleinopathy, which was created by 

LV-mediated over expression of α-synuclein in mouse and rat brain (Lauwers et al., 2003), through 

expression or inhibition of PD- related genes (parkin, synphilin-1). Adult C57BL mice and Wistar rats 

will be stereotactically injected with lentiviral vectors (encoding disease-specific genes and/or the 

luciferase reporter gene) (n=10-20 per group). 

1.4 Models of Huntington’s Disease (HD): 

Two different models will be developed in rodents. 

A) The first model will be obtained through chronic subcutaneous injections of the neurotoxin 3- 

nitropropionic acid as a phenotypic model of HD causing behavioural, anatomical and biochemical 

alterations highly reminiscent of the human pathology. Molecular mechanisms involved in the 3NPinduced 

pathology in rats have recently been characterized in our laboratory and point to major 

analogies with the human pathology (Bizat et al 2003). The present experiments will be made to 

further identify molecular mechanisms of 3NP-induced striatal degeneration in this model and further 

characterise the energetic dysfunction in 3NP-treated rats (n=8-10 diseased, 8-10 controls) and nonhuman 

primates (n=5 diseased and 5 controls). 

B) Genetic models of HD will be obtained through intra-cerebral, viral vector-mediated, gene transfer of 

the mutated huntingtin gene (Regulier et al 2004). Intracerebral injections of lentiviral vectors will be 

performed under general anaesthesia in 10 Wistar rats (1-2 µl in striatum, bilaterally). Previous 

experiments in rats (Regulier et al 2004) have already demonstrated the feasibility and the relevance of 

this model as a behavioural replicate of HD. Efforts will be made to study these models using noninvasive 

imaging techniques and post-mortem biochemical and histological methods to identify 

mechanisms of striatal neurodegeneration and further investigate their relevance to HD pathology 

(number of rats involved =8-10 diseased, 8-10 controls). 

1.5 Hereditary Spastic Paraplegia (HSP) 

Hereditary Spastic Paraplegia due to Paraplegin deficiency is an autosomal recessive disease resulting in a 

progressive form of spastic paraplegia for which no cure is currently available. This mitochondrial disease 

primarily affects axons of cortical and spinal motor neurons. The isolation of the disease-causing 

mutations as well as the creation of a mouse model recapitulating the disease (obtained by Paraplegin 

gene targeting, Ferreirinha et al 2004) were both performed at TIGEM. In an effort to rescue the disease 

phenotype in the paraplegin -/- mice we are currently injecting Adeno-associated viral (AAV) vectors 

intramuscularly to target peripheral neurons. Taking advantage of the ability of such vectors to perform 

retrograde transport along the axon of the transduced neurons we will assess gene transfer in the spinal 

cord motor neurons of normal and paraplegin -/- animals. To do so we will inject in the quadriceps and 

tibialis anterior of 129SvJ wild type and paraplegin -/- mice (n= 20/group, Auricchio et al 2003). AAV 

vectors encoding a cellular marker, lacZ, or a marker protein, the dopamin transporter, which can be 

imaged by micro-SPECT (Auricchio et al 2003). 

1.6 Models of atherosclerosis 

A) ApoE deficient mice (n=20) will be fed a lipid-rich diet for at least 10 days. Next, the animals will be 

anaesthetized with a mixture of ketamine (100 mg/kg i.p.) and xylazine (5 mg/kg s.c.), the left carotid 

artery will be surgically exposed via a midline incision over an area from the chin to the sternum that 

had been sterilized with 1% iodine solution. The salivary gland will be separated and the artery 

dissected proximal to the bifurcation. A silicone cuff, 5 mm in length, will be placed around the 

periphery of the artery proximal to the bifurcation. The surgical site will then be closed with a 6-0 

nylon suture and the mice will be allowed to recover. To prevent infections, the animals will be treated 

with ampicilline (s.c.) following surgery. Over the course of 10 days, an arterial malformation 

develops down-stream from the position of the cuff that resembles an early atherosclerotic lesion (Ivan 

et al., 2002). 

B) Hyperlipidemic New Zealand White rabbit model (n=6). Male New Zealand White rabbits will be given 

an abdominal aortic balloon injury, using an arterial embolectomy catheter. After 2 months on a


cholesterol-enriched diet, Russell’s viper venom (0.15 mg/kg i.p.) and histamine (0.02 mg/kg i.v.) will 

be administered twice with a 24-hr interval. The rationale of this model is that denudation causes the 

development of macrophage-rich atherosclerotic plaques, while subsequent venom treatment leads to 

the induction of plaque rupture at a selected site and a selected time point (Abela et al., 1995). 

1.7 Models of myocardial ischemia 

A) Coronary ischemia/reperfusion model in mice of strain C57/Bl6 and/or SV129 (n=25). For this purpose 

either the cryoinjury (a copper probe of 4x4 mm is pressed onto the left free ventricular wall 3 times 

for 20 sec) or the ligation of the left coronary artery (LCA) is employed. This results in irreversible 

infarctions of various sizes. For both the operations the mice are sedated, intubated and ventilated. 

Isoflurane is applied in order achieve deep anaesthesia. Thoracotomy is performed as reported in detail 

(Roell et al. 2002a, Roell et al. 2002b). 

B) Reversible cardiac infarction method. This approach consists of operating mice and fixing a string 

loosely around the LCA. Thereafter, for one week, the LCA can be compressed intermittently up to 

when ST elevations on the ECG appear. These mice develop chronic ischemic heart disease (n=12 

mice and n=12 mice for control) 

2. Identification of biochemical, metabolic, molecular and histopathological findings in the tissue of interest. 

2.1:Cerebral ischemia: 

A) Investigating the tissue at risk in cerebral ischemia by means of invasive techniques that will allow to 

study in this specific region the molecular characterization of gene and protein expression (with the 

view of identifying molecular targets for imaging), and to find out, by means of neuropathological 

studies, the fate of this tissue with time (with the view of identifying cell death markers for imaging). 

The study involves the following sub studies :A1) expression of genes related to cell death /survival 

(heat-shock protein family, Bcl-2 family, TIMP, (Ferrer & Planas, 2003)), and inflammation (proinflammatory 

cytokines and adhesion molecules). A2) Activation of intracellular (STAT (Justicia et 

al., 2000) and extracellular (matrix metalloproteinases (Justicia et al., 2003)) signaling molecules. A3) 

Histopathological characterization of the tissue at risk (necrosis/apoptosis, leukocyte infiltration) 

(Ferrer & Planas, 2003). A4) Expression (transcription and protein synthesis) of serine proteases and 

their inhibitors, named serpins (tPA, plasminogen, PAI-1, protease nexin-1, neuroserpin). 

B) Investigating the inflammatory reaction in stroke and correlating data with neuropathological and 

imaging findings. 

2.2 Alzheimer’s Disease (AD): 

A) In vivo models: Characterisation of the glial reaction by means of immunohistological tools. Assessment 

of the pharmacological activity of selected ER mediators (SERMs) on brain inflammation. 

B) In vitro models: B.1) Neuronal Pentraxin 1 (NP1) is a glycoprotein homologous to the pentraxins of the 

acute phase immune response. We have recently shown that NP1 is part of the program of apoptotic 

neuronal death (DeGregorio-Rocasolano et al., 2001). Expression of NP1 occurs well before 

neurotoxicity and we have proposed that NP1 may be a marker for the neurodegeneration of specific 

neuronal populations in AD. This hypothesis will be tested in vitro by investigating whether neurotoxic 

treatment of the human neuroblastoma cell line SH-SY5Y with the amyloid β peptide increases the 

expression of NP1 before cell death. B.2) The involvement of certain transcription factors (PU.1, 

C/EBPα and C/EBPβ) in glial activation after exposure of mice glial cell cultures to the 1-42 amyloid 

β peptide will be studied (Casal et al., 2002). 

2.3 Parkinson’s Disease (PD): Neuronal loss, neuropathological alterations and neurotransmitter dysfunction with 

neuropathological and molecular alterations within the different experimental models. 

A) The following studies will be carried out in striatum and substantia nigra in the rat 6-OHDA model of 

PD: 1) Tyrosine hydroxylase immunoreactivity; 2) expression of inflammatory mediators 

(proinflammatory cytokines, cyclooxygenase-2 and nitric oxide); 3) expression of cell death/survival 

mediators (Bax, Bcl2, Bclx, caspase-3) (Mladenovic et al., 2004). 

B) Glial activation (Cicchetti et al., 2002): 1) with glial fibrillary acidic protein immunoreactivity to label 

astrocytes and OX-42 immunoreactivity to label microglia (Rodrigues et al., 2004); 2) glial cells


produce and release trophic factors after lesion, which induce survival and sprouting of neurons 

(Akerud et al., 1999); in this context the involvement of glial-derived neurotrophic factor (GDNF) in 

gliosis in the substantia nigra will be evaluated by RNase protection analysis and 

immunohistochemistry. 

C) Proton magnetic resonance spectroscopy will be used to determine changes in brain metabolites 

implicated in cerebral energetics, neuronal and glial dysfunction. These approaches will be applied 

both to rodent and non-human primate models (Dautry et al., 2000; Henry et al 2002). 

2.4 Huntington’s Disease: see 2.3C 

2.5 Hereditary Spastic Paraplegia (HSP): Characterization of viral-mediated gene transfer. Detection of lacZ and 

dopamin transporter gene transfer by histological and non-invasive imaging techniques respectively, will be 

instrumental to subsequently design and track in vivo paraplegin gene transfer by AAV vectors for the rescue 

of our animal model phenotype. 

2.6 Atherosclerosis: A) Biological characterization of atherosclerotic plaques with the final goal to B) develop a 

multi-modality molecular imaging algorithm, which allows for accurate identification of localization and 

instability of plaques. This information is crucial for the determination of individual risk in clinical 

atherosclerosis. 

- In the mouse model, the arterial lesions will be subjected to detailed characterization by means of (immuno) 

histochemical techniques. The analysis will include plaque phenotyping (HE staining) and measurement of 

macrophage content (CD68 immunostaining). 

- In the rabbit model, tissue specimens from the abdominal aorta will be prepared and analyzed for the presence and 

abundance of the markers indicated above. In addition, thrombolytic markers will be quantified. 

2.7 Myocardial ischemia: Imaging of A) pathological and B) molecular data will be C) correlated to identify 

imaging and therapeutic targets. The pathological and molecular processes that will be addressed include cell 

death, apoptosis, and scar tissue formation. Van Gieson staining will be used in order to precisely define the 

localization and extent of the fibrotic areas. After stem cell treatment using transgenic cells (expressing GFP) 

these cells will be identified based on their native fluorescence of anti-GFP staining. 

3. Imaging of pathological disturbances by micro-PET, micro-SPECT, and micro-MRI in the animal models. 

Correlating point 2 with imaging data. For neurological research, this work will be carried out in close interaction 

with WP7, which is devoted to non-invasive phenotyping of animal models for neurodegenerative diseases, and 

with WP9, which is devoted to neuroinflammation. While the emphasis of WP7 and WP9 is made on imaging, the 

stress of the present WP is on the pathological and molecular disturbances, and only essential imaging studies will 

be carried out for validation purposes. Continuous flow of information between WP5, WP7 and WP9 will be 

established. Likewise, for cardiovascular research image validation is being performed within WP11.1, WP11.2 

and WP12. 

3.1 Imaging by micro-PET and micro-SPECT: 

a) The induction of adhesion molecules using 125 I- or 123 I-labelled antibodies against VCAM-1 and ICAM-1 will 

be visualised by micro-SPECT using a pinhole collimator (Kawachi et al., 2000) and studies will be validated 

with a quantitative in vivo model based on quantification of radiolabelled antibodies in the tissue post-mortem 

by liquid scintillation counting (Sans et al., 1999), immunohistochemistry and Western blot. 

b) Imaging of metabolism in ischemia will be done by PET using 18 F-FDG (n= 8/10 rats per group). Metabolic 

data will be correlated to tissue damage as assessed by MRI and histopathology. 

c) Non-invasive imaging of viral-mediated gene transfer in the HSP model, by imaging with micro-SPECT the 

dopamin transporter (Auricchio et al 2003).


3.2 Imaging by MRI: 

a) MicroMRI will be used to determine volume changes in different brain structures (Kooy et al, 2001, 

Hoogenraad et al, 2002) and for fibre tracking to discern and quantify alterations in brain connectivity (Mori 

et al., 2001), which result from neurodegeneration. 

b) Perfusion-weighted MRI will be applied to estimate brain perfusion. Data will be correlated to 

histopathology. 

c) Conventional contrast agents will be used for tracing BBB leakage in the same rats and non-human primates 

(n=5 per group, diseased and control). Data will be correlated to histopathology. 

d) High resolution MRI will be used to characterize the inflammatory process (macrophages) (Saleh et al., 

2004), (n=10 Wistar rats). This will be correlated to the inflammatory reaction as assessed by 

immunohistological methods. 

e) Various MRI techniques will be used for the high-resolution in vivo phenotyping of atherosclerotic lesions in 

the mouse and rabbit models of atherosclerosis. These include proton-density weighted, T2-weighted as well 

as pre- and post-contrast (Gd-DTPA)-enhanced T1-weighted MRI. 

f) MRI studies of myocardial infarction in the mouse will involve a series of techniques for assessing the global 

and local function of the heart, using CINE and tagging MRI, respectively, as well as for measuring the extent 

and severity of tissue injury. The latter will include the measurement of tissue viability on the basis of the 

delayed contrast enhancement following Gd-DTPA injection. 

4. Global examination of findings obtained with invasive methods and data from the different imaging 

modalities in each animal model of disease. 

5. Coordinating the exchange of models and data within the network. Following studies from the inflammation 

team, we will test and validate diagnostic markers for brain injury and neurodegeneration such as protease 

activity (MMPs), apoptosis (Annexin A5), immune cells (macrophages, T-cells, granulocytes), oxidative stress 

and gene expression in transgenic reporter models using combination of imaging techniques 

Deliverables 

D5.0 Meeting with WP5 members for initiation of work plan for neurological and for cardiovascular diseases (1 

mo) 

D5.1 Characterisation of hallmarks of disease in the pre-established animal models with invasive methods (6 mo) 

and in new animal models (18 mo), and characterization of viral-mediated gene transfer (18 mo) in the 

selected models of disease. 

D5.2 Characterisation of biochemical, molecular and histopathological alterations in the different experimental 

models (18 mo) 

D5.3 Characterization of the glial reaction in AD, PD and stroke, and characterization of the inflammatory 

dynamics in the stroke model (12 mo) 

D5.4 Integrating imaging with neuropathological and molecular alterations in the models of AD, PD, HD and 

stroke, and non-invasive imaging of viral-mediated gene transfer in the model of HSP. Connection with 

related WPs. (18 mo) 

D5.5 Characterisation of biochemical, molecular and histopathological alterations in the ischemic heart, and 

biological characterization of atherosclerotic plaques (12 mo) 

D5.6 Labelling of progenitor and/or stem cells and evaluation of the biological effects in vitro after cardiac 

ischemia (6 mo). 

D5.7 Integrating imaging with pathological and molecular alterations in each model of cardiovascular diseases; 

re-identification of stem cells after transplantation into the injured mouse heart. Connection with related 

WPs. (18 mo) 

D5.8 Integration of the resulting data for each disease. Exchange of animal models. Links to other WPs (18 mo)


D5.9 reporting on the relevant and applicable regulations of ethical issues (12 mo) 


M5.0 Common meeting of all partners: Organization of the specific work plan and establishment of detailed 

interactions between partners (1 mo) 

M5.1 Coordination of the exchange between partners and establishment of animal models (6 mo) 

M5.2 Characterization of histopathological and behavioural disturbances in specific diseases (12 mo) 

M5.3 Characterization of molecular disturbances in specific diseases (18 mo) 

M5.4 Characterization of histopathological, behavioural and molecular correlates of imaging findings in the 

experimental models of diseases. Links with WP6, WP7, WP9, WP11.1, WP11.2, and WP12 (18 mo) 

M5.5 Characterization of disease hallmarks and gene transfer (in the selected animal models) that can be studied by 

imaging. Links with WPs, as above. (18 mo) 

M5.6 Integration of findings obtained with invasive methods and data from the different imaging modalities. Links 

with related WPs (18 mo) 

M5.7 Identification of molecular targets for the development of imaging markers. Integration of all studies for each 

disease. Links to other WPs (18 mo) 


Experimental procedures in animals are subjected to approval by the Ethics Committee of each local Institution 

according to the local regulations of each country and in compliance with the European guidelines for animal 

experiments, housing and care, and for the use of transgenic animals. 

Work by the team responsible for WP5, partner 5, is subjected to approval the by the Ethics Committee of the Medical 

School of the University of Barcelona and will be conducted following the legal local current guidelines by the 

‘Generalitat de Catalunya’ (decree 214/1997) and in accordance with the European current guidelines (86/609/CEE). 

Animals to be used include rats and mice of different strains. Personnel directly involved in the animal work have the 

adequate authorised licence by the ‘Servei de Ramaderia del Departament d’Agricultura, Ramaderia, i Pesca de la 

Generalitat de Catalunya’. Assessors for Partner 5 in ethical issues concerning WP5: Dr. America Giménez Lagunas, 

specialist in Laboratory Animal Science: Category D of FELASA (Federation of European Laboratory Animal Science 

Associations) and Assessor of Animal Welfare by the Generalitat de Catalunya (according to decree 214/1997), who 

belongs to the University of Barcelona, will participate in the project as manager of ethical aspects concerning the 

experimental studies. Dr. Antoni Trilla, Associate Professor of Public Health of the University of Barcelona, Senior 

Consultant and Director of the Assessment, Prevention and Support Unit (UASP) of the Hospital Clinic of Barcelona, 

and Member of the Ethics / IRB Committee, will also collaborate in the project as assessor of ethical issues. 

The 3R principle for animal experimentation will be followed. First, we design the experiments in order to use the 

minimum amount of animals. Second, we care after the welfare of laboratory animals: a) animals are maintained under 

standardised environmental conditions of temperature and humidity and a day/night light cycle; animals are kept in 

appropriate housing cages with no more than 4 animals per cage; animals are allowed free access to food and water, 

unless special treatments or interventions are required in the procedures previously approved by the Ethics Committee; 

b) chirurgical interventions are made under general anaesthesia (halothane, isoflurane, ketamine/xylazine, or 

pentobarbital) and in addition local anaesthetics are used to avoid animal suffering; c) animals are killed under 

anaesthesia for biochemical, molecular and histological characterisation. Third, alternative methods to the use of 

animals, such as cell cultures, are employed when possible, and the testing of biological actions of novel probes for 

imaging will be first carried out in vitro, prior to proceed with animal studies. 

Mouse stem cells: For cardiac ischemic inbred mice of the strain C57/Bl6 and/or SV129 will be used. In order to reidentify 

the injected cells, stem cells will be used, which are harvested from the β-actin-EGFP or the α-actin-EGFP 

mouse. The local ethical committee approves all experiments using mice. The number of mice required in order to obtain 

statistically significant data sets are estimated in collaboration with the local Department of Biometrics and Medical 

Statistics of the University of Bonn. Only animal stem cells will be used in this workpackage. No human embryonic stem 

cells will be used. Therefore, ethical guidelines on the use of (embryonic) human stem cell do not apply here.


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Koutsourakis, N. Van Camp, M. Verhoye, A. Van der Linden, I. Kaverina, F. Grosveld, C.I. De Zeeuw, N. Galjart. (2002) Targeted 

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1430-1440 

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28. Sauer H, Oertel WH. Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-OHDA: a 

combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 1994; 59: 401-415.


WP 6: Evaluation of the role of estrogen and estrogen receptors in a mouse model of 

Alzheimer disease and generation of novel reporter systems 


Activity Type 


Participant id P6: Maggi P11: Carlsen P12: Tavitian P1: Jacobs 


participant 

P6: 54 P11: 0 P12: 0 P1: 18 


1. Understanding the relevance of inflammatory processes in the progression of neurodegenerative diseases 

2. Generating novel models for in vivo imaging of intracellular processes 

Specific Objectives 

1. To evaluate the role of estrogen and estrogenic drugs on the inflammatory reaction in Alzheimer’s Disease 

(AD) 

2. To analyse the molecular mechanism of estrogen anti-inflammatory activity 

3. To generate novel vector for bimodal in vivo imaging of gene expression 


1. It is known that inflammation is associated with the pathological hallmark of brain diseases and it participates in the 

toxic reactions that trigger neurodegeneration. We have recently shown that estrogen is a potent anti-inflammatory 

agent in the brain, limiting the activation of resident inflammatory cells and monocytes infiltration through brain 

parenchyma. Since estrogens are widely prescribed drugs for the prevention of menopausal stmptoms, we intend to 

evaluate whether these molecules may hinder brain inflammation. We will make use of the APP23 mice, a transgenic 

mouse strain generated by Staufenbiel M. and collaborators, which bear a mutated form of the human gene encoding the 

amyloid precursor protein (APP). This mutation has been found in a hereditary form of AD and confers to the 

transgenic mice the typical histopathological sings and behavioural deficit of AD. We will pursue the following 

experimental design: 

1.1 Ovariectomy and pharmacological replacement of APP23 female mice with estradiol and two selected 

SERMs (raloxifene, tamoxifene). The replacement will be done at different times after ovariectomy using 

subcutaneous pellets. Adult animals will be ovariectomized, estrogen/SERM replacement will be done at the 

time of ovariectomy or 15 days-one month later. The analysis of the phenotype will be carried out in separate 

groups of animals at month 8, 12 18 of age. We plan to use about 10 animals/group thus about 70-80 animals 

will be utilized. (Maggi) 

1.2 Analysis of the histological and biochemical sings of inflammation in mice brain will be carried out 

evaluating Congo red staining and measuring specific inflammatory markers (IL-6; IL-1; IFNgamma, MMP9, 

iNOS) in the brain areas affected by neurodegeneration or amyloid deposit. (Maggi) 

1.3 multi-tracer PET imaging with [11C]FMZ as surrogate marker for neurodegeneration; [11C]MP4A as 

marker for the affection of the cholinergic system; [18F]FDG as marker for glucose metabolism will be used to 

analyze brain damages in the APP23 mice (Maggi Tavitian Jacobs) 

2. We have recently demonstrated that estrogen activates estrogen receptor alpha (ERα) to inhibit the inflammatory 

response, while the other isoform of the receptor, ERα, is dispensable for this activity. ERs are transcription factors that 

trigger the initiation of gene expression once ERs are activated by estrogen. In addition, it has been shown that ERα 

modulates the activity of cytoplasmic enzymes and molecules that intervene in the signal transduction pathways 

associated with membrane receptors. Expression of pro-inflammatory genes, such as IL-6, TNF- α, iNOS and MMP-9 

is known to be repressed by estrogen, however, the underlying mechanism still remains unknown. We propose to 

identify the specific molecules that are targeted by ERα in inflammatory cells. Our work will be: 

2.1 to analyse the activation pathway of one of the most important pro.-inflammatory transcription factors, 

namely NF-kB, in the presence or absence of activated ERα. In vivo imaging of NF-kB using transgenic 

luciferase reporter mice will be used. Our preliminary results suggested that the transcriptional activity of these 

proteins is inhibited by estrogen. (Maggi) 

2.2 To study whether cytoplasmic enzymes, such as the phosphatidyl-inositol-3 kinase (IP3K), and other 

enzymes involved in the regulation of transcription factor activity, namely histone deacetylases (HDAC), are


under the control of ERα. To perform these experiments we will make use of primary brain macrophage cells 

(microglia) and macrophage cell cultures transiently transfected with ERs plasmids.(Maggi) 

3. We will generate vectors for double reporter mice in which a single promoter (initially, as a proof of principle 

responsive to estrogens) will direct the transcription of a single transcript coding for two reporter genes with IRES 

(ribosome entry) sequences interposed between them. As reporter genes, we will utilize a gene encoding luciferase and 

a gene encoding a protein able to bind labelled radioligands (either viral timidine kinase (TK) or mutated dopamine D2 

receptor lacking signal-transduction capabilities). We will use the vectors generated to stably transfect cells and 

measure by direct binding and light emission the relative expression of the two reporters. We will further evaluate the 

intensity of the signal obtained with the vector by injecting the stably transfected cells in mice and comparing the 

intensity of the signal depicted by PET and optical imaging (Maggi Jacobs Tavitian) 

Deliverables 

D 6.1 Assessment of the pharmacological activity of estrogen and selected ER mediators (SERMs) on brain 

inflammation 

D 6.2 Identification of the mechanisms involved in estrogen anti-inflammatory activity. 

D 6.3 

D 6.4 

D 6.5 

D 6.6 

Vectors genetically engineered to express luciferase and D2 receptor (lucIRESD2) and d2IREStk39 

Stably transfected cells with the lucIRESD2 and and d2IREStk39 reporter 

Assessment of ratio of expression of the two reporter in vivo 

Common data for the detection sensitivity of cells expressing lucIRESD2 reporter by optical imaging and 

PET 


Milestones 

M 6.1 

M 6.2 

M 6.3 

M 6.4 

M 6.5 

M 6.6 

M 6.7 

assessment of the effect of estrogen chronic treatment on microglia activation in AD brain (12mo) 

elucidation of the molecular mechanism of anti-inflammatory action of estrogen in monocytes (15mo) 

assessment of the effect of the chronic treatment with SERMs on microglia activation in AD brain (18mo) 

Vectors genetically engineered to express luciferase and D2 receptor (lucIRESD2) and d2IREStk39 (6 mo) 

Stably transfected cells with the lucIRESD2 and d2IREStk39 reporters (12 mo) 

Assessment of ratio of expression of the two reporter in vivo (12 mo) 

Common data for the detection sensitivity of cells expressing lucIRESD2 reporter by optical imaging and 

PET (18 mo) 


All the experiments including the use of mice will be carried out in accordance with the Amsterdam protocol on 

animal protection and welfare, animal experiments must be replaced with alternatives wherever possible. Suffering by 

animals must be avoided or kept to a minimum. This particularly applies (following the Directive 6/609/EEC) to 

animal experiments involving species which are closest to human beings. The University of Milan is appointing an 

Ethical Committee responsible for the evaluation of the ethic principle governing each of the experiments proposed.


WP7: Non-invasive phenotyping of animal models for neurodegenerative diseases 

Workpackage number WP 7 Start date or starting event: Start of program 

Activity Type 


Participant id P8: Van der Linden P1: Jacobs P3:Aime P5: Planas P14: Baekelandt 


participant 

P41: Van Laere P6: Maggi 

P8: 18 MM P1: 18 MM P3: 9 MM P5: 18 MM P14: 18 MM 

P41: 18 MM P6: 4 MM 


To validate a novel library of diagnostic molecular imaging markers for in vivo imaging in defined rodent and nonhuman 

primate models for neurodegenerative diseases. The imaging partners of DiMI will integrate with those partners 

who construct new animal models by providing tools and expertise to validate their models, i.e. to study how well the 

models mimic the human pathology using (miniaturized or similar) clinical diagnostic tools. 


1. Multimodality Phenotyping of 6 0HDA-PD rat model 

2. Multimodality Phenotyping of lentiviral PD rat model 

3. Optical imaging Phenotyping of lentiviral PD mouse model 

4. Multimodality Phenotyping of QA (Quinolinic Acid) Huntington rat model 

5. MRI phenotyping of different ALS genotype mice: 

6. Implementation of animal brain atlases for automatic VOI definitions 


1. ANIMAL MODELS ENVISIONED TO INVESTIGATE DURING FIRST 18 MONTHS OF DIMI 

Parkinson (PD) models: will include 

1) 6-OHDA model for PD in Wistar rats (n= 10 diseased versus n=10 controls) 

2) Wistar rats stereotactically injected with lentiviral vectors (encoding disease-specific genes) in specific 

brain regions. rats (n= 10 diseased versus n=10 controls) 

3) C57BL mice stereotactically injected with lentiviral vectors (encoding disease-specific genes and/or the 

luciferase reporter gene) for bioluminescence (n= 10 diseased versus n=10 controls 

4) Phenotypic (neurotoxin induced) lesion models of Parkinson's disease (n= 10 diseased versus n=10 

controls 

Huntington's disease (HD) models will: include 

chronic QA lesions in rats ( n= 10 diseased versus n=10 controls) 

Amyotrophic Lateral Sclerosis (ALS) mice: we will use different genotypes from P.Carmeliet, KUL, Belgium: 

1) Vegfdelta/delta mouse model: deletion in the hypoxic response element of the VEGF gene by using 

Cre/loxP-mediated gene targetting. Mouse background FVB/N. (n= 10 diseased versus n=10 controls) 

2) SOD mice: mice expressing the SOD1(G93A) transgene (super oxidase dismutase. Mouse background 

mixed. (n= 10 diseased versus n=10 controls) 

3) intercrossed mice (both Vegf and SOD1). Background mixed (n= 10 diseased versus n=10 controls) 

HIV-based vectors 

All experiments with the HIV vectors (GMO) by partner 14 are performed in agreement with the regulations prescribed 

by local, national (Belgian) and European laws. Partner 14 has several laboratories of BL-2 biosafety level for HIV 

vector work, including an animal neurosurgery room for stereotactic gene delivery. Attests from Medical Biosafety 

Surveillance and a statement of compliance to work with lentiviral vectors are available in the laboratory.


2. PHENOTYPING BY NON INVASIVE IMAGING METHODS 

2.1. Phenotyping of rodents by microMRI at 7T 

• Tracing neurodegeneration: micro MRI will be used to determine volume changes in different brain structures 

as a result of neurodegeneration (Sijbers et al., 1997; Fransen et al, 1998; Kooy et al, 1999,2001, Hoogenraad 

et al, 2002, Spittaels et al, 2002). 

• Tracing cerebral perfusion alterations: perfusion-weighted MRI will be applied to estimate brain perfusion. 

• Tracing neural activity and its vascular response: Haemodynamic/vasogenic responses will be investigated in 

the brain during different degrees of electrical stimulation of the paw and during different physiological 

challenges (hypoxia, hypercapnia) using functional MRI based on Blood Oxygenation Level Dependent 

(BOLD) contrast (Mueggler, et al. 2001, 2002, 2003) or Arterial Spin Labelling (ASL) contrast. SEP will be 

performed under similar experimental settings. 

• Tracing BBB leakage: Comparison between conventional and newly developed contrast agents. 

2.2. Phenotyping by microPET and SPECT 

MicroSPECT (using a pinhole collimator) : 

• monitoring of dopamine transporters in animal models (Lauwers et al, 2003) using 123 I-FP-CIT and brain 

perfusion ( 99m Tc-ECD) 

• brain perfusion ( 99m Tc-ECD), dopamine transporter ( 123 I-FP-CIT) and benzodiazepine receptors (123I- 

Iomazenil) using microSPECT (YAP-PET): pilot study in 10 rats 

MicroPET : 

• Quantitative assessment of dopamine transporters ([ 18 F]FPCIT) or 11 C-PE2I dopamine receptors ([ 11 C]- 

raclopride), cerebral glucose metabolism ([ 18 F]FDG), benzodiazepin receptor densitiy as surrogate marker for 

neuronal integrity ([ 11 C]FMZ) and acetylcholinesterase activity ([ 11 C]MP4A) or [ 11 C]MP4P), quantitative 

imaging of amyloid plaques using existing tracers [ 11 C]-6-OH-BTA1 or 11C-PIB-2 

• Quantititative assessment of exogenous gene-expression through the HSV-1 thymidine kinase (HSV-1-tk) as 

PET reporter gene 

• Multimodal imaging using various tracers with special reference to a comparison between SPECT and PET 

imaging as well as those tracers used in clinical application 

• Quantitative imaging of amyloid plaques using 11 C-PIB and 6-OH-BTA1 -C11 

• PET both small animal PET (Neurofocus PET scan) and HRRT/HR+ tomographs. Ligands include dopamine 

transporter, dopamine receptors, central nicotinic receptors, F-DOPA, FDG, FMZ and MP4A/PMP 

• 99TC-HMPAO/99TC-ECD, 123I-IOMAZENIL, 123I-FP-CIT 

• brain glucose metabolism in a rat model of striatal lesion using microPET (YAP-PET) and ([ 18 F]FDG: pilot 

study in 10 rats 

2.3. Visualisation of transgene expression by optical (bioluminescence) imaging 

Luciferin is used as an exogenous substrate and can be utilized for the visualisation of luciferase as a reporter gene in 

the brain of laboratory animals. Several groups (6,14) have a cooled highly sensitive CCD cameras to detect 

luminescence in rodent brain. 

Although not immediately applicable in the clinic, this technique is cheap, easily introduced and a valuable addition to 

PET, SPECT, and MRI for brain research in animal models (Wu et al., 2001; Bhaumik and Gambhir, 2002; De et al., 

2003). 

• Construction of different HSV-1 amplicon and lentiviral vector transfer plasmids mediating proportional 

coexpression of luciferase and HSV-1-tk or VZV-tk under constitutive and tet-regulatable promoters 

• Characterization of the vectors expressing luciferase and HSV-1-tk or VZV-tk in vivo after stereotactic 

injection of the vectors in mouse and rat brain with optical and microPET imaging. Optimization of 

bioluminescent imaging parameters with respect of dose of substrate, time course of imaging, administration of 

substrate, sensitivity of imaging, influence of anatomy and location of different brain areas, confirmation of 

expression of luciferase and HSV-1-tk or VZV-tk post mortem by immunohistochemistry 

• Generation and validation of vectors engineered for multimodality imaging containing luciferaseIRES D2 

receptors


3. VALIDATE MULTIMODALITY IMAGING PARAMETERS (MRI, PET, OI) BY STANDARD INVASIVE 

HISTOPATHOLOGY 

Histopathology will be performed after the different in vivo imaging sessions on a subset of the animals. The data 

will be digitalised and processed and registered with anatomical MR images of the same animals using multi-rigid 

and elastic transformation techniques of co-registration. Using this approach, the whole registration between the 

histological volume and any of the MRI or PET 3D volume can be achieved (Dauguet et al, MICCAI, Saint Malo, 

2004, in press). 

Correlation of optical imaging and microPET imaging with LV-mediated transgene expression will be performed 

by immunohistochemical analysis of the transgene at different time points after stereotactic injection. 

In the PD animal models, correlation of the SPECT and microPET imaging parameters will be performed 

histologically by quantification of dopaminergic neurons in the substantia nigra and of tyrosine hydroxylase in the 

striatum. 

4. IMAGE REGISTRATION AND 3D MERGING OF IMAGES OBTAINED WITH DIFFERENT IMAGING 

MODALITIES: To compare images obtained through different imaging modalities and to combine the image 

information obtained from each image separately, coregistration is required: images are positioned in the same reference 

framework using registration techniques based on mutual entropy to map images of different modalities on each other 

(Maes, 1997). Registered images subsequently can be merged in order to display the separate image information of the 

modalities in a combined way. Also development of automatic voxel-of-interest (VOI) delineation, on the basis of a 

brain atlas will be accomplished.. Evaluation of anatomy-based reconstruction schemes using microMRI and 

microPET/SPECT for partial volume correction and optimized quantification in PD rat models. 

Deliverables 

D7.0 Common meeting of partners 

D7.1 Multimodality Phenotyping of 6 0HDAPD rat model 

D7.2 Multimodality Phenotyping of lentiviral PD rat model 

D7.3 Optical imaging Phenotyping of lentiviral PD mouse model 

D7.4 Multimodality Phenotyping of QA (Huntington disease model) in rats 

D7.5 MRI phenotyping of different ALS genotype mice 

D7.6 Implementation of animal brain atlases for automatic VOI definitions 

Milestones 

M7.0 Common meeting of partners 

M7.1 Multimodality Phenotyping of 6 0HDA PD rat model: 9 months 

M7.2 Multimodality Phenotyping of lentiviral PD rat model: 18 months 

M7.3 Optical imaging Phenotyping of lentiviral PD mouse model: 18 months 

M7.4 Multimodality Phenotyping of QA (Huntington's disease model) in rats: 12 months 

M7.5 MRI phenotyping of different ALS genotype mice: 6 months 

M7.6 Implementation of animal brain atlases for automatic VOI definitio:18 Months


Ethical rules concerned with the use of laboratory animals in WP 7 

We have provided details of the species (and strains where appropriate) of animals to be used in the text of the WP 7. 

We have also given details and numbers of animals proposed. Since statistical significance needs at least a data set of 

6 animals, we have chosen 10 animals per experimental group for rodents and 5 animals per experimental group for 

non-human primates to make sure we have included all extra tests that might seem necessary. 

Since the aim of this network is to develop and evaluate Diagnostic Molecular Imaging tools it is obvious that we 

should work with animals and not with cells since the ultimate targets of the diagnostic tools will be patients who can 

only be tackled by non invasive in vivo investigation methods such as imaging. 

Transgenic mice were chosen because of the multiplicity of animal diseases models developed in this species and non 

human primates because of their closer link with humans. 

Since we are exclusively dealing with non invasive in vivo imaging methods, the only manipulation the animals will 

be submitted to is anaesthesia and this is done to increase the comfort of the animal by decreasing its restraining and 

manipulation stress. During anaesthesia, all animals are very accurately monitored to maintain optimal physiological 

parameters (comparable with circumstances in a human operation theatre,. After anaesthesia the animals are allowed 

to recover in an acclimitised recovery chamber after which they can join their mates. Animals are submitted to 

several imaging protocols and there is no reason to sacrifice them after the experiments, unless correlative 

histopathological data are required. 

Protection of Animals 

In accordance with the Amsterdam protocol on animal protection and welfare, animal experiments must be replaced 

with alternatives wherever possible. Suffering by animals must be avoided or kept to a minimum. This particularly 

applies (pursuant to Directive 6/609/EEC) to animal experiments involving species which are closest to human beings. 

Altering the genetic heritage of animals and cloning of animals may be considered only if the aims are ethically 

justified and the conditions are such that the animals' welfare is guaranteed and the principles of biodiversity are 

respected. 

All the WPs are and will be in accordance with National and European guidelines for animal experiments, housing 

and care, and for the use of transgenic animals. Our laboratories have and will have the obligatory accreditation of the 

authorised Ministries and are and will be registered under license numbers. All academic centres have very strict 

policies regarding the ethics of animal use for scientific experiments. Moreover, the Academic Authorities stimulate 

the use of in vitro methods above in vivo models. 

Literature 

1. E. Fransen, R. D’Hooghe, G. Van Camp, M. Verhoye, J. Sijbers, E. Reyniers, P. Soriano, H. Kamiguchi, R. Willemsen, K.E. Koekoek, C.I. De 

Zeeuw, P.P. De Deyn, A. Van der Linden, V. Lemmon, R.F. Kooy, P. Willems, “L1 knockout mice show dilated ventricles, vermis hypoplasia 

and impaired exploration patterns”, Human Molecular Genetics 7(6): 999-1009 (1998). 

2. R. F. Kooy, E. Reyniers , M. Verhoye, J. Sijbers, C.E. Bakker, B.A. Oostra, P.J. Willems and A. Van der Linden, “Neuroanatomy of the fragile X 

knockout mouse brain studied using in vivo high resolution Magnetic Resonance Imaging (MRI)”, European Journal Human Genetics 7: 526-532 

(1999). 

3. F. Kooy, M. Verhoye, V. Lemmon, A. Van der Linden, “Brain studies of mouse models for neurogenetic disorders using in vivo magnetic 

resonance imaging (MRI)”, European Journal Human Genetics 9:153-159 (2001). 

4. C.C. Hoogenraad, B. Koekkoek, A. Akhmanova, H. Krugers, B. Dortland, M. Miedema, A. van Alphen,W. Kistler, M. Jaegle, M. Koutsourakis, 

N. Van Camp, M. Verhoye, A. Van der Linden, I. Kaverina, F. Grosveld, C.I. De Zeeuw, N. Galjart, “Targeted mutation of Cyln2 in the Williams 

syndrome critical region links CLIP-115 haploinsufficiency toneurodevelopmental abnormalities in mice”, Nature Genetics 32:116-127 (2002). 

5. K. Spittaels, C. Van den Haute, J. Van Dorpe, D. Terwel, K. Vandezande, R. Lasrado, K. Bruynseels, M. Irizarry, M. Verhoye, J. Van Lint, 

J.R.Vandenheede, D. Ashton, M. Mercken, R. Loos, B. Hyman, A. Van der Linden, H. Geerts, F. Van Leuven, “Neonatal neuronal 

overexpression of glycogen synthase kinase-3beta reduces brain size in transgenic mice”, Neuroscience 113(4):797-808 (2002). 

6. J. Sijbers, M. Verhoye, P. Scheunders, A. Van der Linden, D. Van Dyck, and E. Raman "Watershed based segmentation of 3D MR data for 

volume quantization", Magnetic Resonance Imaging 15(6):679-688 (1997). 

7. Mueggler T., Sturchler-Pierrat C., Baumann D., Raush M., Staufenbiel M. Compromised hemodynamic response in amyloid precursor protein 

transgenic mice. J. Neuroscience (2002) 22 (16):7218-7224. 

8. Mueggler T., Baumann D., Rausch M., Rudin M. Bicuculline-induced brain activation in mice detected by functional magnetic resonance 

imaging. MRM (2001) 46: 292-298. 

9. Mueggler T, Baumann D, Rausch M, Staufenbiel M, Rudin M Age-dependent impairment of somatosensory response in the amyloid precursor 

protein 23 transgenic mouse model of Alzheimer's disease.Neurosci. 2003 Sep 10;23(23):8231-6 

10. F. Maes, A. Collignon, D. Vandermeulen, G. Marchal, P. Suetens, Multimodality image registration by maximization of mutual information , 

IEEE transactions on Medical Imaging, 16(2), 187-198, 1997. 

11. Jacobs AH, Dubrovin M, Hewett J, Sena-Esteves M, Tan C, Slack M, Sadelain M, Breakefield XO, Tjuvajev JG (1999b) Functional coexpression 

of HSV-1 thymidine kinase and green fluorescent protein: Implications for non-invasive imaging of transgene expression. Neoplasia 

1: 154-161


12. Jacobs AH, Winkeler A, Hartung M, Slack M, Dittmar C, Kummer C, Knoess S, Galldiks N, Vollmar S, Wienhard K, Heiss WD (2003) 

Improved HSV-1 amplicon vectors for proportional coexpression of PET marker and therapeutic genes. Hum Gene Ther 14: 277-297 

13. Wu JC, Sundaresan G, Iyer M, Gambhir SS. “Noninvasive optical imaging of firefly luciferase reporter gene expression in skeletal muscles of 

living mice.” Mol Ther. 4(4):297-306 (2001). 

14. Bhaumik S, Gambhir SS. “Optical imaging of Renilla luciferase reporter gene expression in living mice.” Proc Natl Acad Sci U S A. 99(1):377- 

82 (2002). 

15. De A, Lewis XZ, Gambhir SS. “Noninvasive imaging of lentiviral-mediated reporter gene expression in living mice.” Mol Ther. 7(5):681-91 

(2003).


WP8.1: Identification of novel neuroimaging targets in neurodegenerative disease 

Workpackage number WP8.1 Start date or starting event: Start of Program 

Activity Type 


Participant id P31 P1: Jacobs P3: Aime P4: Guilloteau P8: vdLinden 


participant 

P31: 72 P1: 0 P3: 0 P4: 0 P8: 0 

Objectives 

Current tools for the diagnosis of neurodegenerative dementia in the elderly are difficult to implement in a primary care 

setting due to practitioner constraints Few if any of the short term cognitive tests have been assessed against “gold 

standard” diagnostic test batteries with end point neuropathological assessment, and so far have not been uniformly 

recommended [1]. Neuroimaging PET and SPECT has shown improvements in clinical accuracy [2,3,4] and many 

studies have shown brain atrophy particularly of the hippocampus and medial temporal lobes on MRI to be associated 

with dementia [5,6]. In many instances however, these methods lack disease specificity, and it is difficult to detect early 

disease, requiring longitudinal assessment over several years to ensure that age related changes are not being detected 

[7]. There is therefore a pressing need to identify markers for use in disease diagnosis. The use of functional genomics 

with whole genome microarrays and quantitative PCR to identify changes in gene expression coupled to quantitative 

western blotting to validate protein expression permits the rapid identification of potential new targets for neuroimaging 

in neurodegenerative disease [8]. 

Objectives: Identification of novel targets for the future development of neuroimaging ligands in neurodegenerative 

disease including Alzheimer’s disease and related dementias. Whole genome microarray gene expression profiling will 

be performed in: 

a) Patients showing extensive pathology, elderly normal individuals with no cognitive impairment or neuropathology, 

and where possible individuals with no cognitive/motor impairment but with early stage pathology. 


We will use microarray based gene expression profiling of post mortem human brain tissue to identify new targets for 

molecular imaging in the CNS [8]. 

With regards to brain tissue being investigated in WP8.1, tissue is made available from the local tissue bank in 

Newcastle, where contributors have given informed consent prior to death for further studies on their tissues. For tissue 

donation from studies with prospective assessment during life, patients and their families are approached during life 

(with ethical approval), by trained autopsy liaison nurses for a declaration of intent to donate (DOI). The whole autopsy 

procedure is explained in lay terms, describing the actual procedures being undertaken by the pathologist. The person is 

then asked in advance if they wish to consent to these procedures after their death, and also given a choice as to which 

tissues they would wish to be retained for research purposes. The next of kin who are present at this interview also give 

their assent to any procedures. The next of kin are then contacted following death and are again visited by trained 

autopsy liaison nurses, who seek to reconfirm that they are happy with the original DOI. The next of kin are then asked 

to give their consent for a post mortem to be carried out and are offered choices, which include the extent of tissue 

donation, whether the tissue can be used in genetic research, and whether the research team can access medical records. 

a) Cases will be matched as closely as possible for gender, post mortem delay and agonal state (pH). mRNA will be 

isolated from the frozen unfixed brain material from cognitively intact individuals, and from individuals who have been 

followed as part of clinical assessment and treatment and who show typical neurodegenerative pathology, or early stage 

pathological changes. A minimum of six cases in each group will be used to identify reproducible and consistent 

changes in mRNA expression. Tissues are available from the required number of individuals in the tissue bank 

associated with the study. The following tissue regions will be sampled: 

1. Hippocampal formation as a key region involved in short term memory and integrative formation processing. 

2. Cerebellum as control region that shows an absence of pathology and does not relate to any major 

neuropsychological indicators of cognitive decline. 

Gene expression profiling will be achieved using whole genome microarray (approximately 40,000 human genes) with 

validation using q-PCR [8]. Expression at the protein level will be quantified using western blotting where possible. 

Task 8.1.1 Microarray analysis of Alzheimer brain tissue. Analysis of cerebellar and hippocampal tissue from AD


cases for alterations in gene expression. 

Task 8.1.2 Analysis of protein expression. Identification of important changes in the expression of proteins using 

western blotting in AD brains. 

Deliverables 

Validated series of target genes whose expression at protein level is up or down regulated in AD brain. 

D8.1.1 Sectioning of tissues for laser capture 

D8.1.2 Extraction and quality control of RNA 

D8.1.3 Amplification and array hybridisation 

D8.1.4 Western blot based validation of targets 

D8.1.5 Discussion and selection of imaging targets 

D8.1.6 reporting on the relevant and applicable regulations of ethical issues (12 mo) 

Milestones 

Dissemination of a target list of expressed genes for Alzheimer’s disease and early pathology within the Network 

M8.1 Sectioning of tissues for laser capture 

M8.2 Extraction and quality control of RNA 

M8.3 Amplification and array hybridisation 

M8.4 Western blot based validation of targets 

M8.5 Discussion and selection of imaging targets 

Ethical Rules Concerned with the Use of Human Tissues 

Since the ultimate aim of this workpackage is the identification of novel targets for the detection of human 

neurodegenerative disease, human tissue has to be used. Animal tissues are not suitable since most models of human 

neurodegenerative disease only display certain aspects of the disease which they are meant to model and not all of the 

features present. Therefore to maximise the use of the resources and to gain the most appropriate answers, human 

post mortem tissue will be used. The amount of tissue and the number of cases to be used is based on previous 

experience in identifying gene expression changes in human tissues. 

The use of human tissue in the project in Newcastle has been consented to by the respective Local Research Ethics 

Committee (LREC 2003/31) and conforms to the UK MRC Guidelines on the use of tissue in medical research (see 

Human Tissue and Biological Samples for use in Research - Operational and Ethical guidelines (2001) 

(http://www.mrc.ac.uk/pdf-tissue_guide_fin.pdf); Personal Information in Medical Research (2000), 

(http://www.mrc.ac.uk/pdf-pimr.pdf); Health and Social Care Act 2001: "Section 60" (http://www.mrc.ac.uk/pdfpimr_summary.pdf) 

Good Research Practice (2000) (http://www.mrc.ac.uk/pdf-good_research_practice.pdf). 

Additionally the use of the material conforms to the principles enshrined in the Charter of Fundamental Rights of the 

European Union (2000), The Convention on Human Rights in Medicine (1997), and the Declaration of Helsinki. All 

material to be used is obtained with prior informed consent from the individuals and this is assented to in advance by 

the next of kin (see “Description of Work”). This is of paramount importance in the consenting process when 

individuals with some form of cognitive impairment are being studied. At death, and in line with UK Legal Guidance, 

formal informed consent for autopsy and tissue retention for medical research is obtained from the next of kin. Use of 

the tissue whilst having been approved by the LREC, is also approved by the Newcastle Brain Tissue Resource which 

consists of an independent Chairperson, lay-members, and scientific advisors, who scrutinise application and grant 

final use of any tissues.



1. Knopman, D.S., DeKosky, S.T., Cummings, J.L., Chui, H., Corey-Bloom, J., Relkin, N., Small, G.W., Miller, B. and Stevens, J.C., Practice 

parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of 

Neurology, Neurology, 56 (2001) 1143-53. 

2. de Leon, M.J., Convit, A., Wolf, O.T., Tarshish, C.Y., DeSanti, S., Rusinek, H., Tsui, W., Kandil, E., Scherer, A.J., Roche, A., Imossi, A., Thorn, 

E., Bobinski, M., Caraos, C., Lesbre, P., Schlyer, D., Poirier, J., Reisberg, B. and Fowler, J., Prediction of cognitive decline in normal elderly 

subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET), Proc Natl Acad Sci U S A, 98 (2001) 10966-71. 

3. Kotrla, K.J., Chacko, R.C., Harper, R.G., Jhingran, S. and Doody, R., SPECT findings on psychosis in Alzheimer's disease, Am J Psychiatry, 152 

(1995) 1470-5. 

4. Lobotesis, K., Fenwick, J.D., Phipps, A., Ryman, A., Swann, A., Ballard, C., McKeith, I.G. and O'Brien, J.T., Occipital hypoperfusion on SPECT 

in dementia with Lewy bodies but not AD, Neurology, 56 (2001) 643-9. 

5. Jack, C.R., Jr., Petersen, R.C., Xu, Y., O'Brien, P.C., Smith, G.E., Ivnik, R.J., Boeve, B.F., Tangalos, E.G. and Kokmen, E., Rates of 

hippocampal atrophy correlate with change in clinical status in aging and AD, Neurology, 55 (2000) 484-89. 

6. Kantarci, K., Xu, Y., Shiung, M.M., O'Brien, P.C., Cha, R.H., Smith, G.E., Ivnik, R.J., Boeve, B.F., Edland, S.D., Kokmen, E., Tangalos, E.G., 

Petersen, R.C. and Jack, C.R., Jr., Comparative diagnostic utility of different MR modalities in mild cognitive impairment and Alzheimer's 

disease, Dement Geriatr Cogn Disord, 14 (2002) 198-207. 

7. Laakso, M.P., Lehtovirta, M., Partanen, K., Riekkinen, P.J. and Soininen, H., Hippocampus in Alzheimer's disease: a 3-year follow-up MRI 

study, Biol Psychiatry, 47 (2000) 557-61. 

8. Wilson, KE, Ryan MM, Prime JE, Pashby DP, Orange PR, O’Beirne G, Whateley JG, Bahn S, Morris CM (2004) Functional Genomics: 

Application in Neurosciences. J Neurol Neurosurg Psych, 75: 529-538.


WP8.2: Early diagnosis of neurodegenerative disease 

Workpackage number WP8.2 Start date or starting event: Start of programme 

Participant id 

P1:Herholz P7:Knudsen P10:Bengel P17:Brooks P20:Ebmeier P29:Leenders 

P34:Pappata P36:Perani P39:Salmon P41:Van Laere P45:Masdeu P33:Nordberg 

Person-month per P1: 6 P7: 6 P10: 6 P17: 6 P20: 12 P29: 6 

participant 

P34: 9 P36: 6 P39: 6 P41: 12 P45: 6 P33: 6 

Objectives 

The subsets of the aim of this workpackage are: 

• in a large scale study to map and follow the functional status of relevant neuroreceptor systems or other 

biomarkers in patients with neurodegenerative disorders and in a normal ageing population with the best 

methods currently available, 

• to validate currently used methods for PET or SPECT data analysis and to explore new approaches towards 

comparisons between normal and diseased brains taking brain atrophy into account, 

• to relate the findings from molecular imaging with progression rates and over-all prognosis, 

• on the basis of these results, to establish the diagnostic value of neuroreceptor imaging tools for a nosological 

classification in the elderly patient with memory disturbances or parkinsonism, 

• on the basis of the obtained results to point to new areas for potential drug development. 

These goals will be achieved by a joint effort of 11 European centres with proven expertise within both dementia 

research and molecular brain imaging. Research groups in Europe are actively bringing new imaging techniques into 

scientific clinical application. Only through a concerted action and large-scale studies it will become possible to 

compare these approaches in terms of their practicability and efficacy. This network will permit to facilitate the transfer 

of experimental techniques into the clinical arena, and through standardization procedures including standardized data 

evaluation it will enable a better comparison between the outcome of the studies. 


Inclusion criteria and clinical workup for patients and healthy control subjects will closely follow those already defined 

in previously EU-funded projects (NEST-DD contract QLK6-1999-02178 coordinated by K. Herholz, 2000-2003, and 

NCI-MCI contract QLK6-2000-00502 coordinated by G.M. Knudsen, to be terminated by February 2005). 

The following patient groups will be included: 

• Mild cognitive deficits (MCI) according to Petersen et al. (Petersen, 2001) 

• Mild dementia (CDR stage 0.5 or 1) of Alzheimer (AD), Lewy body (DLB) or vascular type (VD) who are still 

able to provide valid informed consent (Buckles, 2003) 

• Parkinson disease at risk of dementia, but not yet demented 

• Normal controls 

All subjects will be examined clinically, with documentation according to standard rating scales, neuropsychologically, 

and with T1 and T2-weighted MRI according to a common baseline protocol at all participating sites. Patients will be 

followed by yearly clinical and neuropsychological examinations for at least two years to detect progression. 

The following molecular imaging techniques will be performed in the subprojects: 

1. Acetylcholine esterase activity by C-11-MP4A PET in 20 MCI patients and 20 age-matched controls (P1, P41) 

2. Serotonin (5HT 4 ) receptors by C-11-SB207145 in 10 patients with mild AD and 10 control subjects (P7) 

3. Nicotinic receptors with I-123-A85380 SPECT in 10 patients with MCI and 10 controls (P20) 

4. Amyloid deposition by C-11-PIB PET in 20 patients with MCI, 10 mild AD, and 20 controls (P33, P41, P10) 

5. Benzodiazepine receptor binding by C-11-flumazenil PET in 20 patients with mild vascular dementia, 10 mild 

AD and 10 normal controls (P45) 

6. Benzodiazepine receptor binding by I-123-iomazenil SPECT in 10 patients with MCI, 10 mild AD and 10 

normal controls (P34) 

7. Dopamine transporters by C-11-FECIT PET and by I-123-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4- 

iodophenyl)nortropane (DaTSCAN) SPECT in 20 patients with Parkinson disease, 10 mild DLB, and 10 

controls (P36) 

8. Serotonin (5HT 1A ) receptors in 20 patients with MCI and 20 controls (P39, P45)


Deliverables 

D8.2.0 Meeting with WP8.2 members for final agreement and initiation of work plan 

D8.2.1 Protocol drafts to perform standardized and coordinated baseline studies (by end of month 3, to be 

accepted and consolidated for submission to ethics committees) 

D8.2.2 Approvals from local ethics committees (12 mo) 

D8.2.3 Approval by the respective ethics committees will be presented to the EC before start of subject 

recruitment (13 mo) 

D8.2.4 Presentation of molecular techniques to be used in this protocol to other participants and to other 

interested parties, in particular pharmaceutical industry (12 mo, 18 mo) 

D8.2.5 Start of studies with inclusion of first patients and controls (18 mo) 


Milestones 

M8.2.0 

M8.2.1 

M8.2.2 

M8.2.3 

Common meeting of partners (1mo) 

Definition of coordinated and detailed study protocols for submission to ethics committees (6 mo) 

Start of clinical studies after approval by ethics committees (14 mo) 

Recruitment of first patients and controls (18 mo) 


Inclusion criteria and clinical workup for patients and healthy control subjects will closely follow those already 

defined in previously EU-funded projects (NEST-DD contract QLK6-1999-02178 coordinated by K. Herholz, 2000- 

2003, and NCI-MCI contract QLK6-2000-00502 coordinated by G.M. Knudsen, to be terminated by February 2005). 

Studies will be performed according to the applicable laws and regulations (see ethics section), and approval by the 

respective ethics committees will be presented to the EC before start of subject recruitment (deliverable 2). Apart 

from the more general objectives listed above, the proposed studies will test the hypothesis whether a particular 

imaging marker or transmitter deficit predicts development/progression of clinical dementia. Subject numbers 

between 10 and 20 for each subject group are sufficient because only methods with a high prediction probability that 

can be detected with this study size would be candidates for further studies. 

Literature 

1. Brooks DJ, Frey KA, Marek KL, Oakes D, Paty D, Prentice R, Shults CW, Stoessl AJ. Assessment of neuroimaging techniques as biomarkers of 

the progression of Parkinson's disease. Exp Neurol. 2003;184 Suppl 1:68-79. 

2. Buckles VD, Powlishta KK, Palmer JL, Coats M, Hosto T, Buckley A, Morris JC. Understanding of informed consent by demented individuals. 

Neurology 2003; 23;61(12):1662-6 

3. Herholz K. PET studies in dementia. Ann Nucl Med. 2003;17:79-89. 

4. Knudsen GM: Assessment of neuroreceptor changes in healthy ageing and in Alzheimer’s disease with emission tomography. In Abe K, et al, eds. 

Molecular Mechanism and Epochal Therapeutics for Ischemic stroke and Dementia. Int Congress Series 2003; 1813:1-10. 

5. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winblad B. Current concepts in mild cognitive 

impairment. Arch Neurol. 2001; 58(12):1985-92


WP9: Neuroinflammation 

Workpackage number WP9 Start date or starting event: Start of Programme 

Activity Type 



P7: Knudsen P1:Jacobs P5: Planas P17: Brooks P33: Nordberg P34: Pappata 

P36: Perani P42: Vivien 

Person-months per P7: 30 P1: 6 P5: 12 P17: 24 P33: 12 P34: 6 

participant 

P36: 24 P42: 24 

Objectives: 

Many neurodegenerative disorders are in various stages of the disease also associated with inflammatory responses, 

some of which can be viewed as deleterious, leading to exaggerated and unwanted neuronal damage. Since 

inflammation is such an essential feature in many brain disorders, visualization of inflammatory responses is likely to 

provide not only information about extent, localization and course of the disease process but it may also prove to 

accurately reflect treatment responses. The aim of this workpackage is to explore the potential of molecular imaging 

with MR and PET to accurately detect and follow neuroinflammation. The work will encompass methodological 

development of MR-technology and synthesis of new PET- and MR-probes for detection of inflammation. After 

successful development, the probes will be evaluated first in in vitro studies, then in vivo, in normal animals. In 

addition, the currently used PET-tracer for microglia activation, [ 11 C](R) –PK11195, will be validated against standard 

histological examinations. The outcome of the molecular imaging techniques will be investigated against state-of-the 

art histological examination, including immunohistochemistry, autoradiography, and in-situ hybridization. The 

different methods performance will be investigated in animal models of stroke, Parkinson’s, and meningitis. The 

techniques will be taken into patients with parkinsonism, multiple sclerosis, memory disorders, prion protein disease, 

and Huntington’s disease where the degree of inflammation as evaluated by molecular imaging techniques is related 

to disease severity and progression. 


The aims of this WP are to 

I. develop and validate new methodology using established and new molecular imaging probes for MR and 

PET and investigate their ability to accurately reflect inflammation as compared to histological examinations. 

II. investigate the involvement and time course of gliosis in relation to disease severity or –progression, as 

revealed by molecular imaging 

III. 

IV. 

relate gene expression profiling to the propagation and perpetuation of neuronal degeneration 

determine whether blood-derived tissue plasminogen activator (tPA) can influence neuronal damage after 


Description of subprojects: 

I. Develop and validate new methodology using established and new molecular imaging probes for MR and 

PET 

1. Q-space methodology will be developed at a 3T MR-scanner in order to characterize micro-structural changes in 

patients with 50 newly diagnosed patients with multiple sclerosis. Local ethical approval is already established. 

(P7) 

2. Blood-brain barrier integrity will be investigated in 10 patients with multiple sclerosis by means of serial 

quantitative T1 MR-imaging measurements at 3T using bolus contrast agent administration with subsequent 

kinetic analysis. Local ethical approval is already established. (P7) 

3. t-PAstop will be labelled with 11 C-labelled as a probe for both exogenous and endogenous tPA; the probe is 

validatated in terms of tissue distribution and metabolism of 11 C-tPAstop-tPA complexes after intravenous 

injection in 8 fully anesthetized control rats. After the PET-examination, the rats are decapitated (P42) 

4. Paramagnetically labelled tPA will be synthesized for MR scanning purposes (P42) 

5. Paramagnetically labelled tPA will be evaluated after intravenous injection in 8 fully anaesthetized control rats 

for determination of blood-brain barrier passage and brain distribution. Rats are decapitated, brains are taken out 

and fixed prior to MR scanning. (P42)


6. Development of new radioligands for in vivo PET studies of microglia activation. New PET radioligands for the 

in vivo study of microglia activation will be performed in 15 rats with monolateral striatal injection of an 

excitotoxin, quinolinic acid (QA). This is a well established model for neurodegenerative disease, such as 

Parkinson’s disease and it has the inherent benefit that one half of the brain can serve as normal reference tissue, 

thereby reducing the number of sacrificed animals. Experiments are performed under general anaesthesia 8 days 

after the lesion, by intravenous injection of approx. 100:Ci specific radiotracer. The surgery will be performed 

under pentobarbital anaesthesia and every suffering of the animals will be minimized in the mean period. (P36) 

II. 

Involvement and time course of markers of gliosis in relation to disease severity and –progression 

1. Activated microglia in terms of radioligand binding to peripheral T 3 -benzodiazepine receptors will be will be 

evaluated ex-vivo, either by tissue dissection or authoradiography and using [ 11 C](R) –PK11195 as a tracer. It 

will also be visualized with PET and [ 11 C](R) –PK11195; the specificity and sensitivity of [ 11 C]PK11195 binding 

to identify microglial activation will be determined in 12 rats where intrastriatal administration of QA (see above) 

has been done. The presence of activated microglia will be confirm using immunohistochemical techniques. For 

evaluation of the longitudinal degeneration of striatum and the relative activation of microglia, we will perform 

additional ex-vivo binding studies with [C-11]PK11195 at 15, 30 and 60 days after QA administration (5 animals 

each time frame). (P36) 

2. In coordination with WP5, [ 11 C]PK11195 PET binding assessments will be done in a rat stroke model with 

middle cerebral artery occlusion/reperfusion, as described in WP5, in ten ischemic rats and ten control rats. Rats 

will be investigated fully anaesthetized and in conjunction with the PET-scan they will be decapitated. (P5) 

3. The effects of exogenous as well as endogenous t-PA in the development of ischemic brain damage is examined. 

Brain lesion sizes will be assessed following intravenous t-PA injection in four groups, each consisting of 8 rats 

1) intrastriatal injection of NMDA +/- subsequent intravenous injection of recombinant tPA 2) occlusion of the 

middle cerebral artery (MCA) +/- subsequent intravenous injection of recombinant tPA 3) control rats for 1) and 

2). Rats are investigated 24 hours after NMDA injection or MCA occlusion. For NMDA experiments, NMDA is 

injected into left striata (50 nmole in 3 µl) 30 min. prior intravenous injection of rectPA (0.9 mg/kg) and 

excitotoxic lesion measured at 24 hours. MCA animal models are described in WP5. The ability following 

intravenous injection of labelled-tPA to cross the BBB and of tPA to promote neuronal damages will be assessed 

from PET-scanning and subsequent histological examinations. MR analyses will be performed in parallel by 

using paramagnetic labelled tPA in control and diseased rats. PET studies will also be performed by using 

complexes of recombinant tPA with 11 CtPAstop in 4 baboons in control condition and if judged necessary 

following occlusion of the middle cerebral artery (same animals). The baboons are Papio anubis baboons, bred in 

captivity, Primate Center of Le Rousset, France. (P42) 

4. Fourty patients with idiopathic and atypical Parkinsons disease will be studied longitudinally over 2 years with 

[ 11 C](R) –PK11195 and [ 18 F]-dopa PET in order to determine the relationship between the pattern and size of the 

immune response and rate of loss of nigrostriatal dopaminergic dysfunction over time. (P17) 

5. Ten patients with MCI and ten patients with AD will be investigated with the amyloid tracer [ 11 C]PIB and 

compared to a marker of inflammation [ 11 C]deprenyl. (P33) 

6. Ten patients with multiple sclerosis will be investigated with MR and [ 18 F]FDG to correlate patterns of cortical 

metabolism to that of the MR and clinical findings. (P34) 

7. [ 11 C](R) –PK11195 PET studies will be conducted in ten patients with mild cognitive impairment, ten patients 

with Alzheimer’s disease, five patients with prion protein disease, five patients with Huntington’s disease, and in 

ten healthy subjects. (P36) 

III. Validation of molecular imaging probes against gold-standard histological examinations 

The performance of MR methods for their ability to accurately reflect inflammation will be evaluated in the 20 rats 

with meningitis and 20 control rats. Meningitis is induced in adult male Wistar rats, housed three in each cage with 

food and drink ad libitum. The rats are anaesthetized with isoflurane and infected by transcutaneous intracisternal 

injection of by inoculation with 107 colony forming units/ml of Streptococcus pneumoniae, serotype 3. After 

inoculation, the rats are allowed to recover from anaesthesia. Studies are undertaken in full anaesthesia 14 hours at the 

latest, after inoculation. After the MR scan, the rats are decapitated and standard invasive histopathology and 

autoradiography/in situ hybridisation will be performed. The identification of specific neuroinflammatory markers in 

PET and MR agents have been described in II.3. (P7)


IV. Gene expression profiling during propagation and perpetuation of neuronal degeneration 

is determined using microarray techniques, proteomics, and flow cytometry in blood samples from patients with 

multiple sclerosis (described in I.2), after their informed written consent has been obtained. MR-scans will be 

conducted three times within the first 6 months, and blood samples will be taken in conjunction with the scans (P7) 

Deliverables 

D9.1 Establishment of in- and exclusion criteria for all patient groups (3 M) 

D9.2 Specification of ethical aspects with particular emphasis on patients with degenerative brain disorders 

and dementia and national regulations (3 M) 

D9.3 Specification of ethical aspects in animal models with particular emphasis on national regulations (3 M) 

D9.4 Establishment of [ 11 C](R) –PK11195 in other DiMI laboratories (12 M) 

D9.5 BBB, microglial probes and tPA probes validated (15 M) 

D9.6 Establishment of the ability of tPA and tPAstop-tPA complexes to cross the blood-brain barrier and 

tissue distribution (6M) 

D9.7 Implementation of protocols for MR-imaging (6 M) 

D9.8 Initial histopathological validation of current neuroimaging markers of inflammation (18 M) 

D9.9 Initial blood-brain barrier integrity studies in patients with multiple sclerosis (18 M) 

D9.10 Initial in-vivo studies in models of cerebral ischemia (12 M) 

D9.11 Cross-sectional MR and/or PET in patients with MS, parkinsonism, memory dysfunction, HD, and 

prion disease (18 mo) 

D9.12 Paramagnetically labelled tPA made available to other partners (15 mo) 

D9.13 Biochemical inflammatory markers, gene expression, and proteonics in patients (12 mo) 


Milestones within the first 18 months 

M9.1 Q-space methodology implemented at 3T MR-scanner and evaluated in healthy subjects (12 M) 

M9.2 Q-space MR-studies conducted in patients with multiple sclerosis (18 M) 

M9.3 Blood-brain barrier integrity investigated in patients with multiple sclerosis by 3T MRI using bolus 

contrast agent administration (18M) 

M9.4 t-PAstop will be labelled with 11 C (6 M) 

M9.5 Brain tissue distribution and metabolism of 11 C-tPAstop-tPA complexes after intravenous injection in 

control rats (9 M) 

M9.6 Paramagnetically labelled tPA synthesized (9 M) 

M9.7 Paramagnetically labelled tPA is evaluated after intravenous injection in control rats (18 M) 

M9.8 Development of new PET radioligands for in vivo studies of microglia activation (12 M) 

M9.9 New PET radioligands evaluated in healthy and in QA injected rats (18 M) 

M9.10 Specificity and sensitivity of [ 11 C]PK11195 binding to identify microglial activation in QA rats through 

histological gold-standard evaluation (18 M) 

M9.11 [ 11 C]PK11195 PET binding assessments in a rat stroke model (18 M) 

M9.12 Cross-sectional study in patients with idiopathic and atypical Parkinsons disease with [ 11 C](R)–PK11195 

and [ 18 F]-dopa PET is completed (15 M) 

M9.13 Cross-sectional study in patients with MCI and AD with [ 11 C]PIB and [ 11 C]deprenyl is completed (15 M) 

M9.14 Cross-sectional study in patients with multiple sclerosis and healthy control subjects with MR and 

[ 18 F]FDG is completed (15 M) 

M9.15 Cross-sectional study in patients with mild cognitive impairment, Alzheimer’s disease, prion protein 

disease, or Huntington’s disease with [ 11 C](R) –PK11195 is completed (18 M) 

M9.16 Study of correlations between MR methods and standard invasive histopathology and autoradiography/in 

situ hybridisation in rats with and without meningitis completed (18 M) 

M9.17 Microarray techniques and proteomics in patients with multiple sclerosis are compared to MR imaging 

methods (18 M) 

Ethical rules concerned with the use of laboratory animals in WP9 

Details on ethical rules to be conformed with in WP9 are given in Section 11. Ethical Issues. As mentioned in Section 

11 all experimental procedures in animals and studies involving humans or human material are subjected to approval 

by authorities according to national legislation. 

The partners in WP9 involved with human studies all have many years of experience with ethical legislation and have 

a vast numbers of open protocols that have been approved in the past. With respect to ethical aspects, there are no


exemptions within the work described above that principally differ from their previous protocols. studies will be 

performed in patients which are legally able to give consent. For patients with neurodegenerative disorders, only those 

that are able to receive, understand and accept an informed consent will be included. This is not likely to present any 

major problem because WP9 is focused on early detection of neurodegeneration, that is, the patients are only mildly 

affected by their neurodegenerative disorder and can legally determine the own rights. With informed consent 

imaging data will be stored in the DiMI clinical database. Children and demented patients who are legally not able to 

give consent are excluded from WP9. 

Blood and cerebrospinal fluid samples from patients are usually acquired on a routine basis for diagnostic 

classification. Cerebrospinal fluid samples will not be collected from control subjects. The patients can at any time ask 

to have their sample removed and destroyed. After ethical approval for collection, storage and analyses of blood and 

cerebrospinal fluid samples, patients will be informed that additional laboratory test as a part of the research study is 

planned and their informed written consent will be obtained. Aliquots of blood and spinal fluid samples will be 

prepared at the respective centres and stored according to national guidelines. The informed consent data form will be 

anonymized locally and sent to a central database in Copenhagen, Denmark (P7), by electronic or fax transmission. 

Thus, personal data of the donors are kept within the confidentiality of the assessing physician and the head of the 

respective department, who is participating in DiMI. Blood and spinal fluid samples are then subjected to microarraybased 

gene expression profiling to search for new genes involved in the regulation of neuroinflammation potentially to 

be used as surrogate markers in terms of in vivo imaging. Results will be stored in a central DiMI-related database in 

Copenhagen, Denmark (P7). P7 has extensive experience in human genetic studies and in how to comply with the 

local and national regulations with regards to the collection, storage and use of genetic material and information. 


minimum amount of animals needed. Further, we care for the welfare of laboratory animals: 

a) animals are maintained under standardized environmental conditions of temperature and humidity and a day/night 

light cycle; animals are kept in appropriate cages with no more than 4 animals per cage; animals are allowed free 

access to food and water; 

b) surgical interventions are always performed under general anaesthesia; after surgery, local anaesthetics are applied 

to avoid animal suffering. Finally, methods alternative to the use of animals, such as cell cultures, are employed 

where possible and applicable, and the assessments of biological actions of novel probes for imaging is always 

first carried out and validated in vitro, prior to animal studies. Details on the single projects are given above. 

Related literature authored by DiMI partners 

1. Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, Jones T, Banati RB. In-vivo measurement of 

activated microglia in dementia. Lancet. 2001;358:461-7. 

2. Banati RB, Goerres GW, Myers R, Gunn RN, Turkheimer FE, Kreutzberg GW, Brooks DJ, Jones T, Duncan JS. [11C](R)- 

PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen's encephalitis. Neurology. 

1999;53:2199-203. 

3. Gerhard A, Banati RB, Goerres GB, Cagnin A, Myers R, Gunn RN, Turkheimer F, Good CD, Mathias CJ, Quinn N, 

Schwarz J, Brooks DJ. [(11)C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy. Neurology. 

2003;61:686-9. 

4. Yu WF, Nordberg A, Ravid R, Guan ZZ. Correlation of oxidative stress and the loss of the nicotinic receptor alpha 4 

subunit in the temporal cortex of patients with Alzheimer's disease. Neurosci Lett. 2003;338(1):13-6. 

5. Chuquet J, Benchenane K, Liot G, Fernandez-Monreal M, Toutain J, Blanchet S, Eveno E, Auffray C, Pietu G, Buisson A, 

Touzani O, MacKenzie ET, Vivien D. Matching gene expression with hypometabolism after cerebral ischemia in the 

nonhuman primate. J Cereb Blood Flow Metab. 2002;22:1165-9. 

6. Docagne F, Nicole O, Gabriel C, Fernandez-Monreal M, Lesne S, Ali C, Plawinski L, Carmeliet P, MacKenzie ET, 

Buisson A, Vivien D. Smad3-dependent induction of plasminogen activator inhibitor-1 in astrocytes mediates 

neuroprotective activity of transforming growth factor-beta 1 against NMDA-induced necrosis. Mol Cell Neurosci. 

2002;21:634-44. 

7. Melton LM, Keith AB, Davis S, Oakley AE, Edwardson JA, Morris CM. Chronic glial activation, neurodegeneration, and 

APP immunoreactive deposits following acute administration of double-stranded RNA. Glia. 2003;44:1-12. 

8. Hussain RI, Ballard CG, Edwardson JA, Morris CM. Transferrin gene polymorphism in Alzheimer's disease and dementia 

with Lewy bodies in humans. Neurosci Lett. 2002;317:13-6. 

9. Sager TN, Topp S, Torup L, Hanson LG, Egestad B, Moller A. Evaluation of CA1 damage using single-voxel 1H-MRS 

and un-biased stereology: Can non-invasive measures of N-acetyl-asparate following global ischemia be used as a reliable 

measure of neuronal damage? Brain Res. 2001;892(1):166-75. 

10. Sellebjerg F, Jensen CV, Larsson HB, Frederiksen JL. Gadolinium-enhanced magnetic resonance imaging predicts 

response to methylprednisolone in multiple sclerosis. Mult Scler. 2003;9:102-7. 

11. Hogh P, Oturai A, Schreiber K, Blinkenberg M, Jorgensen OS, Ryder L, Paulson OB, Sorensen PS, Knudsen GM. 

Apoliprotein E and multiple sclerosis: impact of the epsilon-4 allele on susceptibility, clinical type and progression rate. 

Mult Scler 2000;6:226-30.


WP10: Stem cell trafficking in the CNS 


Activity Type 



P1:Jacobs P15:Kirik P25:Hoehn P8:vdLinden 52: Sykova P10:Bengel 

P26:Hofstra P9:Moonen P14:Baekelandt 

Person-months per P1: 30 P15: 24 P25: 33 P8: 24 52: 24 P10: 0 

participant 

P26: 0 P9: 0 P14: 30 

Objectives: 

Cell transplantation has over the last two decades emerged as a promising approach for restoration of function in 

neurodegenerative diseases, in particular Parkinson´s and Huntington´s disease. The recent demonstration that (i) 

immature neural progenitor cells with multipotent properties can be isolated from both the developing and adult 

central nervous system (CNS), (ii) these cells can be maintained, propagated and modified in culture, (iii) modified 

cells can be transplanted back into the body, (iv) they migrate into diseased sites due to chemokines or cytokines, and 

that (v) they potentially differentiate into various cell types, has provided a new interesting tool for restorative cell 

replacement in the damaged or diseased brain. Moreover, it has been shown that overexpression of BDNF after 

transduction with an adenoviral vector in the adult mouse ventricular zone can induce the recruitment of endogenous 

progenitor cells to the olfactory bulb and the neostriatum (Benraiss et al. 2001). 

The principal goal of this WP is to graft defined subsets of murine neural stem (NSC) and progenitor cells (NPC) as 

well as rat ensheating glial cells and rat bone marrow stromal cells and compare their in vivo properties with respect to 

their ability to differentiate into cells within the neural lineage in the developing and adult central nervous system. 

Special emphasis will be made on the ability of NPC/NSC’s to home to injury sites in the adult rat brain. Moreover, 

the potential of lentiviral vectors (LV) to transduce endogenous neural precursor cells in situ in the adult rodent brain 

with subsequent induction of (i) proliferation (LV-mediated GDNF expression), (ii) migration, (iii) differentiation and 

(iv) repair of brain damage resulting from neurodegeneration shall be explored. 

In this respect, molecular imaging techniques open up new possibilities in our ability to study aspects of graft 

integration into the host brain circuitry with regard to several aspects: 

1. induction of NPC in vivo. 

2. tracking of labelled stem cells in vivo during their migration towards the target site thus understanding the 

dynamics of survival and migration. 

3. monitoring the differentiation in normal host environment in vivo. 

4. possibility to provide image-guided control of differentiation due to expression of specific (trans)genes 

(cytokines, others). 

5. guiding the use of stem cells as vectors in gene therapy. 


1. to optimize strategies for labelling NPC and NSC for visualization by optical, radionuclide and MR imaging. 

2. to optimize parameters for visualization of grafted NPC/NSC in the brain in vivo by microPET and MRI. 

3. to monitor NPC/NSC migration, maturation, and integration in experimentally injured brain site in vivo. 

4. to develop molecular imaging markers for non-invasive assessment of stem cell differentiation. 

5. to transduce NPC/NSC with transgenes under NPC/NSC-specific and regulatable promoters. 

6. to transduce endogenous neural precursor cells in adult mouse brain after stereotactic delivery of LV-GFP. 

7. to induce proliferation of transduced NPC by local over-expression of neuronal growth factors (GDNF). 

8. to recruit transduced NPC into regions of neurogenesis (bulbus olfactorius) or neurodegeneration. 

9. to induce and non-invasively follow neuro-regeneration by recruited and transduced NPC in animal models of 

neurodegeneration. 

10. to develop new methods for visualizing the functional impact of NPC/NSC grafts.



1. Labelling of NPC and NSC with MRI contrast agents: in vivo MRI results of labelled stem cell populations have 

demonstrated the detection of a few hundred cells while single cells have been observed in vitro at high magnetic 

field strength. The objective is to further improve the MRI sensitivity for detection and tracking of smaller cell 

numbers in vivo involving two strategies: i) improving labelling strategies of NPC/NSC with MRI contrast 

agents; and ii) improving MRI detector hardware for enhancement of sensitivity per recording time unit. 

Experiments in vivo will be performed in 10-20 rats in a model of focal cerebral ischemia and slow 

neurodegenerative diseases (esp. Parkinson's disease) as outlined below (Hoehn, Moonen, Sykova, Kirik). 

2. Genetically engineer NPC/NSC to make them suitable for the detection by radionuclide and optical imaging 

methods: radionuclide and optical imaging methods are potentially more sensitive in detecting stem cells. NPC 

and NSC will be transduced with the PET marker gene HSV-1-tk as well as the optical imaging marker gene 

luciferase in co-expression cassettes allowing detection of these cells by both imaging methods. Various vector 

systems will be explored for transduction (HSV-1, retro-/lentiviral, AAV). These co-expression constructs will 

then be used in the 2nd period of the proposal to co-express additional therapeutic genes. This work involves 

experiments in cell culture, only (Jacobs, Kirik, Hofstra, Bengel, Moonen). 

3. Evaluation of the effects of cell labelling and genetic modification for imaging on the behaviour of NPC/NSC. 

Recent reports have indicated a high tolerance of stem cells for labelling and genetic modification. However, 

some reports have indicated some loss of homing capabilities. Rigorous testing will be performed on all stem cell 

types (native and modified) to evaluate toxicity, capacity of differentiation and homing capabilities. Toxicity will 

be assessed in cell culture by trypan blue exclusion staining. Capacity of differentiation will be tested in cell 

culture by withdrawal of growth factors and serum in the presence of substrate and in vivo by imaging 

(MRI/PET) as well as by immunohistochemistry using the differentiation markers beta III tubulin, tau and NeuN 

for neurons, S100ß and GFAP for glia, galactocerebrosidase for oligodendrocytes and markers for immature cells 

(e.g. nestin). Experiments in vivo will be performed in 10-20 rats in a model of focal cerebral ischemia (Kirik, 

Hoehn, Sykova, Jacobs) 

4. Stem cell proliferation and differentiation is thought to occur under the local influence of cell signalling, e.g. via 

cytokines and chemokines. Controlled expression of these signals therefore has the potential of guiding cell 

differentiation. We will use tetracycline regulated and tissue specific promoters to control HSV-1-tk and 

luciferase gene expression. During the first 6 months cytokines will be reviewed and the most promising 

cytokine gene will be cloned into vector backbones which have been selected in subproject 2. Experiments will 

involve cloning of the vectors and assessment of regulation in cell culture (Jacobs, Kirik, Hoehn, Hofstra, Bengel, 

Moonen). 

5. Induction and guidance of endogenous NPC by lentiviral vectors in vivo. LV-GFP and LV-GFP-IRES-luciferase 

will be injected in the subventricular zone of mouse and rat brain. BrdU will be used as a label for cell 

proliferation, nestin as a marker for NPC, NeuN as a marker for neurons. Immunohistochemical stainings of 

GFP-positive cells in the RMS and the bulbus olfactorius will be a read out for efficiency of transduction of NPC. 

Migration of NPC to the bulbus olfactorius will be followed by optical imaging. In a second phase, LV will be 

constructed with NPC-specific promoters and encoding growth factors (GDNF, etc.) Initial characterization 

experiments will be performed in C57BL mice (n=10-20), in normal Wistar rats (n=10-20) and in 6-OHDA 

lesioned Wistar rats (n=10-20). These data will then be compared to the migration and differentiation of NPC 

after transduction of LV encoding different neuronal growth factors in the same animal models. (Baekelandt, van 

der Linden). 

6. Labelling and imaging of NPC/NSC with magnetoliposomes in vivo. Magnetoliposomes will be stereotactically 

injected in the SVZ and the migration of NPC to the bulbus olfactorius will be followed by MRI. Different types 

of magnetoliposomes (5) will be injected after optimizing the dose with one type (15 mice) in the lateral ventricle 

of control mice (25 mice). The mice will be imaged at day 3 and day 30 to visualize the neuronal recruitment. 

From this an optimal NPC tracking protocol with MRI and magnetoliposomes will be established. In a second 

phase, the influence of transduction with LV encoding neuronal growth factors and of a neurotoxic lesion (6- 

OHDA) on the recruitment and migration will be investigated. Recruitment to areas of neurodegeneration of 

magnetized NPC will be followed by MRI. This will be compared to the optical imaging and 

immunohistochemical characterization described in 5. At the end of the experiments described in 5 and 6, the 

animals will be euthanized by an overdose of anaesthesia and the brains will be perfused for histological analysis. 

If the imaging objectives are obtained, the number of animals needed will be reduced significantly, since 

histological analysis at different time points will be omitted. (Baekelandt, Van der Linden) 

7. Imaging endogenous gene expression and functional reconstitution after NPC and NSC replacement. 

Reconstitution of cerebral glucose metabolism, neuronal integrity and dopaminergic function will be imaged by 

multitracer microPET ([ 18 F]FDG, [ 11 C]FMZ, [ 18 F]FDOPA, [ 11 C]RAC) compared to functional scores and


invasive techniques (immunohistochemistry.). Experiments in vivo will be performed in 10-20 rats in a model of 

focal cerebral ischemia (Jacobs, Hoehn). 

Deliverables 

D10.0 Meeting with WP10 members for initiation of work plan (1 mo) 

D10.1 Common protocol for improved labelling of NP/NSC with MRI contrast agents (12, 18 mo) and in vitro 

assessment of sensitivity of MRI detection of labelled cells (6, 12, 18 mo). 

D10.2 Common protocol for magneto-liposomes targeting specifically NPC (12, 18 mo). 

D10.3 Genetically engineered NPC/NSC expressing tkIRESluc (6, 12, 18 mo). 

D10.4 Detection of tkIRESluc expressing NPC/NSC using PET and optical imaging (12, 18 mo). 

D10.5 Common data for the detection sensitivity of NPC/NSC by MRI, PET and optical imaging (12, 18 mo). 

D10.6 Assessment of behaviour of native/modified NPC/NSC with respect to toxicity due to labelling procedure, 

differentiation capabilities and homing potential with multimodal imaging (6, 12, 18 mo). 

D10.7 Vectors for controlled and specific tkIRESluc marker gene expression in NPC/NSC (12, 18 mo). 

D10.8 Multi-tracer microPET/microSPECT in the assessment of metabolism and function after NP/NSC 

transplantation (18 mo). 



M10.0 Common meeting of partners (1 mo) 

M10.1 Improved techniques for labelling of NPC/NSC (6, 12 mo) 

M10.2 Improved techniques for multi-modal, high-resolution, sensitive imaging of NPC/NSC (12, 18 mo). 

M10.3 In vivo transduction of NPC using LV vectors in mouse and rat brain (6, 12, mo). 

M10.4 Induction of proliferation and differentiation after LV transduction of NPC (12, 18 mo). 

M10.5 Vectors serving controlled expression of imaging genes, cytokines and growth factors (12, 18 mo). 

M10.6 Recruitment of transduced NPC into regions of ischemia and/or neurodegeneration with multimodal 

imaging (12, 18 mo). 

M10.7 Correlation of stem cell behaviour in vivo with metabolism and function (12, 18 mo). 

Ethical rules concerned with the use of laboratory animals in WP 10 

Experimental procedures in animals are subjected to approval by the Local Ethics Committee, installed by the Local 

German Government Authorities in Cologne. All animal experimentation will be conducted in accordance with the 

European current guidelines (86/609/CEE) as well the National Institutes of Health animal protection guidelines. The 

animals in our animal house at the Max-Planck-Institute for Neurological Research in Cologne include Sprague- 

Dawley- and Wistar-rats and C57Black- and SV129-mice. Animals are provided by a supplier (Charles River, Lyon , 

France). Personnel directly involved in the animal work are adequately trained and licenced animal carers, under 

regular inspection by an official veterinarian appointed by the Local Government Authorities. Assessors for Partners 1 

and 25 in ethical issues concerning WP10: Prof. Dr. Günter Mies, specialist in Laboratory Animal Science and 

appointed by the Local Government Authorities for the supervision of implementation of the ethical instructions, as 

set and defined in the official permissions for animal experimentations, issued by the Local Government Authorities. 


minimum amount of animals needed. Further, we care for the welfare of laboratory animals: a) animals are maintained 

under standardized environmental conditions of temperature and humidity and a day/night light cycle; animals are 

kept in appropriate cages with no more than 4 animals per cage; animals are allowed free access to food and water; b) 

surgical interventions are always performed under general anaesthesia (halothane or isoflurane; with N 2 O); after 

surgery, local anaesthetics are applied to avoid animal suffering; c) animals are always sacrificed under general 

anaesthesia. Finally, methods alternative to the use of animals, such as cell cultures, are employed where possible and


applicable, and the assessments of biological actions of novel probes for imaging is always first carried out and 

validated in vitro, prior to animal studies. 

Handling and surgical procedures of animals for the experiments planned in WP10: 

Male Wistar rats (body weight 280-320 g) are used for the induction of stroke. All surgical procedures are done under 

general anaesthesia. For stroke induction, the intraluminal filament occlusion technique is applied where a suture is 

advanced through the internal carotid artery to the branching-off point of the middle cerebral artery (MCA) thereby 

blocking blood supply to the territory supplied by the MCA. After one to two hours of MCA occlusion, the filament is 

withdrawn and reperfusion of the MCA re-established. Wounds are sutured and treated with local anaesthetics. 

Two weeks later, stem cells are implanted stereotactically (typically 30.000 to 60.000 cells in 1 µl medium). Wounds 

are sutured and treated with local anaesthetics. 

At various times during the survival period, animals are anaesthetized for the repetitive execution of imaging sessions. 

At the end of the survival period, animals are perfusion fixated under general anaesthesia and brains are prepared for 

immunohistochemical and histological analysis. 

Literature 

1. Hoehn M, Küstermann E, Blunk J, Wiedermann D, Trapp T, Wecker S, Föcking M, Arnold H, Hescheler J, Fleischmann BK, Schwindt W, 

Bührle C. Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of 

experimental stroke in rat. Proc Natl Acad Sci U S A. 2002; 99(25):16267-72. 

2. Erdö F, Bührle C, Blunk J, Hoehn M, Xia Y, Fleischmann B, Föcking M, Küstermann E, Kolossov E, Hescheler J, Hossmann KA, Trapp T. 

Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J Cereb Blood Flow Metab 2003; 23:780-785. 

3. Jacobs A, Winkeler A, Hartung M, Slack M, Dittmar C, Kummer C, Knoess C, Vollmar S, Wienhard K, Heiss WD. Improved HSV-1 

amplicon vectors for proportional coexpression of PET marker and therapeutic genes. Human Gene Therapy 2003;14:277-297 

4. Alonso G. Neuronal progenitor-like cells expressiong polysialylated neural adhesion molecule are present on the ventricular surface of the 

adult rat brain and spinal cord. J Comp Neurol 1999, 414: 149-166. 

5. Benraiss, A., Chmielnicki, E., Lerner, K., Roh, D. and Goldman, S.A. Adenoviral brain-derived neurotrophic factor induces both neostriatal 

and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. J Neurosci, 2001, 21: 6718-6731.


WP11.1: Multimodality characterization of atherosclerotic plaques 


Acitivity Type 



P40a:Schäfers P40b:Bremer P26:Hofstra P2:Clark P10:Bengel 

P32:Nicolay P37:Poelmann P18:Carrio P9:Moonen P27:Horn P28:Laugier 

Person-months per P40a: 36 P40b: 12 P26: 9 P2: 18 P10: 0 

participant 

P32: 0 P37: 0 P18: 0 P9: 0 P27: 0 P28: 0 

Objectives: 

Most of the morbidity and mortality in developed countries is caused by atherosclerosis of arteries (coronary, carotid, 

aorta), resulting in coronary heart disease with its principal manifestations angina pectoris, myocardial infarction, 

sudden cardiac death and heart failure or stroke. Although atherosclerosis is a chronic disease process which develops 

over decades, its most dangerous complication, the "acute coronary event", results from a sudden occlusion of an artery 

at a vulnerable atherosclerotic plaque site by a thrombus. The development of these plaques and their morphological 

and molecular features determining its stability and progression to instability are still not completely known and 

understood. 

At present different new morphological and molecular imaging modalities are available or under development, which 

uniquely further characterize the development and progression of arteriosclerotic plaques in vivo. Among these are 

magnetic resonance imaging MRI to depict plaque morphology and macrophage density as well as scintigraphic 

techniques (SPECT/PET) and optical imaging to characterize the molecular inflammatory and apoptotic activity heavily 

involved in plaque development and progression. 

Animal models of arteriosclerotic plaques and acute vascular injury (e.g. hypercholesterolemic watanabe rabbits, apoE -/- 

mice) are available. The correlative combination of all techniques and specific animal models is not available at a single 

site in Europe, only within a work package such as the one presented here the challenge of a multimodality 

investigation of animal models can be faced. On a long-term basis (second period) an integration of the knowledge and 

the imaging techniques, the latter being transferable into clinical protocols, from animals to patients will lead to 

significantly improved clinical diagnostics with respect to the early individual identification of vulnerable 

arteriosclerotic plaques. 

Specific Objectives: 

To characterize the molecular activity of arteriosclerotic plaques developing in animal models (ApoE -/- mice without 

and with carotid ligation and rabbits under hypercholesterolemic diet) by animal-PET, animal-SPECT, optical imaging 

and PET/CT with respect to 

1. Glucose consumption/macrophage density and activity 

2. MMP activity 

3. Apoptosis. To non-invasively characterize carotid plaques in patients using molecular imaging of apoptosis. In 

patients with a significant carotid artery stenosis scheduled for carotid end-arterectomie non-invasive detection of 

apoptosis will be performed using SPECT imaging of radiolabelled Annexin-A5. Apoptosis in the plaque is closely 

linked to plaque instability. The effect of plaque stabilizing medication (statins) on the uptake of Annexin-A5 in 

the plaque will be studied by sequential non-invasive imaging. The total number of patients to be studied is 20, of 

which 10 will receive statin therapy. 

4. Angiogenesis



A Multimodality arteriosclerosis imaging program in animals 

The following animal models of arteriosclerotic plaques are available and will undergo the multimodality imaging 

program: 

• ApoE -/- mice with hypercholesterolemic diet (Nakashima et al. 1994; P40a and P26) 

• ApoE -/- mice with carotid ligation and hypercholesterolemic diet (Ivan et al. 2002; P40a) 

• Hyperlipidemic watanabe rabbit (Atkinson et al. 1989;P2 and P26) 

Animals will undergo 

1. Molecular imaging of glucose consumption (high resolution 18 F-FDG-PET) as surrogate marker of macrophage 

activity (Rudd et al. Circulation 2002). PET Studies will be performed in 30 ApoE -/- mice with and without carotid 

ligation at different stages (Schäfers). Analogously, PET studies will be performed in 20 hyperlipedemic New 

Zealand white rabbits (Clark/Weissberg). 

2. Molecular imaging of the activity of proteolytic enzymes in plaques using high-resolution SPECT/PET with 

radiolabelled MMP-inhibitors and optical imaging with fluorescent MMP substrate (Bremer et al. 2001, Schäfers et 

al. 2004). PET Studies will be performed in 30 ApoE -/- mice with and without carotid ligation at different stages 

(Schäfers, Bremer) 

3. Molecular imaging of apoptosis in plaques by Annexin-A5 in 20 ApoE -/- mice (Hofstra, Schäfers) 

4. Molecular imaging of αvβ3 integrin expression in plaques using high-resolution PET. PET Studies will be 

performed in 30 ApoE -/- mice with and without carotid ligation at different stages (Schäfers, Bengel) 

5. Molecular imaging of smooth muscle cell proliferation in plaques of 20 ApoE-/- mice (Carrio, Schäfers) 

6. High resolution morphological characterization of plaques using high field animal MRI (Poelmann, Nicolay) 

B Molecular imaging to non-invasively charaterize molecular activity of human carotid plaques 

7. Non-invasive imaging of apoptosis in human carotid plaques and assessment of the effect of different treatments. 

Deliverables 

D11.1.0 Meeting with WP11.1 members for initiation of work plan. 

D11.1.1 Common data for glucose consumption (PET) in different plaque stages in ApoE -/- mice and rabbits (6, 12 

mo). 

D11.1.2 Common data for MMP activity (PET, optical) in different plaque stages in ApoE -/- mice (12, 18 mo) 

D11.1.3 Common data for apoptosis in different plaque stages in ApoE -/- mice (12, 18 mo) 

D11.1.4 Common data for αvβ3 integrin expression (PET) in different plaque stages in ApoE -/- mice (18 mo) 

D11.1.5 Common data for smooth muscle proliferation in different plaque stages in ApoE -/- mice (18 mo) 

D11.1.6 Data for morphological characterization in different plaque stages in ApoE -/- mice (18 mo) 

D11.1.7 Data for non-invasive detection of apoptosis in different plaque stages and effect of treatment in human 

carotid plaques (18 mo) 


Milestones 

M11.1.0 Common meeting of partners (1 mo). 

M11.1.1 Correlation of molecular imaging results in different plaque stages and animal strains (12, 18 mo) 

M11.1.2 Correlation of morphological and molecular imaging results in different plaque stages and animal strains 

(18 mo) 

M11.1.3 Correlation of imaging results with ex vivo histology/immunohistochemistry (18 mo)


M11.1.4 Non-invasive assessment of apoptosis in human plaques and response to therapy (18 mo) 

Ethical rules concerned with the use of laboratory animals in WP11.1 

All animal work is already covered by licences according to local, national and EU regulations (see also WP5). 

Animals are specially bred for lab use. All animal experiments will be performed under permanent general anaesthesia 

with serial control of breathing, ECG and temperature. Radioligands and contrast agents will be injected intravenously 

in anaesthetized animals and imaging will be performed thereafter over a time course of up to 2 hours. Afterwards 

animal will be allowed to recover. In a subset of animals (1/3) animals will be sacrificed after the imaging study and in 

vivo imaging results will be validated by extensive correlation with histology/immunochemistry/autoradiography ex 

vivo. 

All human work is licensed according to the national regulations including an IRB approval of the University Hospital 

Maastricht (Hofstra). Within our institute we have several IRB approved protocols on the non-invasive detection of 

apoptosis using radio-labelled Annexin-A5. Within the IRB approval and regulations a signed patient informed 

consent is mandatory. Patients with a significant carotid artery stenosis eligible for carotid artery endartery-ectomie are 

considered candidates for the study. Patients will undergo sequential imaging of plaque apoptosis in the carotid artery 

plaque, one directly after inclusion, and a second one day before the scheduled carotid artery operation. The difference 

in uptake between the first and second SPECT image of radio-labelled Annexin A5 will be used as a surrogate endpoint 

for plaque stabilisation. The endartery-ectomie histologic specimens will be analyzed with respect to apoptosis, 

and compared with the results obtained with SPECT imaging of radio-labelled Annexin-A5. 

Literature 

1. Atkinson JB, Hoover RL, Berry KK, Swift LL. Cholesterol-fed heterozygous watanabe heritable hyperlipidemic rabbits: a new model for 

atherosclerosis. Atherosclerosis 1989; 78:123-136 

2. Bremer C, Tung CH, Weissleder R. In vivo molecular target assessment of matrix metalloproteinase inhibition. Nat Med 2001;7:743-748 

3. Hofstra L, Liem ICH, Dumont EA, Boersma HH, van Heerde WL, Doevendans PA, De Muinck E, Wellens H, Kemerink GJ, Reutelingsperger 

CP, Heidendal GA. Visualisation of cell death in vivo in patients with acute myocardial infarction. Lancet 2000;356:209-212. 

4. Ivan E, Khatri JJ, Johnson C, Magid R, Godin D, Nandi S, Lessner S, Galis ZS. Circulation 2002;105:2686-2691 

5. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. ApoE-deficient mice develop lesions of all phases of atheroslerosis throughout the 

arterial tree. Arterioscler Thromb 1994;14:133-140 

6. Rudd JH, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, Johnstrom P, Davenprot AP, Kirkpatrick PJ, Arch BN, Pickard JD, 

Weissberg PL. Imaging of atherosclerotic plaque inflammation with 18 F-fluordesoxyglucose poistron emission tomography. Circulation 

2002;105:2708-2711 

7. Ruehm SG, Corot C, Vogt P, Kolb S, Debatin JF. Magnetic resonance imaging of atherosclerotic plaque with ultrasmall superparamagnetic 

particles of iron oxide in hyperlipidemic rabbits. Circulation 2001;103:415-422. 

8. Schäfers M, Riemann B, Kopka K, Breyholz HJ, Wagner S, Schäfers KP, Law MP, Schober O, Levkau B. Scintigraphic Imaging of Matrix 

Metalloproteinase Activity in the Arterial Wall In Vivo. Circulation 2004, 109: 2554-2559.


WP11.2: Characterization of myocardial angiogenesis 


Activity Type 



P10:Bengel P9:Moonen P21:Fleischmann P40:Schäfers P37:Poelmann P32:Nicolay 

P28:Laugier P26:Hofstra P1:Jacobs P41:van Laere 


participant 

P28: 6 P26: 6 P1: 0 P41: 12 

Objectives: 

Induction of angiogenesis holds great promise for the treatment of myocardial ischemia, and is being evaluated in 

various clinical phase I/II trials. Success in the clinical setting is currently monitored indirectly by improvement of 

symptoms or nonspecific clinical tests, and controversial results have been obtained. An improved understanding of 

therapeutic mechanisms is desired and methods for specific noninvasive monitoring and guidance of angiogenesis 

therapy are sought after (Avril et al, Eur J Nucl Med 2003). 

Gene transfer of proangiogenetic genes is the most promising approach for therapy at present. Recently, noninvasive 

imaging techniques for the detection of gene expression have been established using suitable reporter genes. In 

oncology, it has been shown that these techniques can be applied for detection of successful gene transfer, for 

measuring tissue-specific expression of exogenously administered genes, and for detection of the expression of 

endogenous genes using promoters which are specific for the presence of endogenous gene products. In the 

cardiovascular setting, reporter gene imaging has up to now been accomplished using genes driven by strong but 

nonspecific constitutional promoters which do allow for identification of transfer of exogenous genes. These 

techniques have not yet been applied for monitoring of angiogenesis gene therapy. Furthermore, no reporter gene 

methods to identify tissue-specific genetic properties have been applied yet. 

The biologic mechanism of angiogenesis also involves overexpression of a series of proteins such as integrins as a 

group of adhesion molecules, and matrix metalloproteinases (MMP) as extracellular proteolytic enzymes. These 

molecules can be directly targeted using radiolabelled RGD peptides or Gd-DTPA containing RGD-liposomes which 

bind to α v β 3 -integrin (Haubner et al, Cancer Res 2001), or with MMP inhibitors such as prinomastat (Bremer et al, 

Nat Med 2001), labelled for optical or radionuclide imaging, respectively. Such tracers have been successfully applied 

by different groups in tumor models to identify angiogenesis and effects of antiangiogeneic therapy. 

The primary objective of this work package is to establish imaging strategies for specific molecular characterization 

of angiogenesis which will allow for an in-depth evaluation from genotype to phenotype. Strategies for imaging of 

exogenously delivered genes and endogenous genes involved in angiogenesis will be evaluated. Also, imaging 

techniques for monitoring the expression of proteins involved in angiogenesis, such as integrins and MMP, will be 

tested. Established techniques to measure physiologic parameters such as contractile function and blood flow will 

serve as additional markers. 


1. to design vectors for tissue specific overexpression of reporter genes and proangiogenetic genes 

2. to design vectors for monitoring of specific endogenous myocardial genes 

3. to evaluate the feasibility of the aforementioned vectors for noninvasive in vivo imaging 

4. to establish molecular imaging approaches for visualization of the expression of angiogenesis-related proteins 

5. to determine the time course of integrin and MMP expression in ischemically damaged myocardium 

6. to characterize the relationship between gene expression, expression of related proteins, and 

functional/physiologic effects following angiogenesis induction in the heart 

7. to establish tools for future specific monitoring of clinical myocardial angiogenesis therapy 


1. For monitoring of endogenous gene expression, adenoviral vectors will be constructed which express reporter 

genes under transcriptional control of specific weak promoters (myosin, β-actin as target for myocardial-specific 

promoters, the hypoxia-responsive element (HRE) as a promoter sensitive to endogenous HIF1α expression,


HSP70 as a heat-sensitive promoter). To increase promoter strength while maintaining specificity, the specific 

promoter may be enhanced by TSTA (two-step transcriptional amplification) and drive a transcription 

transactivator, which then activates a minimal promoter to drive expression of the reporter gene. Reporter genes 

employed will be the luciferase gene for optical bioluminescence imaging, and/or the herpesviral thymidine 

kinase gene and/or sodium-iodide symporter gene for nuclear imaging. Feasibility of the vectors and 

corresponding reporter probes will first be evaluated in vitro in cardiac cells. Magnitude and specificity of 

reporter probe uptake will be compared, and validated against reporter gene mRNA and protein expression 

determined by PCR, Northern and Western blotting, and enzyme assays. In a second step, feasibility, sensitivity 

and specificity of each given vector will be determined in vivo in 40 rats and 10 pigs using models of myocardial 

gene transfer. Rats will receive nonsurgical direct myocardial virus injection and pigs will receive surgical direct 

intramyocardial vector injection. All experiments and subsequent imaging, which is done 2 days later, will be 

performed under general anaesthesia. Following vector delivery, animals will be allowed to recover. After 

imaging, 2 days later, animals will then be sacrificed and hearts will be removed for postmortem analysis. 

Available imaging modalities will be compared, and results will be validated against ex vivo imaging, 

autoradiography and immunohistochemistry. (Bengel, Fleischmann, Jacobs, Moonen, van Laere) 

2. Specific adenoviral vector systems for expression of the angiogenetic factor VEGF will be designed. These 

vectors feature coexpression of a gene for noninvasive imaging of transgene expression (herpesviral thymidine 

kinase, sodium/iodide symporter, luciferase) via accumulation of labelled reporterprobes. They also feature either 

constitutional promoters, promoters which can be controlled exogenously (heat-sensitive promoter), or tissuespecific 

promoters (e.g. αMHC). Vectors will be tested in cardiac cells in vitro and in vivo in hearts of 40 rats 

with regard to their suitability for reporter gene imaging and with regard to VEGF expression. Similar to the 

previous subproject, rats will receive nonsurgical direct myocardial virus injection under general anaesthesia. 

Following vector delivery, animals will be allowed to recover. After imaging, which is done under general 

anaesthesia 2 days later, animals will then be sacrificed and hearts will be removed for postmortem analysis. 

(Bengel, Fleischmann, Moonen, Jacobs) 

3. Using a rat model of myocardial ischemia / reperfusion (surgical occlusion of LAD for 30 minutes under general 

anaesthesia, then reperfusion; after surgery animals are allowed to recover for 2 days, assisted by analgesia using 

opiates), the natural time course of regional myocardial uptake of labelled RGD peptides and MMP inhibitors 

will be determined in 30 animals by repeated imaging using PET, MRI, or optical imaging. Imaging is performed 

under general anaesthesia at 2, 5, 10 and 30 days after ischemia/reperfusion surgery, and animals are sacrificed 

for postmortem analysis of the heart after the final imaging session. Findings of protein expression will be related 

to measures of regional perfusion, contractile function, metabolism and tissue viability, and will be validated 

against ex vivo analysis of organ count rates, autoradiography and immunohistochemistry for integrins and MMP. 

(Bengel, Schäfers, Nicolay, Poelmann) 

4. Angiogenesis gene therapy using the optimal adenoviral vector will be performed in the previously described 

model of the acutely ischemic rat heart. The model will be identical to that described under point 3, except for the 

additional injection of vector into the ischemic myocardial area directly following ischemia and reperfusion 

during the initial surgical procedure. Time course of regional myocardial uptake of labelled RGD peptides and/or 

MMP inhibitors will be determined in 30 animals by repeated PET and MRI, again at days 2, 5, 10 and 30 under 

general anaesthesia, followed by sacrifice of animals at the last imaging time point. In vivo findings will be 

related to measures of regional perfusion, contractile function, metabolism and tissue viability, and validated 

against ex vivo analysis of organ count rates, autoradiography and immunohistochemistry for integrins and/or 

MMP. For an in-depth description of molecular changes due to therapy, results will be compared with those 

previously obtained in untreated animals. (Bengel, Schäfers, Moonen, Hofstra, Nicolay, Poelmann, Laugier) 

Deliverables 

D11.2.1 

D11.2.2 

D11.2.3 

D11.2.4 

D11.2.5 

D11.2.6 

D11.2.7 

Vectors for induction and in vivo monitoring of angiogenesis gene therapy (6 mo) 

Vectors for monitoring of endogenous cardiovascular genes (6, 12 mo) 

Meeting of WP participants for initiation of in vivo studies (6 mo) 

Common protocol for in vivo imaging of reporter gene expression (6, 12 mo) 

Common protocol for in vivo imaging of integrin expression using MRI and PET (12 mo) 

Detection of myocardial MMP expression using PET and optical imaging (12 mo) 

Time course of expression of angiogenesis-related proteins in myocardial ischemia (12, 18 mo). 

D11.2.8 Repeatable noninvasive imaging approach for detection of endogenous cardiovascular gene expression (18 

mo)


D11.2.9 

reporting on the relevant and applicable regulations of ethical issues (12 mo) 


M11.2.1 Improved techniques for monitoring of myocardial gene expression (12 mo) 

M11.2.2 In vivo imaging of reporter genes using weak, specific promoters in the myocardium (12 mo). 

M11.2.3 Improved techniques for imaging of myocardial expression of angiogenesis-related genes and proteins (12 

mo). 

M11.2.4 Baseline characterization of vector-mediated angiogenesis in myocardium (18 mo). 

M11.2.5 Correlation of the expression of exogenous and endogenous genes in myocardium with other 

noninvasively determined biologic characteristics (contractile function, perfusion, metabolism, apoptosis, 

integrin expression, MMP expression) (18 mo). 

Ethical issue 

Research will be conducted in Germany, The Netherlands, Belgium and France. No studies in humans or transgenic 

animals will be performed. Animal experiments involve mainly rats (models of myocardial gene transfer and 

ischemia/reperfusion), and to a smaller degree pigs (model of myocardial gene transfer). All experiments will adhere 

to national laws of animal protection. For detailed description of animal procedures see above Description of 

subprojects 


1. Blasberg RG, Tjuvajev JG. Molecular-genetic imaging: current and future perspectives. J Clin Invest. 2003;111:1620-9. 

2. Bengel FM, Anton M, Avril N, Brill T, Nguyen N, Haubner R, Gleiter E, Gansbacher B, Schwaiger M. Uptake of 

radiolabeled 2'-fluoro-2'-deoxy-5-iodo-1-beta-D-arabinofuranosyluracil in cardiac cells after adenoviral transfer of the 

herpesvirus thymidine kinase gene: the cellular basis for cardiac gene imaging. Circulation. 2000;102:948-50. 

3. Bengel FM, Anton M, Richter T, Simoes MV, Haubner R, Henke J, Erhardt W, Reder S, Lehner T, Brandau W, Boekstegers 

P, Nekolla SG, Gansbacher B, Schwaiger M. Noninvasive Imaging of Transgene Expression by Use of Positron Emission 

Tomography in a Pig Model of Myocardial Gene Transfer. Circulation. 2003;108:2127-33. 

4. Avril N, Bengel FM. Defining the success of cardiac gene therapy: how can nuclear imaging contribute? Eur J Nucl Med 

Mol Imaging. 2003;30:757-71. 

5. Haubner R, Wester HJ, Weber WA, Mang C, Ziegler SI, Goodman SL, Senekowitsch-Schmidtke R, Kessler H, Schwaiger M. 

Noninvasive imaging of alpha(v)beta3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron 

emission tomography. Cancer Res. 2001;61:1781-5. 

6. Bremer C, Tung CH, Weissleder R. In vivo molecular target assessment of matrix metalloproteinase inhibition. Nat Med. 

2001;7:743-8. 

7. Guilhon E, Quesson B, Moraud-Gaudry F, de Verneuil H, Canioni P, Salomir R, Voisin P, Moonen CT. Image-guided control 

of transgene expression based on local hyperthermia. Mol Imaging. 2003;2:11-7.


WP12 : Cardiac stem cell therapy monitored by Molecular Imaging 


Activity Type 




P9:Moonen P21.Fleischmann P10:Bengel P26:Hofstra P3: Aime P37:Poelmann 

P18: Carrio P32:Nicolay P1:Jacobs 

P9: 36 P21: 15 P10: 24 P26: 18 P3: 6 P37: 12 

participant 

P18: 6 P32: 12 P1:12 

Objectives: 

Recent data have largely modified the experimental approach towards cell repair in vivo, particularly by the very 

promising results obtained with stem cells and progenitor cells based on the following interesting characteristics 

of these cells: 

- their large potential to differentiate into several cell types, 

- their “spontaneous” homing to diseased tissues due to the role of chemokines, 

- the possibility to obtain such cells in vivo (for example from bone marrow), to grow them ex vivo, to 

modify them ex vivo, to transplant the modified cells back into the body, and even to regulate their mode 

of action. 

The field of cell repair is of particular importance in the heart. Impaired function following tissue necrosis, e.g. 

following ischemia, may be solved by tissue replacement. Molecular imaging is expected to play an important 

role in the development of such novel cell repair therapies with regard to several aspects: 

- tracking of labelled stem cells in vivo during their migration towards their target thus understanding the 

duration of the migration, the trajectories in vivo, and survival of (modified) stem cells , 

- monitoring the differentiation process in vivo 

- possibility to provide image-guided control of differentiation due to expression of specific (trans)gene 

(cytokines, others) 

- guiding the use of stem cells as vectors in gene therapy. 


1) To further develop methods for labelling stem cells and progenitor cells for visualization by optical, 

Nuclear Medicine and MRI methods 

2) To monitor longitudinally stem cell migration in vivo and their homing towards diseased tissues 

3) To develop molecular imaging markers for non-invasive assessment of stem cell differentiation 

4) To develop MI methods to track labelled stem cells as vectors for gene therapy 


- Labeling of stem cells with MRI contrast agents; 

In vivo MRI results of labelled stem cell populations have shown a detection limit of a few thousand cells per 

millilitre whereas single cells have been observed in vitro at high magnetic field strength. The objective is to 

further improve labelling of different stem cell types for cardiovascular tissues with MRI contrast agent 

allowing tracking of a very small number of stem cells in vivo. (Moonen, Aime, Nicolay, Fleischmann, 

Poelmann) 

- Labelling of stem cells with Nuclear Medicine and Optical contrast agents 

Labelling of a specific stem cell population may also be based on radioactive or optical markers detectable by 

SPECT/PET or optical methods. The sensitivity of such methods is potentially higher than that using MRI 

contrast agents. Several marker genes may be used, and a close interaction with WP3 and other project 

workpackages is therefore envisaged. Briefly, labelling with the luciferase gene will be targeted for optical 

detection and with the thymidine kinase gene for SPECT/PET (Hofstra, Bengel, Carrio, Jacobs) . 

- Evaluation of the effects of cell labelling for imaging on the regeneration potential of various cell types 

Recent reports have indicated a high tolerance of stem cells for SPIO labelling up to 50 microgr/ml. However, 

some reports have indicated some loss of homing capabilities. Rigorous tests will be performed on all stem cell 

types (native and modified) to evaluate toxicity, capacity of differentiation and homing capabilities 

(Fleischmann, Poelmann, Hofstra). 

- Evaluation of different administration routes for transplantation of stem cells 

In recent reports on MRI tracking, stem cells were implanted locally. Intravascular administration of stem cells 

would be attractive to achieve distribution in a whole organ, an important aspect for cell therapy applications in


diffuse diseases. Therefore, MRI guided or fluoroscopy guided direct injection, local intravascular injection, as 

well as systemic injection will be evaluated with respect to side effects (risk of pulmonary embolism) and 

efficacy of homing (Moonen, Poelmann) in 30 rats and 10 pigs. 

- Evaluation of stem cell homing and migration in an animal model of heart ischemia based on the use of marker 

genes 

Well established animal models for heart ischemia are required to test the action of stem cells using molecular 

and functional imaging methods. Stem cells, carrying different marker genes, will be injected in and around an 

ischemic lesion in the heart of well established mouse animal models for ischemic heart disease (cryoinfarction, 

n=25; left coronary artery ligation, n=25; interaction with WP5). Stem cells will be tracked by MRI and PET. 

Ultrasound analysis will be performed for evaluation of heart function (Fleischmann, Hofstra, Nicolay, Jacobs). 

- Development of image-guided control mechanisms for stem cell differentiation 

Stem cell multiplication and differentiation is thought to occur under the local influence of cell signalling, e.g. 

via cytokines and chemokines. Controlled expression of these signals therefore has the potential of guiding cell 

differentiation. We will use the recently developed model of expression control based on local heat (using MRI 

guided Focused Ultrasound) and a heat-sensitive promoter (Heat Shock Protein HSP70) in a feasibility study in 

stationary tissues of 10 rats and 10 mice. In addition, tissue specific promoters will be explored in close 

interaction with WP 11.1 and 11.2 (Moonen, Bengel, Fleischmann). 

- Development of molecular imaging markers for non-invasive assessment of stem cell differentiation. 

Recent reports have indicated stem cell differentiation using conventional histological approaches. In light of 

the development of methods for image-guided control of differentiation, new methods are needed that allow 

non-invasive imaging of cell differentiation processes. This long term objective will be achieved using 

enhanced expression of cell markers (Fleischmann, Bengel, Hofstra, Moonen). 

- Development of MI methods to track labelled stem cells as vectors for gene therapy 

Stem cells are increasingly being used not only for cell repair purposes but also as vectors for gene therapy, e.g. 

in order to promote growth of new vessels (pro-angiogenesis therapy). The objective is to modify stem cells 

with transgenes coding for growth factors such as the Vascular Endothelial one (VEGF) under control of tissue 

specific promoters or under control of the HSP70 promoter allowing an image guided expression control 

mechanism (Moonen, Bengel) in a feasibility study of 10 rats. 

Deliverables 

D12.1 Improved labelling of cardiac stem cells with MRI contrast agent and in vitro assessment of 

sensitivity of MRI detection of labelled cells 

D12.2 Transfection of cardiac stem cells with marker genes (e.g. luciferase, TK) that allow visualization 

using optical and PET/SPECT methods 

D12.3 Detection of modified stem cells using optical and PET/SPECT methods and evaluation of detection 

sensitivity 

D12.4 Assessment of viability of native and modified stem cell with respect to toxicity due to the labelling 

procedure, differentiation capabilities and homing potential 

D12.5 Development of different administration approaches for labelled stem cells: image-guided 

intracardiac injection, local intravascular injection, systemic intravascular injection 

D12.6 Assessment of stem cell homing and migration in an established mouse model of cardiac ischemia 

D12.7 Development of target gene markers for identification of differentiation and demonstration in vitro 

D12.8 Transfection of stem cells with marker genes under control of the hsp70 promoter or tissue-specific 

promoters and demonstration of image-guided expression control in vitro and in vivo 


Milestones 

M12.1 Multi-modality, sensitive, tracking of stem cells 

M12.2 Controlled expression of marker and therapeutic genes in transplanted stem cells in animal models 

M12.3 Administration of labelled stem cells: image-guided intracardiac injection, local intravascular 

injection, systemic intravascular injection 

M12.4 Noninvasive asessment of stem cell differentiation in vivo



Most of the work in this workpackage is in cell cultures. However, since the aim of this network is to develop 

and evaluate Diagnostic Molecular Imaging tools it is obvious that work with animals is necessary to achieve our 

goals. Since the Molecular Imaging techniques are non invasive, the same animals can be followed over time 

thereby minimizing the number of experimental animals. All animal studies will be performed under the local 

and national guidelines summarized elsewhere in the project description. 

Details of the species and number of animals to be used have been provided above in the text of the WP12. Since 

statistical significance needs at least a data set of 6 animals, we have chosen a minimum 10 animals per 

experimental group (D12.5, D12.8) to make sure we have included all extra tests that might seem necessary. The 

number of the required animals as a model for cardiac ischemia (D12.6) has been estimated by partner P21 

together with the local Department of Biometrics and medical statistics (University Bonn) in order to obtain 

statistically relevant data. All the above mentioned experiments on mice are approved by the local authorities. 

Since we are exclusively dealing with non invasive in vivo imaging methods, the only manipulation the animals 

will be submitted to (except for the cardiac ischemia model) is anaesthesia and this is done to increase the 

comfort of the animal by decreasing its restraining and manipulation stress. During anaesthesia the animals are 

very accurately monitored to maintain optimal physiological parameters (comparable with circumstances in a 

human operation theatre). After anaesthesia the animals are allowed to recover in an acclimitised recovery 

chamber. Animals are submitted to several imaging protocols and there is no reason to sacrifice them after the 

experiments, unless correlative histopathological data are required. 

For the cardiac ischemia model, male wild type (wt) mice of the strain C57/Bl6 or SV129 are used for operation. 

General anesthesia and intubation is followed by anterolateral thoracotomy and standardized cryoinfarctions 

(copper probe, 3 mm diameter) to the left ventricular wall or left coronary artery ligation. Reliable intramural 

injection of cells is achieved by use of a holding device and vital dye staining. Prior to the surgical procedure and 

three days post operation, 100 mg/kg Cefuroxim (Glaxo Wellcome, Bad Oldesloe, Germany) and 100 mg/kg 

Metamizol (Aventis, Frankfurt, Germany) are injected intramuscularly. The above mentioned surgical procedure 

is routine in the laboratory of P21. The mice tolerate the surgical operation well. At different time points after the 

surgery ultrasound analysis is performed; for this purpose the animals are re-anesthezized. The animals do not 

suffer additional inconveniences because of the operation. Further details are provided in WP5. The 

experimental protocol has been approved by the authorities for P21. 

Ethical rules concerned with the use of stem cells 

Only animal stem cells will be used in this workpackage. No human embryonic stem cells will be used. 

Therefore, ethical guidelines on the use of (embryonic) human stem cell do not apply here. 

Literature WP12 

1. Sachinidis A, Fleischmann BK, Kolossov E, Wartenberg M, Sauer H, Hescheler J. Cardiac specific differentiation of mouse embryonic 

stem cells. Cardiovasc Res. 2003 May 1;58(2):278-91. 

2. Hoehn M, Kustermann E, Blunk J, Wiedermann D, Trapp T, Wecker S, Focking M, Arnold H, Hescheler J, Fleischmann BK, Schwindt 

W, Buhrle C. Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation 

of experimental stroke in rat. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16267-72. Epub 2002 Nov 20 

3. Bengel FM, Anton M, Richter T, Simoes MV, Haubner R, Henke J, Erhardt W, Reder S, Lehner T, Brandau W, Boekstegers P, Nekolla 

SG, Gansbacher B, Schwaiger M. Noninvasive Imaging of Transgene Expression by Use of Positron Emission Tomography in a Pig 

Model of Myocardial Gene Transfer. Circulation. 2003;108:2127-33. 

4. Guilhon E, Quesson B, Moraud-Gaudry F, de Verneuil H, Canioni P, Salomir R, Voisin P, Moonen CTW Image-guided control of 

transgene expression based on local hyperthermia. J. Molecular Imaging, 2003; 2: 11 – 17.


WP13: Molecular imaging of NF-κB activation and imaging chronic inflammation 

using optical probes 

Workpackage number 13 Start date or starting event: Start of program 

Participant id P43: Carlsen P11: Blomhoff P40b:Bremer P17b:Jones P35: Parker P38: Rizo 

P1: Jacobs P26:Hofstra P16:Holmdahl P2: Clark 

Person-months per P43: 10.5 P11: 18.5 P40b: 12 P17b: 4 P35: 12 P38: 0 

participant P1: 6 P26: 3 P16:12 P2: 0 

Objectives 

Hallmarks of inflammation include activation of transcription factors (NF-κB), metalloproteinases, activation of 

the complement system, enhanced production of reactive oxygen species (ROS) and activation of mitogen 

activated protein kinases. 

Various in vivo mouse models now exist allowing molecular imaging of specific transcription factors or DNApromoter 

regions using imaging devices for luminescence (luciferase), fluorescence (fluorescent proteins) or PETimaging 

(HSV-tk,). Within the consortium transgenic reporter mice have been generated, which express luciferase 

under the control of NF-κB (NF-κB luc) a transcription factor central in the inflammation process. Using optical 

imaging we have demonstrated the feasibility to monitor NF-κB activity in living mice (Carlsen, 2002). These 

mice will be crossed into genetically modified mouse models that spontaneously develop various autoimmune 

diseases, or have increased susceptibility to inducible chronic inflammation (e.g. collagen induced arthritis). One 

such model has been developed by Bogen’s group in Oslo, which is a combination of two separate transgenic lines, 

that when they are combined start producing abnormal amounts of autoantibodies and develop a variety of 

inflammatory diseases such as arthritis (25%), inflammatory bowels disease (60%) and encephalomyelitis (5%). In 

addition, the Lund group (Holmdahl/Blom) has generated a unique mouse model for arthritis based on positional 

cloning of the Ncf1 gene, a regulator of the ROS response and arthritis severity (Olofosson 2003). This mouse 

strain has a splicing mutation of the Ncf1 gene, which together with other susceptibility genes like MHC class II, 

lead to enhance chronic CIA as well as spontaneous development of arthritis. In addition, the consortium will have 

available a plethora of different rodent inflammation models (listed in B.4.2.1.3. Part C). 

The main objectives in this work package are, during the first 18 months, to utilize optical imaging techniques to 

validate the role of NF-κB in combination with a set of optical imaging agents acting as markers of specific events 

during the chronic inflammatory process. Transgenic models for inflammation and transgenic NF-κB reporter mice 

will be used as model systems to validate such probes. The cooperation with a group focused on instrumental 

techniques will make it possible to devise probes optimized to the capability of existing systems, or to influence the 

design of imaging systems so that they match the optical properties of the new probes. 


1. To test whether NF-κB, as assessed by molecular imaging reflect the disease states in mouse models of 

chronic inflammation disease using luciferase (bioluminescence). 

2. To cross-breed the Ncf1 mutation, the arthritis susceptible Aq gene in the Balb/c genetic background. 

3. Employ existing optical imaging probes (NIRF activated by cathepsin B and H, Annexin-5 in mouse 

inflammation models using fluorescence imaging. 

4. Seek to devise fluorescent probes sensitive to ROS for in vivo imaging. 

5. Devise novel near infrared probes for detection of complement activation. 

6. Validate targeted fluorescent probes to site of inflammation (αβ integrins) 

7. Assess utility of novel lanthanide based imaging probes in cell cultures for detection of ROS. 

8. Correlate various imaging probes in combination with imaging NF-κB activity during the onset and 

progression of autoimmune disease. 

9. Seek to devise fluorescence lifetime imaging, or time resolved imaging, or to influence the design of 

imaging systems so that they match the optical properties of the new probes. 

10. Macrophages play a pivotal role in inflammation. Using the ligand PK11195, which binds with high 

affinity to macrophages, we can monitor macrophage kinetics in vivo. PET scanning has been carried out


using the 11C-labelled ligand and demonstrated an increased signal in response to inflammatory challenge 

in animal models. These studies have been extended to humans and shown that the pulmonary signals are 

affected by lung disease and by cigarette smoking. Initial validations using cellular resolution 

autoradiography of the tritiated analogue of the ligand show localisation to monocyte lineage cells. We 

now have access to PK 11195 labeled with a fluorescent marker and plan to use this in to validate the 

signal further and to define the phenotype of the cells responsible for the signal obtained by PET 

scanning, using FACS analysis. Using this fluorescent analogue we plan to carry out ex vivo and in vitro 

studies in animal models of inflammation. 

11. Make and validate new DNA constructs for generating new transgenic reporter mice with co-expression 

of reporter genes (co-expression cassettes of lucIREStk39gfp/dsred) controlled by NF-κB. 

12. Exchange relevant models/knowledge to members of the consortium for validation using other imaging 

modalities. 


1. Transgenic autoimmune disease model for imaging NF-kB dependent luciferase activity will be generated 

by crossing two different genetically modified mice strains on Balb/C genomic background (TCR-idiotype 

specific and λ 315 -idiotype overexpressing) with transgenic reporter mice for NF-κB that when they are 

combined develop spontaneous autoimmune disease [TCR+/-, NF-κB luc+/-, λ 315 +/- (disease model n=10) 

or TCR-/-, NF-κB luc+/-, λ 315 +/- (negative control, n=10). 

2. NF-κB luc mice will be crossed with a genetically modified mouse (with the Ncf1 mutation as well as the 

MHC class II gene Aq) on the Balb/c genomic background, n=10 each group 

3. The inflammation prone mice and negative controls will be imaged regularly (repetitively) for NF-κB 

activity using the IVIS-100 system, Xenogen: before, during onset and during progression of disease. Mice 

are anesthetized with isofluorane followed by i.p. injection of luciferin (200 µl) during imaging of the 

animals (15 minutes from start of anaesthesia to end of imaging session), and will recover in their 

individual cages in the animal rooms. 

4. Near infrared imaging probes activated by cathepsin B and H, and fluorescently labeled Annexin 5 will be 

employed at a few selected mice during progression of disease by i.v. injection, and imaged using the 

IVIS-100 system from Xenogen (fluorescence option). 

5. At selected points during disease progression, mice will be sacrificed and assessed for clinical 

manifestations by histology, histochemistry, in addition to being assessed for luciferase activity, presence 

of immune cells by flow cytometry, and target genes for NF-κB by RT-PCR. 

6. ROS-probes and tested and validated in relevant cell culture experiments and chronic inflammatory 

disease models. For doing this we will use mice with (wild type on B10.Q andf Balb/c background) and 

without (due to the Ncf1 mutation) ROS production. 

7. PK 11195 labeled macrophage ligand with a fluorescent marker will be used in ex vivo and in vitro studies 

in animal models of inflammation. 

8. Development of a novel fluorophore-stable radical conjugates whose emission is switched on following 

encounter with radical species such as hydroxyl radical (in vitro studies). 

9. Development of near infrared imaging activated by the complement probes (e.g. C5-convertase sensitive). 

Will be tested and validated in appropriate cell systems. 

10. Insert NF-κB binding sites to co-expression cassettes of lucIREStk39gfp/dsred. Testing and validation of 

construct will be done in appropriate cell cultures and finally be prepared for microinjection for production 

of transgenic reporter mice


Deliverables 

D13.0 Meeting with WP13 members for initiation of work plan (3 mo) 

D13.1 Cross-breed λtg and TCRtg mice with NF-κB luc. reporter mice for imaging of NF-κB activity in 

transgenic autoimmune disease model (12 mo). 

D13.2 Imaging cathepsin B and H, and Annexin 5 in inflammation model (18 mo) 

D13.3 Validating fluorescent macrophage ligand PK 11195 in cell cultures (6 mo) and in inflammation models 

(18 mo). 

D13.4 Development of utility of optical imaging probes for complement activation and ROS detection (18 mo). 

D13.5 Establishment of a new mouse strain with spontaneous development of arthritis (with the Ncf1 mutation, a 

susceptible MHC class II gene on the Balb/c background) expressing the NF-κB luc transgene useful for 

image analysis of arthritis (18 mo). 

D13.6 Development of targeted probes (α β integrins) and validation in vitro (18 mo). 

D13.7 Establishment of DNA construct with NF-κB dependent expression of luc, tk and GFP/DsRed (6 mo). 

Validation in cell cultures (12 mo). 

D13.8 reporting on the relevant and applicable regulations of ethical issues (12mo) 

Milestones 

M13.0 Meeting with partners (3 mo). 

M13.1 Imaging NF-κB dependent luciferase activity in two inflammation models (18 mo). 

M13.2 Imaging of cathepsin B and H, and Annexin 5 in autoimmune disease models (18 mo). 

M13.3 Validating fluorescent macrophage ligand PK 11195 in vitro and in inflammation models (6, 18 mo). 

M13.4 Development of utility of optical imaging probes for complement activation and ROS detection (18 mo). 

M13.5 Development of targeted probes (α β integrins) and validation in vitro and in inflammation models (18 

mo) 

M13.6 Multimodal imaging of NF-κB activity in cell culture studies (12 mo). 

Ethical considerations 

The present project involves experiments and drug testing carried out on laboratory animals. In the 

paragraphs below the ethical aspects in relation to objectives, methodology and implications of the results 

are described and carefully considered with respect to increasing the quality of life for large groups of 

patients in the European Community. 

All animal studies will be performed under permission of National Ethical Committees for Animal 

Experimentation and/or Local Animal Ethical Committees providing international standards for animal 

experimentation, which in this particular case will relate to Norwegian and Swedish Laws on Animal 

Welfare. For each animal experiment a written protocol describing in detail the aims and methods used to 

examine the hypothesis of a given study will be submitted and approved by the National Ethical 

Committees before experiments are initiated. Protocols will be accessible by local authorities at any time 

during the experiment and members of National Ethical Committees or local authorities are free to call for 

inspections at any time. In compliance with the rules of the National Ethical Committees a record is kept for 

each experiment. Experiments will be performed by highly skilled persons with long-lasting experience in 

performing science using animals and with all necessary certificates. Animal examination involving models 

using surgical experimentation and imaging of animals will be performed in anaesthetized animals and care 

will be taken to ensure that proper treatment with pain reliving drugs take place if necessary. Every partner 

involved in animal research employ highly skilled technical personnel for animal care-taking. Every partner 

involved in animal research employ highly skilled technical personnel for animal care-taking. 

Partners that are using genetically modified organisms (GMOs) have obtained approval from the Health and 

Safety executive of the National Directorate for Science and Technology. Each GMO has been carefully 

defined and hazards to human health are excluded. Moreover, assessment of risk to human health and the


environment has been and will continue to be provided in detail for each GMO established. Finally, the 

Health and Safety executive of the National Directorate for Science and Technology have approved a 

detailed classification and control measures/safe practices for each GMO. 

Experiments using animal are justified from the point of view that detailed physiological knowledge, the 

role of various genes and evaluation of therapeutic strategies in vivo cannot be obtained in models with 

lower biological analogy to humans such as cell cultures and yeast. The choice of animal models is carefully 

considered with regards to the specific diseases that will be studied. 

The main object in this project is to do repetitive assessments of an imaging marker during the course of the 

experiments. In compliance with the principles of the three Rs (Reduction, refinement and replacement), 

this non-invasive approach will provide a set of data points longitudinally for each animal, thus yielding 

significant information for each animal used in the study. This is in accordance with the principle of 

reducing the number of animals in the particular study in addition to providing methods and technology to 

refine other animal experiments in the future. For examination of specific cellular processes, and for initial 

testing of imaging probes, appropriate cell culture studies will be performed. The animals will be housed in 

authorized animal facilities which are approved by National European Authorities. The welfare of animals 

is secured by highly skilled personnel, which are approved by the National European Authorities to serve as 

animal care-takers at research institutions. 

The models used in this study, will be carefully monitored due to the fact that some of the mice may 

eventually develop adverse effects. Main symptoms in the chronic inflammation models are: 1) weight loss, 

2) skin rash, 3) inflamed/swollen ankles, 4) diarrhea, 5) change in activity pattern. The mice will be 

monitored on a daily basis (inspection of symptoms and weighing). End points will be defined in 

accordance with the Local Ethical Committee. Mice will be sacrificed in compliance with humane methods 

approved by the National Ethical Committee. 

Literature 

1. Carlsen.H, Moskaug,J.O., Fromm,S.H., and Blomhoff,R. (2002). In vivo imaging of NF-κB activity in transgenic mice using luminescence. 

Journal of Immunology. 168(3):1441-6 

2. Austenaa LM, Carlsen H, Ertesvag A, Alexander G, Blomhoff HK, Blomhoff R. (2004). Vitamin A status significantly alters nuclear 

factor-kappaB activity assessed by in vivo imaging. FASEB J. Jun 4. (Epub ahead of print). 

1. Dembic, Z., Schenk, K, and Bogen B.(2000). Dendritic cells purified from myeloma are primed with tumor-specific antigen (idiotype) and 

activate CD4+ T cells. Proc Natl Acad Sci U S A. Mar 14;97(6):2697-702. 

3. Dembic, Z., Rottingen, J.A., Dellacasagrande, Schenk, K, and Bogen (2001). Phagocytic dendritic cells from myelomas activate tumorspecific 

T cells at a single cell level. Blood. 97:2808-2814. 

4. Munthe LA, Os A, Zangani M, Bogen B. (2004). MHC-restricted Ig V region-driven T-B lymphocyte collaboration: B cell receptor ligation 

facilitates switch to IgG production. Journal of Immunology Jun 15;172(12):7476-84. 

5. Ntziachristos V., Bremer C, Weissleder R. (2002) Fluorescence imaging with near-infrared light: new technological advances that enable in 

vivo molecular imaging. European Radiology. 13:195-208 

6. Ji H., Ohmura K., Mahmood U.,Lee DM., Hofhuis F.M.A., Boackle S.A., Takahashi K., Holers V.M, Walport M., Gerard C., Ezekowitz A. 

Carroll M.C., Brenner M., Weissleder R., Verbeek J.S., Duchatelle V., D.Claude, Benoist C. and Mathis D. (2002) Arthritis Critically 

Dependent on Innate Immune System Players. Immunity, Vol. 16, 157–168 

7. Holmdahl R. (2003) Dissection of the genetic complexity of arthritis using animal models. Journal of Autoimmunity Sep;21(2):99-103 

8. Pham W, Lai WF, Weissleder R, Tung CH. (2003) High efficiency synthesis of a bioconjugatable near-infrared fluorochrome. Bioconjug 

Chem. Sep-Oct;14(5):1048-51. 

9. Dumont EA, Reutelingsperger CP, Smits JF, Daemen MJ, Doevendans PA, Wellens HJ, Hofstra L, (2001) Real-time imaging of apoptotic 

cell-membrane changes at the single-cell level in the beating murine heart. Nat Med.Dec;7(12):1352-5. 

10. Marzari R., Sblattero D., Macor P., Fischetti F., Gennaro R., Marks J.D., Bradbury A., Tedesco F. (2002). The cleavage site of C5 from 

man and animals as a common target for neutralizing human monoclonal antibodies: in vitro and in vivo studies. European Journal of 

Immunology Vol. 32 (10): 2773-2782. 

11. Manning, H.C., Goebel, T., Marx J.N., Bornhop, D.J., (2002). Facile, efficient conjugation of trifunctional lanthanide chelate to a 

peripheral benzodiazepine receptor ligand. Org. Letters Vol. 4 (7): 1075-1078. 

12. Olofsson P, Holmberg J, Tordsson J, Lu S, Åkerström B, Holmdahl R: Positional identification of ncf1 as an arthritis severity regulating 

gene in rats. Nat Gen 33:25-32, 2003


WP14: Integrating activities 


Activity Type 


Participant id P13:Meynadier P6:Moonen P1:Jacobs P6:Maggi 


participant 

P13: 18 P6: 0 P1: 11 P6: 0 

Objectives 

1. strengthen the integration of the network by the establishment of DiMI technology and training platforms (DiMI- 

TTP) for sharing imaging facilities, equipment, experience and know-how. 

2. encourage exchange and mobility of personnel. 

3. encourage the integration of SMEs and their links to the academic centres. 

4. develop integrative tools: website & annual conference to enhance information exchange. 

5. measure the degree of integration reached by the network through the four above objectives and through the JPRA. 


The work package is dedicated to the enforcement and measurement of a strong integration amongst the network 

participants. 

1. DiMI-TTP. 

The work package is responsible for the tracking of the DiMI-TTPs establishment and development. It will provide 

appropriate resource identification: available equipment, tools and facilities from the partners laboratories will be 

identified and registered in a secured database on the DiMI web site. A centralised management of this data base 

will identify duplications, synergies and missing entities and will actively help partners to find and share the 

facilities, tools or equipment needed for their projects. 

2. Exchange and mobility of personnel. 

The work package will provide relevant information regarding: 

• training courses 

• facilities for individual “hands-on” training 

• student and post-doctoral fellowships 

• open positions at partner organisations including sabbaticals 

and will keep track of the corresponding personnel exchanges. 

3. Integration of SMEs. 

The work package is responsible for the web-advertisement and active recruitment of SMEs throughout the funding 

period, taking into account the fact that the participation should be flexible and regulated by the specific needs of 

the companies. Help will be provided to facilitate their integration by providing models for participation, IPR, 

etc… 

4. Development of integrative tools: website & annual conference. 

A website will be maintained to facilitate exchanges between DiMI partners. An annual meeting of molecular 

imaging will be organized in collaboration with other European molecular imaging networks (EMIL, etc…) 

5. Measurement of indicators. 

Indicators for the above activities as well as for the integrative activities of the JPRA will be continuously 

measured during the network life.


Deliverables 

D14.1 Electronic tools for an easy website update of the integration levels (6 mo). 

D14.2 Measureables for integration by JPRA (12 mo): 

• number of publications 

• number of novel technological achievements 

• number of newly developed probes 

• number of applications of novel probes and technology in the vertical tasks 

D14.3 Measureables of performance of DiMI-TTPs (12 mo): 








D14.4 Measureables of successful exchange and mobility (12 mo): 



D14.5 Measureables for successful integration of SMEs (12 mo): 

• number of SMEs (instrumentation, software, molecules) involved in DiMI-TTP-related research per year 



D14.6 Measureables for integration through specific integrative tools (12 mo): 

• annual European meeting for molecular imaging : number of attendees from DiMI labs 

• annual European meeting for molecular imaging : number of foreign speakers that have expressed interest in 

attending 

• website: number of visitors to DiMI’s website 

• website: rate of renewal of information 

Milestones 

M14.1 Website operation of network integrative activity measurement (6 mo). 

M14.2 First conference (12 mo).


WP15.1: Activities of the Board for Training (BOT) 


Activity Type 

Other specific activities 

Participant id P12:Tavitian P8:vanderLinden P1:Jacobs P4: Guilloteau 


participant 

P12: 11 P8: 7 P1: 11 P4: 7 

Objectives 

To promote the training of researchers and students in all respective fields of molecular imaging and to create a 

common organisation therefore. 


The BOT work package is dedicated to the enforcement of a strong effort in training in the field of Multimodal 

Diagnostic Molecular Imaging. A common organisation will be set within the DiMI consortium to reach that objective. 

1. Promotion and support of the capacities of the TTPs of the network to offer experienced researchers short- to 

medium-term trainings in specific molecular imaging technologies. 

The BOT is responsible for the organisation of trainings in specific topics within the areas of excellence of each 

DiMI-TTPs. The offers for short- (under one week) and medium (up to three months) trainings from the DiMI- 

TTPs will be registered in the DiMI web site database. When necessary, every effort to obtain input from the SMEs 

and from the other DiMI partners will be made in order to improve the training capacities of the TTP. 

2. Exchange and mobility of researchers and students. 

Fellow partners will be encouraged to submit their specific training needs for the completion of their research 

program to the BOT. The BOT will in turn be in charge of proposing adequate training and formation amongst the 

DiMI-TTPs. The BOT will also be in charge of organising and measuring the actual exchanges of personnel for 

training activities. 

3. Organisation of European courses for doctoral students in Diagnostic Molecular Imaging. 

The BOT will coordinate current local efforts in education in Molecular Imaging in order to reach common 

agreement on the contents of the Education programmes and to strengthen their Educational capacities. The 

objective here is clearly to set the standards for the recognition of a European MDPhD programme in Molecular 

Imaging by the end of the second year of activity. 

4. Raising of awareness of (i) researchers and students, (ii) National bodies (e.g. Universities) and (iii) International 

bodies (E.G. scientific societies,…) about the training and courses. 

The BOT will be responsible for promotion by all relevant media of the Molecular Imaging Training programmes 

inside DiMI. This includes (i) web diffusion, (ii) advertisement at meetings and conferences and inside the relevant 

institutions of the partners of the consortium (iii) tracking of the existing resources, i.e. participation of partners to 

Molecular Imaging teaching activities and identification of similar Educational activities in Universities and (iv) 

communication of proposed training activities and actions to public bodies. 

5. Measurement of BOT activities 

BOT will report (i) every 3 months internally; (ii) every 6 months to the Governing Board; (iii) every 12 months to 

the Scientific management Board. These reports will include the measurables defined below. 

Deliverables 

D15.1.1 Organisation of short and medium-term training 

• First 3 months : identification of the resources and support for their reinforcement when necessary 

• 6 months: definition and starting of the training programmes for each TTP 

• 18 months: measurement of the actual training performed within each TTP; plan for modifications required to


strengthen the training capacities if necessary. 

D15.1.2 Exchange and mobility of researchers and students 

• 3 months: identification of the specific training needs from fellow partners 

• 6 months: publication of the training and formation offers from the DiMI-TTPs. 

• 18 months: measurement of the actual researchers and students training periods within each TTP; plan for 

modifications required to increase the training exchanges if necessary. 

D15.1.3 Organisation of European courses for doctoral students in Diagnostic Molecular Imaging 

• 3 months: identification of the existing Educational programmes 

• 6 months: draft of a proposal for a common European Doctoral course in Molecular Imaging. 

• 18 months: implementation of the common European Doctoral course in Molecular Imaging. 

D15.1.4 Raising of awareness 

• Every 3 months: joint meeting or conference call of the BOT on the progress of training activities 

• Every 6 months: report of the BOT on the progress of training activities to the Governing Board; 

Communication of this report after GB approval on the DiMI website 

• Every 6-12 months: Dissemination to National and International Educational bodies. 

Measureables of performance of the BOT activities 

• number of training programmes proposed (6 months) 

• number of trained researchers and students (12 and 18 months) 

• number of trainees from SME (12 and 18 months) 

• number of months of training activity (18 months) 

• number of educational bodies participating in the European Molecular Imaging doctorate programme (18 months) 

• number of students registered in the European Molecular Imaging doctorate programme (18 months) 

• number of BOT reports and level of disseminations (18 months) 

Measurables will subsequently be produced every year during the network life 

Milestones 

M15.1.1 Common organisation of the training in the DiMI-TTPs (12 mo). 

M15.1.2 European courses for doctoral students in Diagnostic Molecular Imaging (18 mo).


WP15.2: Activities of the Board for Dissemination and Communication (BODIC) 


Activity Type 

Other specific activity 

Participant id P12:Tavitian P5: Planas P1:Jacobs P10: Bengel 


participant 

P12: 17 P5: 5 P1: 18 P10: 5 

Objectives 

To promote the awareness of DiMI activities internally and externally and to create a common set of resources and 

organisation therefore. 


The BODIC work package is dedicated to the external and internal Dissemination and Communication of the activities 

of DiMI in the field of Multimodal Diagnostic Molecular Imaging. A website has been created (www.diagnosticmolecular-imaging.org) 

and an annual plan for dissemination and communication (APDAC) will be implemented to 

reach that objective. 

Structure of the DiMI web site (=>figure in B4.3) 

The DiMI website will have three levels of accessibility (Read > Write > Modify) and four levels of confidentiality 

(Coordinator > BODIC > Partners > PUblic). 

TYPE OF COMMUNICATION/DISSEMINATION ACTIVITY READ WRITE MODIFY 

1. Internal communication includes : 

1.1. Management tools 

1.1.1. Legal documentation (i.e. Programme of activities, Proprietary P, B, C B, C C 

Right Issues, Scientific and Management reporting documents and 

worksheets and guidelines, How to use the web site…) 

1.1.2. Scientific and Management reports validated by the partners and P, B, C P, B, C C 

the different boards of the DiMI consortium 

1.1.3. Information on Congresses, workshops and Training activities P, B, C B, C C 

and offers. 

1.2. Knowledge Management 

1.2.1. Discussion Forums P, B, C P, B, C P, B, C 

1.2.2. Success stories P, B, C B, C C 

1.2.3. Workgroups internal web space P, B, C P, B, C P, B, C 

1.2.4. Validated Scientific Results (i.e. Communications, Publications P, B, C P, B, C B, C 

and Patents) 

1.2.5. Progress reports P, B, C B, C C 

1.3. Knowledge database 

1.3.1. Image database P, B, C B, C C 

1.3.2. Image processing tools P, B, C # B, C C 

2. External communication includes 

2.1. Communication website with links to other sources of information 

2.1.1. Information on DiMI project and activities U, P, B, C B, C C 

2.1.2. Thesaurus on Molecular Imaging and its relevance to society U, P, B, C B, C C 

2.2. Campaigns towards identified audiences, mostly through mail, to U, P, B, C P, B, C C 

disseminate the results and raise public awareness on DiMI activities and 

successes. 

(# restrictions may apply in certain cases)


Annual Plan for Dissemination & Communication (APDAC) 

The BODIC will be responsible for the drafting and release of the APDAC which will be broadly distributed to relevant 

audiences. Top ensure this activity, DiMI BODIC will distribute a request for information to the different bodies of 

DiMI (Managing Board, BIA, BOT, BOKIM, Subproject leaders, Meeting and Workshops organisers, etc) at regular 

intervals and collect and organise the data in a releasable form every 6 months. 

This will set the basis for the organisation of campaigns targeted towards specific audiences such as : Universities, 

Patient organisations, Scientific societies, Organisers of Scientific meetings, Governmental Institutions, Web Forums, 

SMEs, etc. These information campaigns will be discussed and implemented on a yearly basis and will be in the format 

best adapted to the target audience, such as E-mails, leaflets, press releases, etc. .Each year the BODIC will submit to 

the Governing Board the detailed DiMI APDAC including the list of planned Communication and Dissemination 

activities. 

Deliverables 

D15.2.1 Organisation of the web site 

• First 3 months : identification of the necessary resources and proposal for web site budget and 

management 

• 6 months: activities 1.1.1, 1.1.3., 1.2.1 and 1.2.3. start; 2.1.1. starts; test and validation of 1.1.2., 

1.2.4. and 1.2.5 

• 10 months: activities 1.1.2. starts. 

• 12 months: activities 1.2.2., 1.2.4., 1.2.5 and 2.1.2. start; tests for 1.3. 

• 18 months: activities 1.3.1 & 1.3.2. start 

D15.2.2 APDAC 

• 3 months : organisation of data collection system 

• 6 months : first release of the 6 month-interval BODIC APDAC report. 

• 12 months and every subsequent 12-month interval : APDAC 

Measurement of BODIC activities 

BODIC will report (i) every 3 months internally; (ii) every 6 months to the Governing Board; (iii) every 12 months to 

the Scientific management Board. These reports will evaluate the attainance of the deliverables listed above. 

Milestones 

M15.2.1 Fully implemented web site (18 mo) 

M15.2.2 APDAC (12 mo)


WP16: Management of the DiMI Network 


Activity Type 

Management Activities 


P1:Jacobs P2:Clark P3:Aime P4:Guilloteau P5: Planas P6:Maggie 

P7: Knudsen P8: vdLinden P9:Moonen P10:Bengel P11 Carlsen P12 Tavitian 


participant 

P7: 4 P8: 4 P9:4 P10: 4 P11: 4 P12: 4 

P13: 

Meynardier 

P13: 4 

Objectives: 

The Administrative Management Board will be responsible for the overall legal, contractual, ethical, financial and the 

following management tasks: 

• Management issues: workflow/scheduling, communications between partners/commission, control procedure 

changes, conflicts, reporting 

• Contractual issues: Monitoring of execution of deliverables and milestones (annual reviews, mid-terms review, and 

final review). 

• Financial issues: Audit certificates + European commission’s audits, costs justification management, summary 

certified statement, payments and distribution of money within consortium 

• Political issues: exploitation; links to education, science and society; gender equality, ethics, safety, SMEs 

participation 

Description of tasks: 

Management issues · 

T01 scientific coordination together with Project Coordinator 

T02 designing, implementation and updating of the consortium agreement 

T03 management of budget 

T04 management of reports and deliverables towards the Commission 

T05 implementation and updating the web-based DiMI communication system ensuring and efficient 

communication within and outside the network 

T06 facilitating the exchange of documents, worksheets, etc. 

T07 handling queries and correspondences 

T08 arrangements for project meetings and conferences 

T09 coordination of preparation of cost calculations of individual partners 

T10 calls for proposal for new partners 

T11 handling responsibilities with regards to intellectual property queries, exploitation and dissemination 

T12 search for new SMEs and potential industrial partners 

T13 direct interaction with representatives of the GB 

Deliverables 

D16.0 Meeting with WP16 participants to define tasks & scheduling– (Month 1) 

D16.1 Organisational chart with all contacts by partner (scientific, legal, financial, administrative) – (Month 3) 

D16.2 Organisational chart with all Governance Bodies and members (Month 3) 

D16.3 Setting –up of reporting procedures (between partners and Scientific Administrators – (Month 3)


D16.4 Setting –up of financial and accounting reporting procedure of the consortium resources – (Month 3) 

D16.5 EC Annual report – (Month 12) 

D16.6 Financial report including audit certificates – ( Month 12) 

D16.7 Preparation of JPA for the next period – ( Month 6-12; 18-24….) 

Milestones 

M10.1 DiMI Kick-off meeting (Month 1) 

M10.2 First governing board meeting (Month 6) 

M10.3 EC Annual report– (Month 12) 

M10.4 JPA for the next period – ( Month 12) 

M10.5 Provisional budget for next JPA – (month 12)


10 Project resources and estimation of incurred eligible costs 

10.1 Efforts for the full duration of the project 

Project Number: 512146 (DIMI) 

Partner Number 

Research Activity Type 

Partner Name 

Integrated 

Activities 

Jointly executed 

research activities 

Joint Programme of Activities 

Spreading of 

Excellence Activities 

Consortium 

Management 

Activities 

TOTAL per 

participant 

1 MEK 97 373 97 120 686 

2 UCAM-WBIC 60 250 0 13 323 

3 UniTo 60 250 0 13 323 

4 UniTours 60 130 23 13 227 

5 IDIBAPS 60 237 17 13 327 

6 UNIMI 60 271 0 13 344 

7 RH-NRU 60 120 0 13 193 

8 UA 60 167 23 13 264 

9 CNRS 60 220 0 13 293 

10 NUK_TUM 60 192 17 13 282 

11 UiO 60 56 0 13 129 

12 CEA 60 53 93 13 220 

13 BIOSPACE 60 40 0 13 113 

14 K.U.Leuven R&D 0 145 0 0 145 

15 ULUND 0 50 0 0 50 

16 ULUND 0 40 0 0 40 

17 Imperial College Lo# 0 56 0 0 56 

18 Hospital Sant Pau# 0 40 0 0 40 

19 INSERM 0 43 0 0 43 

20 UEDIN 0 44 0 0 44 

21 UKB 0 65 0 0 65 

22 KI 0 45 0 0 45 

24 FZJ 0 45 0 0 45 

25 MPIfnF 0 115 0 0 115 

26 CARIM 0 62 0 0 62 

27 CBI 0 44 0 0 44 

28 CNRS 0 40 0 0 40 

29 AZG 0 49 0 0 49 

30 INP 0 60 0 0 60 

31 UNEW 0 120 0 0 120 

32 TU/e 0 85 0 0 85 

33 KI Neurotec 0 52 0 0 52 

34a CNR-IBB 0 31 0 0 31 

34b FTELE 0 30 0 0 30 

35 DUR 0 235 0 0 235 

36 UVita-P 0 65 0 0 65 

37 LUMC 0 55 0 0 55 

38 CEA 0 48 0 0 48 

39 ULG 0 47 0 0 47 

40 UKM 0 295 0 0 295 

41 KULeuven R&D 0 175 0 0 175 

42 CYCERON 0 46 0 0 46 

43 MT 0 40 0 0 40 

45 UNAW 0 40 0 0 40 

46 UnivTour 0 50 0 0 50 

47 Cyclopharma 0 39 0 0 39 

48 MEDRES 0 37 0 0 37 

49 Visgenyx 0 38 0 0 38 

50 Charles University 0 89 0 0 89 

51 Polatom 0 38 0 0 38 

52 IEM ASCR 0 37 0 0 37 

53 IGT 0 30 0 0 30 

Total per Activity Type 

817 5024 270 280 

Overall TOTAL efforts 

6391


10.2 Efforts for the first 18 months 

Labour in person month


Provisional costs for the first 18 months period 

Labour in k€



Additional direct Costs in k€



Overall Costs in k€


Cost model used by partners 

Participant. Number Participant short name Country COST MODEL OVERHEADS 

1 MEK D AC 20,00% 

2 UCAM-WBIC GB AC 20,00% 

3 UniTo I AC 20,00% 

4 UniTours F AC 20,00% 

5 IDIBAPS E AC 20,00% 

6 UNIMI I AC 20,00% 

7 RH-NRU DK AC 20,00% 

8 UA B AC 20,00% 

9 CNRS F FCF 20,00% 

10 NUK_TUM D AC 20,00% 

11 UiO N AC 20,00% 

12 CEA F FC 83,83% 

13 BIOSPACE F FCF 20,00% 

14 K.U.Leuven R&D B AC 20,00% 

15 ULUND S AC 20,00% 

16 ULUND S AC 20,00% 

17 Imperial College UK AC 20,00% 

18 Hospital Sant Pau E FCF 20,00% 

19 INSERM F FCF 20,00% 

20 UEDIN GB AC 20,00% 

21 UKB D AC 20,00% 

22 KI S AC 20,00% 

23 CEA F FC 83,83% 

24 FZJ D AC 20,00% 

25 MPIfnF D AC 20,00% 

26 CARIM NL AC 20,00% 

27 CBI S AC 20,00% 

28 CNRS F FC 20,00% 

29 AZG Groningen PET Center NL FC 51,30% 

30 INP F AC 20,00% 

31 UNEW GB AC 20,00% 

32 TU/e NL AC 20,00% 

33 KI Neurotec S AC 20,00% 

34a CNR-IBB I FC 81,50% 

34b FTELE.IGM I AC 20,00% 

35 DUR GB FC 20,00% 

36 UVita-P I AC 20,00% 

37 LUMC NL AC 20,00% 

38 CEA F FC 83,83% 

39 ULG B AC 20,00% 

40 UKM D AC 20,00% 

41 KULeuven R&D B AC 20,00% 

42 CYCERON F AC 20,00% 

43 MT N FCF 20,00% 

45 UNAV E FC 20,00% 

46 UnivTours F AC 20,00% 

47 Cyclopharma F FC 20,00% 

48 MEDRES D FC 20,00% 

49 Visgenyx EST FC 20,00% 

50 Charles University CZ AC 20,00% 

51 POLATOM PL FC 20,00% 

52 IEM ASCR CZ AC 20,00% 

53 IGT F FC 20,00%


Provisional budget by Workpackage, month 1-18 

WP1: Partners Effort (person -month and K€) 

WP1 


models 


models 

D1.3 Validation of TOHR imaging on mouse heart 

models 

D1.4 Hardware multipinhole SPECT collimator 

prototype 

D1.5 Software for multipinhole SPECT 


D1.6 Software for registration of MicroSPECT data 

with structural data 

Biospace (13) 

IUniTours (4) 

NUK_TUM (10) 

INP (30) 

KULRD (41) 

UA (8) 

Total 

6 6 12 24 

18 2 20 

3 3 3 9 

3 3 3 9 

12 1 13 

12 2 14 

Total Labour (person-month) 12,0 6,0 6,0 18,0 42,0 5,0 89,0 

Labour (K€) 63,4 29,2 30,8 87,5 204,5 24,4 439,7 

OVERHEADS 0,0 

Total Labour (K€) 63,4 29,2 30,8 87,5 204,5 24,4 439,7 

ADDITIONAL DIRECT COSTS 0,0 

Supplies 5,0 10,0 19,0 15,0 49,0 

Travel 5,0 2,0 5,0 12,0 

TOTAL additional direct costs 5,0 7,0 10,0 24,0 15,0 0,0 61,0 

LABOUR+ADDITIONAL COSTS 68,4 36,2 40,8 111,5 219,5 24,4 500,7 

OVERHEADS 13,7 7,2 8,2 22,3 43,9 4,9 100,1 

OVERALL TOTAL (K€) 82,0 43,4 48,9 133,8 263,4 29,2 600,8



WP2 



D2.1 Adapt Monte Carlo code (SimSET+GEANT4) 

to model microPET 

D2.2 Implement PROMIS 3D image reconstruction 

algorithm on PC-cluster 

D2.3 Implement singles and windowed coincidence 

mode transmission scanning on microPET, and 

implement iterative reconstruction of this data 

D2.4 Verification of microPET data corrections and 

image reconstruction 

D2.5 Measure and assess magnetic field properties 

of 1T split pair magnet 

D2.6 Demonstrate the spatial and temporal 


D2.7 Design and build split coil active shield 

gradients 

D2.8 Investigate the performance of a PET detector 

block operating in the MR imager 



UCAM-WBIC(2) 

MEK(1) 

IDIBAPS (5) 

CEA (12) 

Total 

0 

9 9 

6 6 

6 6 

6 6 6 6 24 

3 3 

6 6 

6 6 

6 6 

6 6 

Total Labour (person-month) 54,0 6,0 6,0 6,0 72,0 

Labour (K€) 198,7 30,8 24,0 23,3 276,8 

OVERHEADS 19,5 19,5 

Total Labour (K€) 198,7 30,8 24,0 42,8 296,3 


Supplies 39,0 5,0 5,0 5,0 54,0 

Travel 2,0 2,0 2,0 2,0 8,0 

TOTAL additional direct costs 41,0 7,0 7,0 7,0 62,0 

LABOUR+ADDITIONAL COSTS 239,7 37,8 31,0 49,8 358,3 

OVERHEADS 47,9 7,6 6,2 61,7 

OVERALL TOTAL (K€) 287,7 45,3 37,2 49,8 420,0



WP3 

D3.0 Report of meeting with WP 3 members for final 


D3.1 Precursors for radiolabelling with fluorine-18 of 

tracer agents for dopamine transporter (DAT) 

D3.2 Written instructions for radiolabelling with 

fluorine-18 of tracer agents for dopamine transporter 

(DAT) using deliverable D3.1 

D3.3 Software for quantification of dopamine 

transporter in vivo using developed 18 F labelled tracer 

agent and positron emission tomography 

UniTours (4) 

KI I(22) 

AZG (29) 

NRU-DK (7) 

KULRD (41) 

MEK (1) 

Total 

0 

6 6 6 18 

0 

3 3 

D3.4 Results of evaluation in vitro and in vivo in 

animals of fluorine-18 labelled tracer agents for 

dopamine transporter 

0 

D3.5 Precursors for radiolabelling with fluorine-18 or 

carbon-11of tracer agents for in vivo visualisation of 


6 6 6 18 

D3.6 Written instructions for radiolabelling with 

fluorine-18 or carbon-11 of tracer agents for in vivo 


0 

D3.7 Results of evaluation in vitro of fluorine-18 or 

carbon-11 labelled tracer agents for visualisation of 


0 


discussion of 1 st year results and further work plan 0 


Labour (K€) 58,3 57,4 0,0 13,5 58,4 0,0 187,6 


Total Labour (K€) 58,3 57,4 0,0 13,5 58,4 0,0 187,6 

ADDITIONAL DIRECT COSTS 

Supplies 80,0 75,0 35,0 35,0 80,0 30,0 335,0 

Travel 2,0 2,0 2,0 2,0 2,0 2,0 12,0 



OVERHEADS 28,1 26,9 10,1 28,1 6,4 99,5 

OVERALL TOTAL (K€) 168,4 161,2 37,0 60,6 168,5 38,4 634,1


WP4.1: Partners Effort (person -month and K€) 

WP4.1 

D4.1.1 Identification of high sensitive Gd(III)-based 

Imaging Probes endowed with specific targeting 

ability. 

D4.1.2 Identification of high sensitive paramagnetic 

CEST agents responsive towards pH and temperature 

D4.1.3 Report on meeting WP members 

D4.1.4 Optimised procedures for cell-labelling using 

soluble Gd(III)-based and CEST Imaging Probes ( 

pynocitosis and electroporation) or insoluble Gd(III)- 

based bio-degradable particles (for labelling 

macrophages) 

D4.1.5 Identification of Imaging Probes (Gd(III)- 

based and CEST agents) for targeting vulnerable 

plaques 

D4.1.6 Set-up of MRI protocols “in vivo” for 

evaluating and optimising the diagnostic properties of 

the developed Imaging Probes 

UniTo (3) 

UniTours (46) (4) 

CNRS (9) 

MPIFNF (25) 

DUR (35) 

KULRD (41) 

Charles (50) 

Total 

12 9 3 6 30 

6 6 12 

12 9 9 30 

18 6 24 

6 12 3 21 

Total Labour (person-month) 54,0 12,0 3,0 9,0 18,0 3,0 18,0 117,0 

Labour (K€) 198,7 58,3 14,6 46,2 66,2 14,6 18,0 416,6 

OVERHEADS 13,2 0,0 13,2 

Total Labour (K€) 198,7 58,3 14,6 46,2 79,5 14,6 18,0 429,9 


Supplies 55,0 25,0 13,0 8,0 12,0 13,0 18,0 144,0 

Travel 6,0 4,0 2,0 2,0 2,0 2,0 2,0 20,0 

TOTAL additional direct costs 61,0 29,0 15,0 10,0 14,0 15,0 20,0 164,0 

LABOUR+ADDITIONAL COSTS 259,7 87,3 29,6 56,2 93,5 29,6 38,0 593,9 

OVERHEADS 51,9 17,5 5,9 11,2 5,9 7,6 100,1 

OVERALL TOTAL (K€) 311,7 104,8 35,5 67,4 93,5 35,5 45,6 694,0



WP4.2 

D4.2.1 Lanthanide-based Optical Probes responsive 

to intracellular analytes. 

UniTo (3) 

UniTours (46) (4) 

CNRS (9) 

DUR (35) 

KULRD (41) 

Charles (50) 

Total 

3 15 3 21 

D4.2.2 Report on 2 nd meeting among WP members 0 

D4.2.3 A lanthanide based Optical Probe for DNAtargeting. 

D4.2.4 Long-lived Optical Probes based on an 

efficient energy transfer between a Lanthanide metal 

complex and aSelected chromophore. 

D4.2.5 Combined Probes containing several chelating 

moieties (10-50) mostly charged with Gd(III) ions 

(for MRI visualisation) and containing one or few 

sites occupied by luminescent lanthanide ions or by 

lanthanide radioisotopes endowed with suitable 

emitting properties for Optical Imaging and PET 

detection, respectively. 

3 3 12 3 6 27 

9 3 9 21 

6 6 3 15 30 


Labour (K€) 44,2 29,2 23,3 187,7 29,2 18,0 331,5 


Total Labour (K€) 44,2 29,2 23,3 225,2 29,2 18,0 369,0 


Supplies 30,0 28,0 6,0 24,0 6,0 15,0 109,0 

Travel 2,0 2,0 2,0 2,0 2,0 2,0 12,0 



OVERHEADS 15,2 11,8 6,3 7,4 7,0 47,8 

OVERALL TOTAL (K€) 91,4 71,0 37,5 251,2 44,7 42,0 537,8



WP5 



IDIBAPS (5) 

FTELE.IGM (34) 

MEK (1) 

UNIMI (6) 

UA (8) 

KULRD (14) 

KULRD (41) 

MPIFNF (25) 

CYCERON (42) 

RH-NRU (7) 

TU/e (32) 

UKB (21) 

UKM (40) 

Total 


in the pre-established (a) animal models, and 

in (b) new animal models with invasive 

methods. 


molecular and histopathological alterations in 

the different experimental models and 

characterization of viral-mediated gene 

transfer in the selected animal models of 

disease. 

3 18 4 12 6 6 6 

12 18 4 12 12 6 64 

55 

D5.3 Characterization of the glial reaction. 

6 12 12 

30 

D5.4 Integrating imaging with 

neuropathological and molecular alterations 

in stroke, PD, AD, and HD; and non-invasive 

imaging of viral-mediated gene transfer in 

HSP. Connection with related WPs.. 

12 3 4 5 3 6 3 6 3 2 47 


molecular and histopathological alterations in 

the ischemic heart, and biological 

characterization of atherosclerotic plaques 

12 2 1 15 

D5.6 Labelling of progenitor and/or stem 

cells and evaluation of the biological effects 

in vitro for cardiovascular research. 

6 6 12 

D5.7 Integrating imaging with pathological 

and molecular alterations in each model of 

cardiovascular diseases; re-identification of 

stem cells after transplantation into the 

injured mouse heart Connection with related 

WPs 

6 12 12 30 


disease. Exchange of animal models within 

the network. Links to other WPs. 

2 2 1 2 2 3 2 2 1 2 2 17 

Total Labour (person-month) 35,0 21,0 6,0 24,0 5,0 16,0 30,0 38,0 29,0 3,0 30,0 22,0 15,0 274,0 

Labour (K€) 140,0 77,3 30,8 88,3 24,4 77,9 146,1 194,9 140,9 13,5 172,8 112,9 77,0 1296,7 


Total Labour (K€) 140,0 140,3 30,8 88,3 24,4 77,9 146,1 194,9 140,9 13,5 172,8 112,9 77,0 1359,7 


Supplies 85,0 60,0 7,0 155,0 2,0 24,0 35,0 19,0 53,0 2,0 50,0 20,0 22,0 534,0 

Travel 8,0 7,0 2,0 19,0 4,0 2,0 6,0 6,0 12,0 2,0 12,0 4,0 4,0 88,0 

TOTAL additional direct costs 93,0 67,0 9,0 174,0 6,0 26,0 41,0 25,0 65,0 4,0 62,0 24,0 26,0 622,0 

LABOUR+ADDITIONAL COSTS 233,0 207,3 39,8 262,3 30,4 103,9 187,1 219,9 205,9 17,5 234,8 136,9 103,0 1981,7 

OVERHEADS 46,6 8,0 52,5 6,1 20,8 37,4 44,0 41,2 3,5 47,0 27,4 20,6 354,9 

OVERALL TOTAL (K€) 279,6 207,3 47,7 314,8 36,4 124,7 224,5 263,9 247,1 21,0 281,8 164,2 123,5 2336,6



WP6 

D6.1 Assessment of the pharmacological activity of 

estrogen and selected ER mediators (SERMs) on 

brain inflammation 

D6.2 Identification of the mechanisms involved in 

estrogen anti-inflammatory activity 

D6.3 Vectors genetically engineered to express 

luciferase and D2 receptor (lucIRESD2) 

D6.4 Stably transfected cells with the lucIRESD2 

reporter 

D6.5 Assessment of ratio of expression of the two 

reporter in vivo 

D6.6 Common data for the detection sensitivity of 

cells expressing lucIRESD2 reporter by optical 

imaging and PET 

UNIMI (6) 

UiO (11) 

CEA (12) 

MEK (1) 

Total 

18 18 

18 6 24 

4 4 

4 4 

4 6 10 

6 6 12 


Labour (K€) 198,7 0,0 0,0 92,3 291,1 


Total Labour (K€) 198,7 0,0 0,0 92,3 291,1 


Supplies 115,0 30,0 145,0 

Travel 4,0 4,0 4,0 4,0 16,0 



OVERHEADS 63,5 0,8 25,3 89,6 

OVERALL TOTAL (K€) 381,3 4,8 4,0 151,6 541,7



WP7 

D7.0 Common meeting of partners 

UA (8) 

KULRD (14) 

KULRD (41) 

MEK (1) 

IDIBAPS (5) 

UniTo (3) 

UNIMI (6) 

Total 

0 

D7.1 Multimodality Phenotyping of 6-0HDA PD rat 

model 

D7.2 Multimodality Phenotyping of lentiviral PD rat 

model 

D7.3 Optical imaging Phenotyping of lentiviral PD 

mouse model 

D7.4 Multimodality Phenotyping of chronic 3NP 

HD rat model 

D7.5 MRI phenotyping of different ALS genotype 

mice 

D7.6 Multimodality Phenotyping of lentiviral HD 

rat model 

D7.7 Multimodality Phenotyping of a lesional model 

of Huntington's disease in rats 

D7.8 Implementation of animal brain atlases for 

automatic VOI definitions 

4 4 4 4 3 19 

4 6 4 8 3 25 

4 8 4 4 20 

4 3 

2 2 2 

4 3 3 

3 3 

3 3 

Total Labour (person-month) 18,0 18,0 14,0 18,0 15,0 6,0 4,0 93,0 

Labour (K€) 87,7 87,7 68,2 92,3 60,0 22,1 14,7 432,6 

OVERHEADS 0,0 

Total Labour (K€) 87,7 87,7 68,2 92,3 60,0 22,1 14,7 432,6 


Supplies 35,0 30,0 40,0 28,0 25,0 15,0 7,0 180,0 

Travel 2,0 2,0 2,0 2,0 2,0 2,0 2,0 14,0 

TOTAL additional direct costs 37,0 32,0 42,0 30,0 27,0 17,0 9,0 194,0 

LABOUR+ADDITIONAL COSTS 124,7 119,7 110,2 122,3 87,0 39,1 23,7 626,6 

OVERHEADS 24,9 23,9 22,0 24,5 17,4 7,8 4,7 125,3 

OVERALL TOTAL (K€) 149,6 143,6 132,2 146,8 104,4 46,9 28,5 752,0 

7 

10 

6



WP8.1 

Meeting with DiMI members for final agreement and 

initiation of work plan 

0 

Sectioning of tissues for laser capture 9 9 

Extraction and quality control of RNA 9 9 

Amplification and array hybridisation 9 9 

Western blot based validation of targets 9 9 

Discussion and selection of imaging targets 0 

Total Labour (person-month) 36,0 36,0 

Labour (K€) 132,5 132,5 

OVERHEADS 0,0 

Total Labour (K€) 132,5 132,5 


Supplies 30,0 30,0 

Travel 2,0 2,0 2,0 2,0 

TOTAL additional direct costs 32,0 2,0 2,0 36,0 

LABOUR+ADDITIONAL COSTS 164,5 2,0 2,0 168,5 

OVERHEADS 32,9 0,4 0,4 33,7 

OVERALL TOTAL (K€) 197,4 2,4 2,4 202,2 

UNEW (31) 

MEK (1) 

UA (8) 

Total



WP8.2 

MEK (1) 

NRU-DK (7) 

NUK_TUM (10) 

D8.2.0 Meeting with WP10 members for final 


D8.2.1 Protocol drafts to perform standardized 

and coordinated baseline studies 3,0 2,0 2,0 7,0 

D8.2.2 Approvals from local ethics committees 

D8.2.3 Approval by the respective ethics 

committees will be presented to the EC before 

0,0 

start of subject recruitment 

D8.2.4 Presentation of molecular techniques to 

be used in this protocol to other participants and 

to other interested parties, in particular 

0,0 

pharmaceutical industry 

D8.2.5 Start of studies with inclusion of first 

patients and controls 

6,0 6,0 6,0 6,0 12,0 6,0 6,0 6,0 6,0 12,0 6,0 6,0 84,0 

Total Labour (person-month) 9,0 8,0 6,0 6,0 12,0 6,0 6,0 6,0 6,0 14,0 6,0 6,0 91,0 

Labour (K€) 46,2 36,0 30,8 22,1 44,2 34,6 22,1 22,1 29,2 68,2 28,7 24,0 408,0 

OVERHEADS 17,7 18,0 35,7 

Total Labour (K€) 46,2 36,0 30,8 22,1 44,2 52,3 40,1 22,1 29,2 68,2 28,7 24,0 443,7 


Supplies 10,0 10,0 33,7 10,5 30,0 30,0 30,0 10,0 80,0 244,2 

Travel 2,0 2,0 2,0 2,0 2,0 2,0 3,0 2,0 2,0 2,0 2,0 2,0 25,0 

TOTAL additional direct costs 12,0 12,0 2,0 2,0 35,7 2,0 13,5 32,0 32,0 32,0 12,0 82,0 269,2 

LABOUR+ADDITIONAL COSTS 58,2 48,0 32,8 24,1 79,9 54,3 53,6 54,1 61,2 100,2 40,7 106,0 712,9 

OVERHEADS 11,6 9,6 6,6 4,8 16,0 10,8 12,2 20,0 8,1 21,2 121,0 

OVERALL TOTAL (K€) 69,8 57,6 39,3 28,9 95,8 54,3 53,6 64,9 73,5 120,2 48,8 127,2 833,9 

ICL (17a) 

UEDIN (20) 

AZG (29a) 

CNR-IBB (34a) 

Uvita-P (36) 

CRCULG (39) 

KULRD (41) 

KII (33) 

UNAV (45) 

Total 

0,0



WP9 

D9.1 Establishment of in- and exclusion criteria for 

all patient groups 

D9.2 Specification of ethical aspects with particular 

emphasis on patients with degenerative brain 

disorders and dementia and national regulations 

NRU-DK (7) 

MEK (1) 

IDIBAPS (5) 

ICL (17a) 

KIN (33) 

CNR-IBB (34a) 

Uvita-P (36) 

CYCERON (42) 

Total 

0 

0 

D9.3 Specification of ethical aspects in animal 

models with particular emphasis on national 

regulations 

D9.4 Establishment of [ 11 C](R )-PK11195 in other 

DiMI laboratories 

D9.5 BBB, microglial probes or tPA probes 

validated 

D9.6 Establishment of the ability of tPA and tPAstop 

tPA complexes to cross the blood-brain barrier and 

tissue distribution 

D9.7 Implementation of protocols for MR-imaging 

1 1 1 1 

2 6 6 6 

1 6 

2 1 1 

D9.8 Initial histopathological validation of current 

neuroimaging markers of inflammation 

6 2 

8 

D9.9 Initial blood-brain barrier integrity studies in 

patients with multiple sclerosis 

11 1 2 14 

D9.10 Initial in-vivo studies in models of cerebral 

ischemia 

1 2 6 9 

D9.11 Cross-sectional MR and/or PET in patients 

with MS, parkinsonism, memory dysfunction, HD, 6 4 23 12 2 18 65 

and prion disease 

D9.12 Paramagnetically labeled tPA made available 

to other partners 

1 6 7 

D9.13 Biochemical inflammatory markers, gene 

expression, and proteomics in patients 

Total Labour (person-month) 30,0 6,0 12,0 24,0 12,0 6,0 24,0 24,0 138,0 

Labour (K€) 135,0 30,8 48,0 88,3 57,4 22,1 88,3 116,6 586,5 


Total Labour (K€) 135,0 30,8 48,0 88,3 57,4 40,1 88,3 116,6 604,5 


Supplies 22,0 10,0 8,0 40,0 20,0 0,0 30,0 16,0 146,0 

Travel 14,0 7,0 2,0 7,0 2,0 4,5 2,0 2,0 40,5 

TOTAL additional direct costs 36,0 17,0 10,0 47,0 22,0 4,5 32,0 18,0 186,5 

LABOUR+ADDITIONAL COSTS 171,0 47,8 58,0 135,3 79,4 44,6 120,3 134,6 791,0 

OVERHEADS 34,2 9,6 11,6 27,1 15,9 24,1 26,9 149,3 

OVERALL TOTAL (K€) 205,2 57,3 69,6 162,4 95,2 44,6 144,4 161,6 940,3 

0 

4 

20 

7 

4



WP10 

MEK (1) 

D 10.0 Meeting with WP10 members for final agreement 

and initiation of work plan 

D 10.1 Common protocol for improved labelling of 

NP/NSC with MRI contrast agents and in vitro 

assessment of sensitivity of MRI detection of labelled 

6 12 12 30 

cells. 

D 10.2 Common protocol for magneto-liposomes 

targeting specifically NPC 

6 6 

12 

D 10.3 Genetically engineered NP/NSC expressing 

tk IRESluc 

6 9 15 

D 10.4 Detection of tk IRESluc expressing NP/NSC using 

PET and optical imaging (12, 18 mo) 

12 9 21 

D 10.5 Common data for the detection sensitivity of 

NP/NSC by MRI, PET and optical imaging 

D 10.6 Assessment of behaviour of native/modified 

NP/NSC with respect to toxicity due to labelling 

procedure, differentiation capabilities and homing 

15 18 6 12 51 

potential 

D 10.7 Vectors for controlled and specific tk IRESluc 

marker gene expression in NP/NSC 

6 12 18 

D 10.8 Multi-tracer microPET/microSPECT in the 

assessment of metabolism and function after NP/NSC 6 12 18 

transplantation 

Total Labour (person-month) 30,0 24,0 33,0 24,0 0,0 0,0 0,0 30,0 24,0 165,0 

Labour (K€) 153,9 114,7 169,3 116,9 0,0 0,0 0,0 146,1 24,0 724,9 

OVERHEADS 0,0 

Total Labour (K€) 153,9 114,7 169,3 116,9 0,0 0,0 0,0 146,1 24,0 724,9 


Supplies 45,0 40,0 40,0 30,0 50,0 40,0 245,0 

Travel 4,0 6,0 4,0 2,0 10,0 10,0 10,0 4,0 4,0 54,0 

TOTAL additional direct costs 49,0 46,0 44,0 32,0 10,0 10,0 10,0 54,0 44,0 299,0 

LABOUR+ADDITIONAL COSTS 202,9 160,7 213,3 148,9 10,0 10,0 10,0 200,1 68,0 1023,9 

OVERHEADS 40,6 32,1 42,7 29,8 2,0 2,0 2,0 40,0 13,6 204,8 

OVERALL TOTAL (K€) 243,5 192,9 255,9 178,7 12,0 12,0 12,0 240,1 81,6 1228,7 

ULUND-I (15) 

MPIFNF (25) 

UA (8) 

NUK_TUM (10) 

CARIM (26) 

CNRS (9) 

KULRD (14) 

IEM ASCR (52) 

Total



WP11.1 

UKM (40a) 

D11.1.0 Meeting with WP11.1 members for final agreement 

and initiation of work plan 

0 

D11.1.1 Common data for glucose consumption (PET) in 

different plaque stages in ApoE -/- mice and rabbits 

12 18 30 

D11.1.2 Common data for MMP activity (PET, optical) in 

different plaque stages in ApoE -/- mice 

18 12 30 

D11.1.3 Common data for apoptosis in different plaque 


6 6 

D11.1.4 Common data for αvβ3 integrinexpression(PET) 

in different plaque stages in ApoE -/- mice 

0 

D11.1.5 Common data for smooth muscle proliferation in 

different plaque stages in ApoE-/- mice 

0 

D11.1.6 Data for morphological characterization in different 

plaque stages in ApoE-/- mice 

0 

D11.1.7 Data for non-invasive detection of apoptosis in 

different plaque stages and effect of treatment in human 

9 9 

carotid plaques 

Total Labour (person-month) 36,0 12,0 9,0 18,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 75,0 

Labour (K€) 184,7 61,6 51,8 87,7 0,0 0,0 0,0 0,0 0,0 0,0 0,0 385,7 


Total Labour (K€) 184,7 61,6 51,8 87,7 0,0 0,0 0,0 0,0 0,0 0,0 0,0 385,7 


Supplies 47,5 15,0 32,5 5,0 6,0 5,0 5,0 5,0 121,0 

Travel 2,0 2,0 2,0 2,0 4,0 4,0 2,0 2,0 4,0 2,0 2,0 28,0 

TOTAL additional direct costs 49,5 17,0 34,5 7,0 10,0 9,0 7,0 7,0 4,0 2,0 2,0 149,0 

LABOUR+ADDITIONAL COSTS 234,2 78,6 86,3 94,7 10,0 9,0 7,0 7,0 4,0 2,0 2,0 534,7 

OVERHEADS 46,8 15,7 17,3 18,9 2,0 1,8 1,4 1,4 0,8 0,4 106,5 

OVERALL TOTAL (K€) 281,0 94,3 103,6 113,6 12,0 10,8 8,4 8,4 4,8 2,4 2,0 641,3 

UKM (40b) 

CARIM (26) 

UKAM_WBIC (2) 

NUK_TUM (10) 

HSP (18) 

TU/e (32) 

LUMC (37) 

CNRS (9) 

CBI (27) 

CNRS (28) 

Total



WP11.2 

NUK_TUM (10) 

CNRS (9) 

D11.2.1 Vectors for induction and in vivo monitoring of 

angiogenesis gene therapy 

6 6 

D11.2.2 Vectors for monitoring of endogenous 


6 6 12 

D11.2.3 Meeting of WP participants for discussion and 

coordination of in vivo studies 

0 

D11.2.4 Common protocol for in vivo imaging of reporter 

gene expression 

6 6 12 

D11.2.5 Common protocol for in vivo imaging of integrin 

expression using MRI and PET 

6 6 6 18 

D11.2.6 Detection of myocardial MMP expression using 

PET and optical imaging 

6 6 

12 

D11.2.7 Time course of expression of angiogenesisrelated 

proteins in myocardial ischemia 

6 6 12 6 6 6 42 

D11.2.8 Repeatable noninvasive imaging approach for 

detection of endogenous cardiovascular gene expression 6 6 6 18 

Total Labour (person-month) 36,0 24,0 0,0 18,0 6,0 12,0 6,0 6,0 0,0 12,0 120,0 

Labour (K€) 184,7 93,1 0,0 92,3 34,6 69,1 23,3 34,6 0,0 58,4 590,1 


Total Labour (K€) 184,7 93,1 0,0 92,3 34,6 69,1 27,9 34,6 0,0 58,4 594,8 


Supplies 60,0 35,0 5,0 40,0 20,0 160,0 

Travel 4,0 6,0 6,0 6,0 4,0 2,0 2,0 6,0 6,0 2,0 44,0 

TOTAL additional direct costs 64,0 41,0 11,0 46,0 4,0 2,0 2,0 6,0 6,0 22,0 204,0 

LABOUR+ADDITIONAL COSTS 248,7 134,1 11,0 138,3 38,6 71,1 29,9 40,6 6,0 80,4 798,8 

OVERHEADS 49,7 26,8 2,2 27,7 7,7 14,2 8,1 1,2 16,1 153,8 

OVERALL TOTAL (K€) 298,4 160,9 13,2 166,0 46,3 85,3 29,9 48,7 7,2 96,5 952,5 

UKB (21) 

UKM (40a) 

LUMC (37) 

TU/e (32) 

CNRS (28) 

CARIM (26) 

MEK (1) 

KULRD (41) 

Total



WP12 

CNRS (9) 

D12.1 Improved labelling of cardiac stem cells with MRI 

contrast agent and in vitro assessment of sensitivity of 6 3 6 6 6 

27 

MRI detection of labelled cells 

D12.2 Transfection of cardiac stem cells with marker 

genes (e.g. luciferase, TK) that allow visualization using 

6 6 6 6 24 

optical and PET/SPECT methods 

D12.3 Detection of modified stem cells using optical and 

PET/SPECT methods and evaluation of detection 

0 

sensitivity 

D12.4 Assessment of viability of native and modified 

stem cells with respect to toxicity due to the labelling 

procedure, differentiation capabilities and homing 

6 6 

12 

potential 

D12.5 Development of different administration 

approaches for labelled stem cells: image-guided 

intracardiac injection, local intravascular injection, 

6 6 12 


D12.6 Assessment of stem cell homing and migration an 

established mouse model of cardiac disease 

6 6 6 6 24 

D12.7 Development of target gene markers for 

identification of differentiation and demonstration in 6 6 6 6 24 

vitro 

D12.8 Transfection of stem cells with marker genes under 

control of the hsp70 promoter or tissue-specific promoters 

and demonstration of image-guided expression control in 

12 6 18 

vitro and in vivo 

Total Labour (person-month) 36,0 24,0 15,0 6,0 12,0 12,0 6,0 18,0 12,0 141,0 

Labour (K€) 139,7 123,1 77,0 22,1 69,1 69,1 24,0 103,7 61,6 689,3 

OVERHEADS 0,0 

Total Labour (K€) 139,7 123,1 77,0 22,1 69,1 69,1 24,0 103,7 61,6 689,3 


Supplies 50,0 25,0 15,0 10,0 10,0 15,0 10,0 20,0 15,0 170,0 

Travel 4,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 18,0 

TOTAL additional direct costs 54,0 27,0 17,0 12,0 12,0 15,0 12,0 22,0 17,0 188,0 

LABOUR+ADDITIONAL COSTS 193,7 150,1 94,0 34,1 81,1 84,1 36,0 125,7 78,6 877,3 

OVERHEADS 38,7 30,0 18,8 6,8 16,2 16,8 7,2 25,1 15,7 175,5 

OVERALL TOTAL (K€) 232,4 180,1 112,7 40,9 97,3 100,9 43,2 150,8 94,3 1052,8 

NUK_TUM (10) 

UKB (21) 

UniTo (3) 

LUMC (37) 

TU/e (32) 

HSP (18) 

CARIM (26) 

MEK (1) 

Total



WP13 

Mice Tech (43) 

D13.0 Meeting with WP13 members for initiation of work 

plan. 

D13.1 Imaging NF-κB dependent luciferase acitivity in 

transgenic autoimmune disease model. 

3,0 12,0 6,0 21,0 

D13.2 Imaging cathepsin B and H, and Annexin 5 in 

inflammation model. 

0,5 3,0 3,5 

D13.3 Validating fluorescent macrophage ligand PK 

11195 in cell cultures and in inflammation models. 

0,5 4,0 4,5 

D13.4 Development of utility of optical imaging probes 

for complement activation and ROS detection. 

0,5 6,0 12,0 18,5 

D13.5 Establishment of a new mouse strain with 

spontaneous development of arthritis (with the Ncf1 

mutation, a susceptible MHC class II gene on the Balb/c 3,0 12,0 15,0 

background) expressing the NF-κB luc transgene useful 

for image analysis of arthritis. 

D13.6 Development of targeted probes (αβintegrins) and 

validation in vitro . 

6,0 6,0 

D13.7 Establishment of DNA construct with NF-κ B 

dependent expression of luc, tk and GFP/DsRed. 3,0 0,5 6,0 9,5 

Validation in cell cultures. 

Total Labour (person-month) 10,5 18,5 12,0 4,0 12,0 12,0 3,0 6,0 0,0 0,0 78,0 

Labour (K€) 56,3 99,2 58,4 14,7 61,6 44,2 12,0 29,2 0,0 0,0 375,5 

OVERHEADS 8,8 0,0 8,8 

Total Labour (K€) 56,3 99,2 58,4 14,7 61,6 53,0 12,0 29,2 0,0 0,0 384,3 


Supplies 57,0 52,0 20,0 10,0 40,0 10,0 5,0 5,0 199,0 

Travel 2,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 16,0 

TOTAL additional direct costs 57,0 52,0 22,0 12,0 42,0 12,0 7,0 7,0 2,0 2,0 215,0 

LABOUR+ADDITIONAL COSTS 113,3 151,2 80,4 26,7 103,6 65,0 19,0 36,2 2,0 2,0 599,3 

OVERHEADS 22,7 30,2 16,1 5,3 20,7 3,8 7,2 0,4 106,5 

OVERALL TOTAL (K€) 135,9 181,4 96,5 32,1 124,3 65,0 22,8 43,4 2,4 2,0 705,8 

UIO (11) 

ULUND-II (16) 

ICL (17b) 

UKM (40b) 

DUR (35) 

CARIM (26) 

MEK (1) 

UCAM-WBIC (2) 

CEA (38) 

Total



WP14 

D14.1 Electronic tools for an easy website 

update of the integration levels 

D14.2 Measureables for integration by 

JPRA 

D14.3 Measureables of performance of 

DiMI-TTPs 

D14.4 Measureables of successful 

exchange and mobility 

D14.5 Measureables for successful 

integration of SMEs 

D14.6 Measureables for integration 

through specific integrative tools 

MEK (1) 

UNIMI (6) 

CNRS (9) 

BIOSPACE (13) 

Total 

3 4 7 

1 4 5 

2 3 5 

2 3 5 

1 3 4 

2 1 3 


Labour (K€) 56,4 0,0 0,0 95,0 151,5 

OVERHEADS 0,0 

Total Labour (K€) 56,4 0,0 0,0 95,0 151,5 


Computer Hardware 4,0 4,0 8,0 

Software 2,0 2,0 4,0 

Supplies 2,0 2,0 2,0 2,0 8,0 

Travel 4,0 4,0 4,0 4,0 16,0 



OVERHEADS 13,7 1,2 1,2 21,4 37,5 

OVERALL TOTAL (K€) 82,1 7,2 7,2 128,4 225,0



WP15.1 

D15.1.1 Exchange and mobility of 

researchers and students 

3 2 2 3 10 

D15.1.2 Organisation of short and 

medium-term training 

3 2 2 3 10 

D15.1.3 Organisation of European courses 

for doctoral students in Diagnostic 

Molecular Imaging 

3 2 2 3 10 

D15.1.4 Raising of awareness 2 1 1 2 6 


Labour (K€) 56,4 34,0 34,1 42,7 167,2 


Total Labour (K€) 56,4 34,0 34,1 78,5 203,0 


Hardware 4,0 4,0 4,0 4,0 16,0 

Software 2,0 2,0 2,0 2,0 8,0 

supplies 2,0 2,0 2,0 2,0 8,0 

Travel 4,0 4,0 4,0 4,0 40,0 56,0 

TOTAL additional direct costs 12,0 12,0 12,0 12,0 40,0 88,0 

LABOUR+ADDITIONAL COSTS 68,4 46,0 46,1 90,5 40,0 291,0 

OVERHEADS 13,7 9,2 9,2 32,1 

OVERALL TOTAL (K€) 82,1 55,2 55,3 90,5 40,0 323,1 

MEK (1) 

UniTours (4) 

UA (8) 

CEA (12) 

shared expenses 

Total



WP15.2 

T1.1.0 Setting up the DiMI Information 

System: Web platform for public and internal 3 2 

communication and dissemination 

T1.1.1. Legal documentation (i.e. Programme 

of activities, Proprietary Right Issues, 

Scientific and Management reporting 1 1 

documents and worksheets and guidelines, 

How to use the web site… ) 

T1.1.2. Scientific and Management reports 

validated by the partners and the different 1 1 

boards of the DiMI consortium 

T1.1.3. Information on Congresses, workshops 

and Training activities and offers. 1 1 

T1.1.4 Establish contacts with European and 

International science and industrial 1 1 1 1 

organisations 

T1.2.1. Discussion Forums 1 1 

T1.2.2. Success stories 1 1 

T1.2.3. Workgroups internal web space 1 1 

T1.2.4. Validated Scientific Results (i.e. 

Communications, Publications and Patents) 

1 1 

T1.2.5. Progress reports 1 1 

T1.3.1. Image database 1 1 1 1 

T1.3.2. Image processing tools 1 1 

T2.1.1. Information on DiMI project and 

activities 

1 1 1 1 

T2.1.2. Thesaurus on Molecular Imaging and 

its relevance to society 

1 1 

T2.2. Campaigns towards identified audiences, 

mostly through mail, to disseminate the results 

and raise public awareness on DiMI activities 1 1 1 1 

and successes. 

MEK (1) 

IDIBAPS (5) 

NUK_TUM (10) 

CEA (12) 

Total 

5 

2 

2 

2 

4 

2 

2 

2 

2 

2 

4 

2 

4 

2 

4 

T4 APDAC 1 1 1 1 4 


Labour (K€) 92,3 20,0 25,7 66,0 204,0 


Total Labour (K€) 92,3 20,0 25,7 121,3 259,2 


Computer Hardware 12,0 4,0 4,0 5,0 25,0 

Software 6,0 3,0 3,0 4,0 16,0 

Supplies 6,0 3,0 3,0 6,0 18,0 

Travel 4,0 4,0 4,0 4,0 16,0 



OVERHEADS 24,1 7,9 28,1 60,0 

OVERALL TOTAL (K€) 144,4 41,9 67,7 140,3 394,3



WP16 

Meeting with all WP16 participants 

administrative management (contractual, 

legal, financial, ethical) 

design and guidance of JPA (integration, 

training, dissemination, exploitation) 

design and guidance of JPRA (management of 

experimental and clinical science with 

translation into health and societal value) 

MEK (1) 

UCAM-WBIC(2) 

UniTo (3) 

UniTours (4) 

IDIBAPS (5) 

UNIMI (6) 

RH-NRU (7) 

UA (8) 

20 20 

6 2 2 2 2 2 2 2 2 2 2 2 2 30 

6 2 2 2 2 2 2 2 2 2 2 2 2 30 

communication with Commission including 

timely reporting and delivery of required 4 4 

documents 

Total Labour (person-month) 36,0 4,0 4,0 4,0 4,0 4,0 4,0 4,0 4,0 4,0 4,0 4,0 4,0 84,0 

Labour (K€) 184,7 14,7 14,7 19,4 16,0 16,0 18,0 19,5 15,5 20,5 21,4 15,5 21,1 397,2 


Total Labour (K€) 184,7 14,7 14,7 19,4 16,0 16,0 18,0 19,5 15,5 20,5 21,4 28,5 21,1 410,2 


Hardware 15,0 15,0 

Software 4,0 4,0 

Supplies 4,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 28,0 

Travel 2,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 26,0 

TOTAL additional direct costs 25,0 4,0 4,0 4,0 4,0 4,0 4,0 4,0 4,0 4,0 4,0 4,0 4,0 73,0 

LABOUR+ADDITIONAL COSTS 209,7 18,7 18,7 23,4 20,0 20,0 22,0 23,5 19,5 24,5 25,4 32,5 25,1 483,2 

OVERHEADS 41,9 3,7 3,7 4,7 4,0 4,0 4,4 4,7 3,9 4,9 5,1 5,0 90,1 

OVERALL TOTAL (K€) 251,6 22,5 22,5 28,1 24,0 24,0 26,4 28,2 23,4 29,4 30,5 32,5 30,1 573,3 

CNRS (9) 

NUK_TUM (10) 

UiO (11) 

CEA (12) 

Biospace (13) 

Total


TTP: Partners Effort (person -month and K€) 

TTP 

MEK (1) 

UCAM-WBIC(2) 

UniTo (3) 

TTP1 Cologne (D) 18 18 

TTP2 Cambridge (GB) 18 18 

TTP3 Torino (I) 18 18 

TTP4 Tours (F) 18 18 

TTP5 Barcelona (E) 18 18 

TTP6 Milano (I) 18 18 

TTP7 Kopenhagen (DK) 18 18 

TTP8 Antwerpen (B) 18 18 

TTP9 Bordeaux (F) 18 18 

TTP10 Munich (D) 18 18 

TTP11 Oslo (N) 18 18 

TTP12 Orsay (F) 18 18 

Total Labour (person-month) 18,0 18,0 18,0 18,0 18,0 18,0 18,0 18,0 18,0 18,0 18,0 18,0 216,0 

Labour (K€) 92,3 66,2 66,2 87,5 72,0 66,2 81,0 87,7 69,8 92,3 96,5 69,8 947,7 


Total Labour (K€) 92,3 66,2 66,2 87,5 72,0 66,2 81,0 87,7 69,8 92,3 96,5 128,4 1006,2 


Animals 2,3 9,8 12,0 1,5 9,0 12,0 6,8 6,0 59,3 

Animal care 9,0 18,0 27,0 

Animal surgery 3,0 4,5 2,3 3,0 12,0 2,0 26,8 

Disposables 0,0 

Reagents, enzymes and isotopes,rx-sources 4,1 9,0 8,0 12,0 5,3 12,0 8,3 6,0 9,0 3,2 4,0 80,7 

MRI instrument measuring time 1,5 12,0 2,5 14,3 22,5 30,0 82,8 

CT instrument measuring time 7,5 7,5 

Focused Ultrasound maintenance 12,0 12,0 

Antibodies 4,5 4,8 2,0 11,3 

Chemical 2,3 12,0 4,0 9,0 4,5 6,0 2,3 4,0 44,0 

Histology 2,3 4,8 2,0 9,1 

maintenence cost of optical camera 12,0 

Imaging maintenence cost of micro PET, SPECT 1,5 15,0 27,0 15,0 24,0 4,5 16,0 103,0 

Cell culture media 1,5 3,0 4,0 8,5 

MRM instrument measuring 0,0 

BLIU measuring time 0,0 

Relaxometer measuring time 1,5 2,5 4,0 

Solvents fot Synthesis 2,3 4,0 6,3 

HPLC, columns,resins 2,3 9,0 5,0 16,3 

Microscopy instrumentation and consumables 13,5 13,5 

NMR spectrometer 4,5 7,0 11,5 

Software licenses 4,5 9,0 13,5 

Waste 6,0 

Hardware 0,9 10,5 11,4 

Travel 3,0 3,0 

TOTAL additional direct costs 23,6 62,4 36,0 60,0 60,0 60,0 22,5 55,5 60,0 72,6 16,7 40,0 569,2 

LABOUR+ADDITIONAL COSTS 115,9 128,6 102,2 147,5 132,0 126,2 103,5 143,2 129,8 164,9 113,1 168,4 1575,4 

OVERHEADS 23,2 25,7 20,4 29,5 26,4 25,2 20,7 28,6 26,0 33,0 22,6 281,4 

OVERALL TOTAL (K€) 139,1 154,4 122,7 177,0 158,4 151,5 124,2 171,8 155,8 197,9 135,8 168,4 1856,9 

UniTours (4) 

IDIBAPS (5) 

UNIMI (6) 

RH-NRU (7) 

UA (8) 

CNRS (9) 

NUK_TUM (10) 

UiO (11) 

CEA (12) 

Total


10.3 EC contribution for the full duration of the project


Among all the DiMI partners, 4 levels of participation have been differentiated: 

− 

− 

− 

The LLeevveel l 11 Partners: WP and TTP leaders who will conduct the JPA over the 5 years 

(partners 1-13). LLeevvel e l 11 Partners will receive 1 postdoc for running the respective TTP and a 

WP. 

Level 1 partners are: MEK (1), UCAM-WBIC(2), UniTo (3),UniTour (4), IDIBAPS (5), 

UNIMI (6), RH-NRU (7), UA (8), CNRS (9), NUK_TUM (10), UiO (11), CEA (12), 

BIOSPACE (13). 

The LLeevveel l 22 partners involved in the JPRA of the first 18 months period (JPRA1) and 

contributing more than 4% to the total costs of the JPA (KULeuven R&D (41)) or are leading 

a research WP (UNEW (31), DUR (35), UKM (40)). 

The LLeevveel l 33 partners involved in the JPRA1 and contributing between 1-4% to the total costs 

of the of the JPA. 

Level 1 partners are: K.U.Leuven R&D (14), ULUND (15), Imperial College Lo# (17), UKB 

(21), KI (22), MPIfnF (25), CARIM (26), TU/e (32), CNR-IBB (34a), FTELE (34b), UVita-P 

(36), LUMC (37), CYCERON (42), Charles University (50), IEM ASCR (52). 

Level 1-3 partners are the active DiMI partners. In total DiMI consists of 31 active partners for the 1 st 

18 months period of funding. 

− 

The LLeevveel l 44 partners involved in the JPRA1 of the first 18 months period and contributing less 

than 0,9%: ULUND (16), Hospital Sant Pau# (18), INSERM (19), UEDIN (20), FZJ (24), 

CEA (23), CBI (27), CNRS (28), AZG (29), INP (30), KI Neurotec (33), CEA (23, 38), ULG 

(39), MT (43), UNAV (45), UniTours (46), Cyclopharma (47), MEDRES (48), Visgenyx (49), 

Polatom (51), IGT (53) 

In that, Level 4 partners (19) contribute not or only very limited to the JPA for the 1 st 18 months. 

Budget for the JPRA for the first 18 months of LLeevveel l 11, LLeevveel l 22 and LLeevveel l 33 partners will be allocated 

according to their contribution to the total costs of the JPA as follows:


LLeevveel l 11 partners will receive salary for 1 post-doc and 30.000 € for supplies to run the TTP and to 

guide the research related to one WP. Leevveel 

l 2 partners will receive 70.000-100.000,- €. LLeevveel l 33 

partners will receive up to a maximum of 52.500,-€. LLeevveel l 44 partners who contribute more than 0.1% 

to the total costs of the JPA will receive a maximum of 12.000,-€ for the first 18 months from the 

shared expenses for travelling, participating in training and dissemination activities and additional 

costs for their contribution to JPA. Partners with a contribution of less than 0.1% will receive a 

maximum of 6.000,-€ for the first 18 months from the shared expenses for travelling, participating in 

training and dissemination activities. 

Six partners of the DiMI NoE are SME’s (12%). Their overall contribution to the total cost of the first 

18 months period is 2.30 %. Four SME’s are contributing less than 0.1 %. These four partners will 

receive a maximum of 12.000 € each in the first 18 months from the shared expenses to give them the 

opportunity to intensively participate in training and dissemination activities and to join WP meetings 

to plan their participation in the respective WP’s for the next funding period. Partner 43 is a LLeevveel l 44 

partner contributing more 0,1% to total JPRA and Partner 13 a LLeevveel l 11 Partner. 

Contribution to JPA 

first 18 months (K€) 

allocated Budget 

first 18 months (K€) 

SME 376,60 237,5 

Shared expenses for SME 60,0 

Total 376,60 297,5 

% Total Budget 2,30 8,5% 

As partners involved in the JPRAs will be changing from one period to the next, it is not possible to 

present the total network effort for the full duration of the project. However, the following budget 

breakdown is anticipated over the full duration of the project. 

Year 

EC Grant 

in which first 6 month 

% of total EC Grant 

1 2335 0,218 10848,2 1394,7 6486,5 4361,7 

2 2155 1167,50 0,201 10011,9 1287,2 5986,5 4025,4 

3 2122 1061,00 0,198 9858,6 1267,4 5894,8 3963,8 

4 2080 1040,00 0,194 9663,5 1242,4 5778,2 3885,3 

5 2008 1004,00 0,188 9329,0 1199,4 5578,1 3750,8 

Total 10700 1,00 49711,2 6391,0 29724,2 19987,1 

total costs (K€) 

labour (person-month) 

labour (K€) 

additional direct costs

LSH-2003-1.2.2-2 DiMI-Diagnostic Molecular Imaging 245/412


10.4 Project management level description of resources and grant 

Mobilisation of internal resources by partners 

The implementation of the JPA of DiMI by the 31 active Level 1-3 partners will require labour 

(expressed in person months) and additional costs (travel, equipment, supplies, meetings, etc.). 

Because the consortium has considered that integration is an evolutionary process and to achieve a 

durable commitment of partners to the JPA, each partner will mobilise part of its own resources 

(people, expertise, equipments, facilities) from its internal molecular imaging programme. 

The list of technical resources i.e. equipments and facilities made available by the partners will be 

updated regularly and published on the DiMI website. 

Estimated costs for the JPA 

In our proposal, the EC grant allocated (3 502 500,- € for 18 months) will not cover the full costs of 

our Joint Program of Activities (16 272 300,- € for 18 months). This means that the partners will 

support with their own resources, the difference between the EC grant and the full cost of the JPA. 

The EC grant will not be used by partners for their internal program even though the partners will rely 

on their internal program to implement the JPA. 

Estimated costs for the first 18 months: 16 272 300,- € 

The estimated costs required by the JPA for the overall duration covers the labour and the external 

costs. 

The eligible costs of the JPA for the first 18 months amount to: 

(2092 person-month = 9729,8 k€) + 6542,5 k€ external costs = 16 272,3 k€. 

*: calculated on the basis of a postdoc salary in the respective countries, see 10.2 

The budget covered by the EC grant for the first 12 months is attached herewith, with detailed 

allocation of person-month and external costs for each workpackage and for each partner. This table 

will be revised and voted by the Steering Committee. 

For the full duration of the project and, as an indication, we can anticipate the following JPA cost: 

The estimated costs for the JPA for the overall duration of the network amount to: 

(6391 person-month = 29724,2 k€) + 19987,1 k€ external costs = 49711,2 k€. 

The growing difference between the real estimated costs of the JPA and the EC grant proposed will 

make an obligation for DiMI to find external resources. Several options will be explored. 

Use of EC Grant for the first 18 months period 

The budget covered by the EC grant will be allocated as follows: 

The detailed allocation by partners for the first 18 months was presented to the Scientific Management 

Board and approved with no dissenting vote in a Conference Call on 20 th September 2004.


PROVISIONAL BREAKDOWN OF THE BUDGET FOR THE FIRST 18 MONTHS PERIOD 

COSTS (Labour+Add. 

Direct Cost) in K€ 

EC Grant in K€ 

Grant/Cost 

Joint Programme of Activities 

1) Integrated Activities 12,76% 

43,41% 

Technological and Training Platforms (1-12, WP14) 2081,8 1520,6 

73,0% 

2)Jointly Research Activities 79,74% 

34,03% 

Workpackages (1- 13) 13005,7 1191,9 

9,2% 

3)Spreading of Excellence Activities 3,75% 

14,5% 

WP15.1 Educational Training 283,1 243,3 

WP15.2 Dissemination & Communication 328,3 263,3 

85,9% 

80,2% 

4)Management Activities 3,52% 

7,02% 

WP16 Management of the Network 573,3 246,0 

42,9% 

5)Reserve 0,23% 1,07% 

Reserve 37,5 37,5 

TOTAL 16309,8 3502,5 

21,5%


Budget allocation for the first 18 months period in k€ approved by the Scientific Management Board


11. Ethical issues 

The description of ethical issues involved in the DiMI proposal is following the “Crucial Information” 

document. 

We herewith confirm that the DiMI proposed research does NOT involve: 

1. Research activity aimed at human cloning for reproductive purposes; 

2. Research activity intended to modify the genetic heritage of human beings which could make such 

changes heritable; 

3. Research activity intended to create human embryos solely for the purpose of research or for the 

purpose of stem cell procurement, including by means of somatic cell nuclear transfer; 

4. Research involving the use of human embryos or embryonic stem cells with the exception of 

banked or isolated human embryonic stem cells in culture. 

Ethical Issues related to the proposed research 

There are several ethical and safety issues which have to be addressed in the DiMI proposal with regards to 

• human studies and clinical trials, particular in patients with neurodegenerative disorders 

• animal experiments including non-human primates 

• murine stem cells 

• HIV-based vectors 

• genetically modified organisms (cell lines, transgenic mice) 

• application of radioactivity 

• disposal of genetically modified, radioactive and chemical waste 

• as yet unidentified ethical and safety issues. 

Molecular imaging allows the assessment of a disease-specific molecular alteration in the living organism in 

vivo. In that, molecular imaging carries great potential for a non-invasive specific diagnosis on the molecular 

level. This will, in long-term, facilitate patient management in various aspects of medicine, especially in 

(1) an improved diagnostic accuracy; 

(2) establishment of targeted therapies; and 

(3) imaging-guided therapies. 

The novel diagnostic probes and molecules to be developed by the DiMI consortium can not be investigated 

in cell culture systems alone. They have to be investigated in animal models and finally in humans. Most 

importantly, they are meant to be investigated in defined transgenic mouse models of specific human 

diseases. Therefore, human studies and animal experiments are critical to the overall goal and success of 

DiMI. 

All DiMI partners have extensive experience in their specific research area including imaging in humans for 

diagnostic purposes and imaging-guided therapies as well as imaging of the living animal. Therefore, all 

partners of the DiMI consortium are aware of and strictly adhere to the respective local, national and 

international rules and regulations which apply for the issues pointed out above. All national guidelines to be 

respected by the DiMI consortium have been summarized in a =>table (see below). All procedures in 

relation to the DiMI activities will be carried out under strict adherence to these national as well as European 

guidelines. In addition, for all human and animal-related work approval from local ethical committees will


be obtained prior to start of the projects. As required by the ERR, an Ethical Management Board has been 

formed (EMB; =>8) which will ensure a strong ethical management of DiMI-related work. Moreover, a 

separate and truly international-oriented Ethical Advisory Committee (EAC; =>8) has been formed with 

representatives from France and Germany, which will advise on and control specifically the ethical aspects of 

DiMI. The Project Coordinator together with the EMB will collect copies of the authorisations of the 

respective ethical committees of human and animal-related studies, and he will take all necessary steps to 

ensure that the work performed in the DiMI network is performed in respect of all required laws and 

regulations and ethical aspects. 

1. National regulations and international codes of conduct 

All DiMI partners have extensive experience in their specific research area including human studies and 

studies in the living animal including acquiring their approval from local ethics committees. All DiMI 

partners have confirmed to strictly adhere to the local, national and international rules, laws, and guidelines as 

they apply for the individual work indicated above and described in the individual WPs. The national 

regulations which apply within the DiMI consortium are summarized as follows: 

Table of Laws affected and respected within the DiMI consortium 

1. Human Studies and Clinical Trials 

Germany Approval by local ethics committee 

Great Britain European Clinical Trials Directive (2001/20/EC), European directive 95/46 CE and the Data 

Protection Act (UK) 1998, MRC operational and ethical guidelines for the use of human tissue 

and biological samples in research 

Italy 

Approval by local ethics committee 

France 

French Code of Public Health (1 st part book II bis) on “The protection of persons in biomedical 

research”, Bioethics law, Law”Huriet-Serusclat” 12/20/1988 revised by code of Public Health 

of sept 1998, Art R.5118 , Art. L.710-5 

Spain 

Approval by local ethics committee: Law on Therapeutic Drugs 25/1990, updated by Royal 

Decree 223/2004, issued on 6 February 2004 

Royal Decree 561/1993, issued on 16 April 1993 (updated by Royal Decree 223/2004, issued on 

6 February 2004). 

Denmark Approval of the local Ethics Committee Law no. 402 as of May 24, 2003 

The Act on Processing of Personal Data (Act No. 429 of 31 May 2000) entered into force on 1 

July 2000. The act implements Directive 95/46/EC 

Belgium Approval by local ethics committee, European Clinical Trials Directive (2001/20/EC), 

Law of 7 May 2004 regarding experiments on the human person 

Norway 

Not performed in Norway 

Sweden 

Approval by local Ethics Committee 

Netherlands - MEC (local Medical Ethics Committees) 

- CCMO 

- GCP 

- BIF (Act on Immunology Pharmaceutics) 

- GGO 

Estonia 

Human Genes Research Act, Estonian Parliament, approved on 13.12.2000, active from 

08.01.2001; published RTI 2000, 104, 685 

Czech Republik Act No 79/1997 Coll., on Pharmaceuticals And on Amendments to Some Related Acts, as 

implied by amendments stipulated by Act No 149/2000 Coll., Act No 153/2000 Coll., Act 

No 258/2000 Coll., Act No 102/2001 Coll., Act No 138/2002 Coll., Act No 309/2002 Coll., Act 

No 320/2002 Coll., and Act No 129/2003 Coll. 

Poland Dz.U. Nr 126 poz. 1381 (06.09.2001), Decree on Pharmaceutical Law, Dz.U. Nr 221 poz. 1864


(10.12.2004) Good Clinical Practice 

2. Animal Experiments Including Non-Human Primates 

Germany Law for Animal Protection (TierSchG,) §§4,6(Anzeige,Organe), §8 (Genehmigung) 

§11 (Haltung), VersuchtiermeldeVO, EU Richtlinien zur Haltung + Versorgung von Tieren 

Great Britain Animals (Scientific Procedures) Act 1986 as amended. 

Italy Decreto legislativo 27 gennaio 1992, n. 116 (in Suppl. ordinario alla Gazz. Uff. n. 40, del 18 

febbraio). -- Attuazione della direttiva (CEE) n. 609/86 in materia di protezione degli animali 

utilizzati a fini sperimentali o ad altri fini scientifici. 

France Decree 2001-486 in agreement with the European Directive 86/609/CEE of 11/24/86 

Spain Royal Decree 223/1988 and Law 25/1990, updated by Royal Decree 223/2004, issued on 6 

February 2004 

Denmark All research project on laboratory animals must be conducted according to the legislation 

protecting the well fare of research animals and approved by the Animal Experiments 

Inspectorate, a board under the Danish Ministry of Justice 

Belgium Law for protection and welfare of animals (Aug. 14 1986) 

Compliance with the European law for animal protection (86/609/EEG) (Oct. 18 1991) 

Order in Council on the protection of laboratory animals (Nov; 14 1993) 

Amendment of the law of 1986 (May 4 1995) 

Norway 

Law for protection and welfare of animals (20th. Dec 1974, Norwegian Ministry of 

Agriculture), Compliance with the European convention for animal protection (86/609/EEG) 

(Oct. 18 1991) 

Sweden 

Law for Animal Protection 

Netherlands - CBD (Committee on Biotechnology in Animals) 

- GGO 

- DEC (local Experimental Animal Committees under the Law of the Experiments in 

Animals) 

Estonia Animal Protection Act, active from 01.01.2003, Estonian Parliament, published RTI 2001, 3, 4 

Czech Republik Laboratory Animals Protection Laws No. 246/1992 and 167/1993, Digest of the Czech 

Republic, including their later updating No. 311/1997 

Poland 

Dz.U. Nr 111 poz.724 (21.08.1997) Decree on Animal protection 

3. Murine Stem Cells 

Germany Law for Gene Technology (GenTG) §§ 1, 6, 7, 8, 9(2), 21, 25(2); GenTSV §§ 2, 5(2) i.V.m. 

Anhang I, § 6 i.v.m. Anhang II, §§ 7(3), 8, 9 i.V.m. Anhang III, §§ 12, 13, 14, 18, 19; 

GenTAufzV, BseuchG §19 

Great Britain HFE (Research Purposes) Regulations 2001 

Animals (Scientific Procedures) Act 1986 as amended? 

Italy 

Not performed in Italy 

France 

Decree of 12/16/1998 Art L.666-8, L.673-8, L.676-2 of the code of Public Health 

Spain 

Not currently approved or regulated 

Denmark Not performed in Denmark 

Belgium Not currently approved or regulated 

Norway 

Law on biotechnology, Norwegian Ministry of Health 

Sweden The Swedish Code of Statutes No. 1991:115, 1995:831 

Netherlands - CCMO (Central Committee Medical Research) 

Estonia 

Not performed in Estonia 

Czech Republik Law under preparation. Not currently regulated. 

Poland 

Not currently regulated.


4. HIV-based Vectors 



GenTAufzV 

Great Britain Genetically Modified Organisms (Contained Use) Regulations 2000 

Deliberate release? If so EPA 1990 and GMO (Deliberate Release) Regs 2002 

Italy 

Not performed in Italy 

France French law 92-654 of July 13, 1992 ; European Directive 98/81/CE of December 5, 1998 

Spain 

Law 31/1995, issued on 8 November 1995, royal decrees that specify its application regarding 

the prevention of risks related to the exposure to biological agents (including BL2 or S2 

facilities to work with HSV and HIV viruse 


Belgium Decree of the Flemish Government of 6 February 2004 (OJ 01.04.2004, p. 18281 

Norway 

Not performed in Norway 

Sweden Law for gene modified organisms, SFS 2000:271 

Netherlands - GGO (Act Genetically Modified Organisms) 

Estonia Law No. 153/2000 and its later updating 174/2000, 78/2004, and 209/2004. 

Czech Republik European Directive Euro 2000/-54/CE of 09/18/2000 

Poland European Directive Euro 2000/-54/CE of 09/18/2000 

4. Genetically Modified Organisms 



GenTAufzV, BseuchG §19 

Great Britain European Directive 90/219/EEC, later replaced by Directive 98/81/EC and for 'deliberate 

release' as detailed in the European Directive 90/220/EEC and the Genetically Modified 

Organisms (Deliberate Release) Regulations 2002 (UK) 

Genetically Modified Organisms (Contained Use) Regulations 2000 

Italy 

D.L. 206/01 which applies the European Directives 90/219/CE and 98/81/CE 

France 

guidelines set down in the Commission de Génie Génétique in agreement with 

European Directives 98/81/CE and 2001/18/CE 

Spain Law 15/1994, of 3 June 1994, Decree 951/1997, issued on 20 June 1997 


Belgium Decree of the Flemish Government of 6 February 2004 (OJ 01.04.2004, p. 18281 

Norway 

Gene Technology Act, Norwegian Directorate for Nature Management 

Sweden Law for gene modified organisms, SFS 2000:271 

Netherlands - GGO 

Estonia Animal Protection Act, active from 01.01.2003, Estonian Parliament, published RTI 2001, 3, 4 

Czech Republik Laboratory Animals Protection Laws No. 246/1992 and 207/2004 (transgenic animals). 

Law No. 153/2000 and its later updating 174/2000, 78/2004, and 209/2004 (genetically 

modified organisms). 

Poland 

European Directive 90/219/EEC, later replaced by Directive 98/81/EC and for 'deliberate 

release' as detailed in the European Directive 90/220/EEC 

5. Application of Radioactivity 

Germany Regulation for radioactivity protection (Strahlenschutzverordnung)§§ 23, 24, 87-92 

Great Britain Radioactive Substances Act 1993, Ionising Radiations Regulations 1999 

Italy 

Regulation for the exposure to ionizing radiation of subjects undergoing research studies: 

article 108 of decreto legislativo 17 march 1995 n° 230, The annexe III of D. Lgs. 26 maggio 

2000, nr. 187 

France 

Decree 2002-460 and Decree 2003-296 in agreement with the Directive 96/26 Euratom 

Spain Law 31/1995, issued on 8 November 1995


Denmark All tracers used for must be approved by the Danish Medicines Agency prior to clinical use. 

National Board of Health Directive No. 823 as of October 31. th, 1997 re. Dose limits. 

Belgium Royal Decree of 20 July 2001 regarding protection of population, workers and environment 

against riks of ionising radiation 

Norway 

Law on protection of radiation, Norwegian Ministry of Health 

Sweden 

Law for radioactivity protection (Strålskyddslagen) 

Netherlands - Regulation for radioactivity protection, - Nuclear Energy Law: art 29 and 32 

Estonia Radiation Act, published RTI, 16.05.1997, 37/38, 569 ; active from 1997 

Czech Republik Law No 18/1997 Sb governing the Peaceful Use of Nuclear Energy and Ionizing Radiation [socalled 

Atomic Law] 

Poland 

Dz.U. nr 239 poz. 2029 (17.12.2002), (Regulation for Secure working with ionizing radiation, 

sources), Dz.U. Nr 241 poz. 2098 (24.12.2002), (Regulation for Safe handling of ionizing 

radiation for medical purposes), in agreement with Euratom Directive 

6. Disposal of Genetically Modified, Radioactive and Chemical Waste 

Germany Law for Gene Technology, GenTSV §§ 13 Strahlenschutzgesetz, GefStoffV 

Great Britain Environmental Protection Act 1990, Special Waste Regulations 1996, Radioactive Substances 

Act 1993, Genetically Modified Organisms (Contained Use) Regulations 2000 

Italy 

TBA 

France French law 92-654 of July 13, 1992 ; European Directive 98/81/CE of December 5, 1998 

OGM: French code of Public Health Art R 44-1 and Art L 531-1 in agreement with the guide of 

the genetic engineering commission. Radioactive: Decree 2002-460 a Decree 2003-296. 

Chemical: Art L 541-1 to L 541-50. (Law 75-633 of 07/15/75). Law 76-663 of 07/19/76 

modified (Art L 511-1 and L 517-2) relative to ICPE 

Spain Law 31/1995, issued on 8 November 1995 

Denmark National Board of Health Directive No 954 as of October 23, 2000 re. Disposal of radioactive 

waste 

Belgium Decree of the Flemish government on waste disposal of 2 July 1981 

GCP procedure for production and disposal of radiolabelled tracers 

Law of July 20, 2001 regarding protection of population, workers and environment in 

compliance with all the EU directives dealing with these matters. 

Norway 

Regulation on hazardous waste, and Law on pollution and waste, Norwegian Ministry of 

Health. 

Sweden 

Law for radioactivity protection, (Strålskyddslagen) 

Netherlands - GGO 

- Regulation for Radioactivity protection 

Estonia Law of Disposals, published RT I 2004, 9, 52; active from 01.05.2004 

Czech Republik Law No. 153/2000 and its later updating 174/2000, 78/2004, and 209/2004. 

Law No 18/1997 Sb governing the Peaceful Use of Nuclear Energy and Ionizing Radiation 

[Atomic Law] 

Poland 

Dz.U. nr 230 poz. 1925 (03.12.2002), (Regulation for Radioactive waste and spent fuel 

treatment) in agreement with Euratom Directive 

2. Use of banked or isolated hES cells in culture, human foetuses, and human foetal tissue 

Does not apply for the DiMI proposal.


3. Use of other human biological samples 

Human biological samples will be acquired as 

• brain tissue samples post-mortem in WP8.1; 

• blood and spinal fluid samples in WP9; 

• plaque samples obtained during endarterectomy in WP11.1. 

With regard to brain tissue being investigated in WP8.1, tissue is made available from the local tissue bank in 

Newcastle (P31), where contributors have given informed consent prior to death for further studies on their 

tissues and where the tissue is stored according to national guidelines. For tissue donation from studies with 

prospective assessment during life, patients and their families are approached during life (after ethical 

approval) by trained autopsy liaison nurses for a declaration of intent to donate (DOI). The whole autopsy 

procedure is explained in lay terms, describing the actual procedures being undertaken by the pathologist. 

The person is then asked in advance if they wish to consent to these procedures after their death, and also 

given a choice as to which tissues they would wish to be retained for research purposes. The next of kin who 

are present at this interview also give their assent to any procedures. The next of kin are then contacted 

following death and are again visited by trained autopsy liaison nurses, who seek to reconfirm that they agree 

with the original DOI. The next of kin are then asked to give their consent for a post mortem to be carried 

out and are offered choices, which include the extent of tissue donation, whether the tissue can be used in 

genetic research, and whether the research team can access medical records. By entering the Newcastle Brain 

Bank, data are being anonymized ensuring confidentiality of personal data. From various regions of the 

brain, mRNA will be isolated for gene expression profiling and the potential identification of new molecular 

disease-specific markers, which might be used for imaging. P31 has extensive experience in the collection of 

autopsied human brain tissue and human genetic studies and complies with the local, national and 

international regulations concerning collection and use of genetic information. Ethical approval have been 

obtained from the local ethics committee and informed consent has also been obtained from the relatives. 

It should be pointed out, that the use of human tissue in WP8.1 headed by P31 (Newcastle) has been 

consented to by the respective Local Research Ethics Committee (LREC 2003/31: documentation available 

upon request) and conforms to 

• the UK MRC Guidelines on the use of tissue in medical research (see Human Tissue and Biological 

Samples for use in Research - Operational and Ethical guidelines (2001)(http://www.mrc.ac.uk/pdftissue_guide_fin.pdf); 

• Personal Information in Medical Research (2000) (http://www.mrc.ac.uk/pdf-pimr.pdf); 

• Health and Social Care Act 2001: "Section 60" (http://www.mrc.ac.uk/pdf-pimr_summary.pdf); 

• Good Research Practice (2000) (http://www.mrc.ac.uk/pdf-good_research_practice.pdf). 

Additionally the use of the material conforms to the principles enshrined in the Charter of Fundamental 

Rights of the European Union (2000), The Convention on Human Rights in Medicine (1997), and the 

Declaration of Helsinki. All material to be used is obtained with prior informed consent from the individuals 

and this is assented to in advance by the next of kin. This is of paramount importance in the consenting 

process when individuals with some form of cognitive impairment are being studied. At death, and in line 

with UK Legal Guidance, formal informed consent for autopsy and tissue retention for medical research is 

obtained from the next of kin as described above. Use of the tissue whilst having been approved by the 

LREC, is also approved by the Newcastle Brain Tissue Resource which consists of an independent 

Chairperson, lay-members, and scientific advisors, who scrutinise application and grant finally the use of any 

tissues.


In WP9, blood samples and spinal fluid samples from patients are usually acquired on a routine basis for 

diagnostic classification. However, giving a blood and spinal fluid sample is not mandatory and can be 

included or dismissed individually. After ethical approval for collection, storage and analyzing blood and 

spinal fluid samples, patients will be informed about additional laboratory test as a part of the research study 

and informed written consent will be obtained. Aliquots of blood and spinal fluid samples will be prepared at 

the respective centres and stored according to national guidelines. The informed consent data form will be 

anonymized locally and sent to a central database in Copenhagen, Denmark (P7), by electronic or fax 

transmission. Thus, personal data of the donors are kept within the confidentiality of the assessing physician 

and the head of the respective department, who is participating in DiMI. Blood and spinal fluid samples are 

then subjected to microarray-based gene expression profiling to search for new genes involved in the 

regulation of neuroinflammation potentially to be used as surrogate markers in terms of in vivo imaging. 

Results will be stored in a central DiMI-related database in Copenhagen, Denmark (P7). P7 has extensive 

experience in human genetic studies and in how to comply with the local and national regulations with 

regards to the collection, storage and use of genetic material and information. 

With regards to non-invasive imaging of apoptosis in human carotid plaques and assessment of the effect of 

different treatment (WP11.1), all human work is licensed according to the national regulations including an 

IRB approval of the University Hospital Maastricht (P26). Within the IRB approval and regulations a signed 

patient informed consent is mandatory. Patients with a significant carotid artery stenosis eligible for carotid 

artery endarterectomy are considered candidates for the study. Patients will undergo sequential imaging of 

plaque apoptosis in the carotid artery plaque, one directly after inclusion, and a second one day before the 

scheduled carotid artery operation. The difference in uptake between the first and second SPECT image of 

radio-labelled Annexin A5 will be used as a surrogate end-point for plaque stabilisation. The endarterectomy 

histologic specimens will be analyzed with respect to apoptosis, and compared with the results obtained with 

SPECT imaging of radio-labelled Annexin-A5. 

4. Use of personal data in bio-banking 

The participating researchers and physicians are responsible for all data protection issues arising from 

research or clinical projects undertaken within the DiMI consortium. Each member of DiMI will ensure the 

confidentiality of any personal data held or transmitted on paper, files, manual or electronic systems or any 

other manner. The European Data Protective Directive 95/46/EC has implications for “explicit consent” for 

any individuals, members of the public/current or former patients, who may be involved in the research as 

data subjects. To comply with the law, information must be: 

• collected and used fairly, stored safely and not disclosed to any other person unlawfully 

• processed fairly and lawfully and shall not be processed unless certain conditions are met 

• obtained for specified and lawful purposes and not further processed in a manner incompatible with 

that purpose 

• adequate, relevant and not excessive 

• accurate and where necessary up to date 

• kept for no longer than necessary 

• processed in accordance with data subjects’ rights 

• protected by appropriate security


5. Research involving persons 

With regards to human studies and tissue samples, all research will be carried out by DiMI partners that have 

extensive experience in conducting this research (P1, P7, P17, P20, P26, P29, P31, P33, P36, P39, P41, 

P45), and it involves patients with neurodegenerative disorders such as mild cognitive impairment, 

Alzheimer’s and Parkinson’s disease, multiple sclerosis, atheorsclerosis and in normal volunteers (WPs 8.2, 

9, 11.1). The overall aim of the clinical imaging studies is to establish the diagnostic value of novel imaging 

tools for a nosological classification in the elderly patient with memory disturbances or parkinsonism, in 

patients with multiple sclerosis and atherosclerosis, and to point to new areas for potential drug development 

on the basis of the obtained results. 

All this research which involves the intervention or interaction with living human participants or human 

tissues or the collection or study of data derived from living human participants requires ethics approval of 

the national or local ethical committees and, if applies, by other respective national organisations. All 

partners are aware and comply with the respective local, national and international rules and regulations as 

they relate to clinical research. The ethical approvals have to be obtained before research is being conducted 

to get guidance to researchers and to responsible authorities to ensure: 

(1) that research involving persons is carried out safely; 

(2) informed consent from the individuals is obtained; 

(3) the autonomy and privacy of the subjects is respected; 

(4) the principles of distributive justice in accordance with the ethical principles are followed. 

All clinical studies will comply with national ethics and legal requirements, the Helsinki declaration in its 

latest version as well as relevant EU legislation in relation to clinical research and clinical trials. Any 

proposed changes in previously approved research to the Ethics Committee must be requested through 

completion and submission of the “Amendment Approval Request Form”. The changes may not be initiated 

without prior review and approval, except where necessary to eliminate apparent immediate hazards to the 

participants. Any adverse events, including both non-serious and serious, involving risk to participants or 

others are reported to the relevant local authorities as well as to the Project Coordinator and the EMB in the 

form of a full written report that should include any amendments to the participant information sheet and 

study protocol. 

It should be noted, that the clinical investigators in DiMI participating in WP8.2, WP9 and WP11.1 will 

contribute patients with Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and atherosclerosis. In 

all cases, participation in the studies are on a voluntary basis. It is expected that each centre will contribute 5- 

10 patients in a 12 months recruitment phase. Research activities involve three activities: 

• neurological and neuropsychological examination to determine and quantify the disease-specific 

deficits 

• imaging by PET, SPECT, MRI (as described in the WPs) 

• taking blood and spinal fluid samples. 

All these procedures are routine approaches in the participating countries in the management of these 

diseases. The added value of DiMI is that all patients in each country will be investigated by an identical 

study protocol. For inclusion in the DiMI-project, patients will be informed about the overall protocol and 

imaging experiment in detail, and informed written consent will be obtained. No payments, inducements or 

other benefits (apart from the participation in a novel diagnostic imaging protocol) will be given to the 

persons enrolled into the study. The DiMI management office will provide a draft form for informed consent,


which will be forwarded to clinical DiMI partners, which has to be translated into the respective national 

language. If the patient agrees to participate in the project, an informed consent form will be signed. 

Consent forms and other relevant ethical issues may be included in the consortium agreement. All DiMI 

partners must involve their local ethical committee for approval of the procedure. At any time, patients can 

withdraw from the project without having disadvantages in the treatment and physical care. It should be 

pointed out, that imaging studies will be performed in patients who are legally able to give consent. This 

holds also true for patients with dementia, because WP8.2 focuses on early detection of neurodegeneration in 

patients only mildly affected by their neurodegenerative disorder not affecting the ability to legally determine 

their own rights. With informed consent imaging data will be stored in the DiMI clinical database. Children 

and demented patients who are legally not able to give consent are excluded from WP8.2 and WP9. 

Healthy volunteers are needed in WP8.2 to evaluate baseline values for the respective radiotracers (outlined 

in WP8.2). Healthy volunteers are studied only in single centres. The local Ethics Committees will approve 

the protocols as listed in WP8.2. The indicated responsible DiMI partners will provide insurance coverage to 

healthy volunteers against adverse events occurring as a result of participation in the research. 

6. Protection of personal data 

The researchers and physicians participating in DiMI are responsible for all data protection issues arising 

from research or clinical projects undertaken in DiMI and described in the chapter above (5.). To include 

patients into one of the described clinical studies, patients will be informed in detail about the goals and the 

details of the protocol and imaging experiment, and informed written consent will be obtained. Each partner 

of DiMI will ensure the confidentiality of any personal data held or transmitted on paper, files, manual or 

electronic systems or any other manner. The participant of the study will receive a study number by inclusion 

into the study. This will ensure the anonymisation and confidentiality of personal data. All imaging data will 

be stored locally in a DiMI-related imaging data base, which will be password-protected. The individual 

computer will be installed in a locked room with no public access. In case imaging data will be suspected to 

a common automated evaluation protocol and, in that, shared by multiple DiMI partners, a specific consent 

will be obtained from the participant at the beginning of the study. It should be pointed out, that the collected 

data will not be used for commercial purposes. 

It should be pointed out again, that before start of DiMI-related clinical studies, each partner has to obtain 

permission from local ethics committee and has to provide the respective ethical permit number to the Ethical 

Management Board (EMB). 

7. Animal Studies 

With regard to experimental animal welfare, all work with laboratory animals including transgenic animals is 

carried out by DiMI partners with extensive experience in conducting animal-related research (all partners), 

and the work will be performed based on the principles of Refinement, Reduction and Replacement (the 

3R’s) in mice (all partners), rats (all partners), rabbits (P40), and mini-pigs (P7). 

The three R principles promote good scientific practice and the search for alternative approaches to in vivo 

experimentation to reduce the number of animals used in research. The DiMI proposal fits, in fact, by its 

methodology very well into the 3R principle, as imaging of the parameter of interest can be performed in the 

living animal avoiding the killing of the animal to investigate the parameter of interest. Apart from WP5,


where image validation necessitates the sacrification of the animal in order to reach its goal, in all other WPs 

the imaging technology often avoids the sacrification of the animal for tissue sampling (refinement). 

Moreover, intra-individual as well as long-term follow-up studies in the same animal leads to a substantial 

decrease in the amount of animals needed (reduction). Genetic modified animals will be used in this project 

to study activity and function of disease-specific genes directly in vivo by imaging. The use of transgenic 

animals can, therefore, further reduce the number of animals to be used (reduction). The proposed animal 

experiments can not be replaced by other methods, but they will enable a better link between basic research 

and clinical application (translation). 

All animal experiments will be performed in accordance to European guidelines (86/609) and for each partner 

according to local and national specific laws (=>table) as well as to the guidelines for animal experimentation 

(Guide for the Care and Use of Laboratory Animals. DHHS Publication No. NIH 85-23 Institute of 

Laboratory Animal Resources Commission on Life Sciences National Research Council National Academy 

Press Washington, D.C. 1996). Animals will be obtained from government-approved animal-raising centres 

and will be maintained in registered scientific and medical departments of the Universities under optimal 

environmental conditions according to national regulations and the Amsterdam protocol. The temperature, 

humidity, ventilation, lighting intensity and day-night cycle, and noise are carefully regulated and maintained 

at appropriate levels for the species. Animals are handled carefully in a way to reduce stress and any risk of 

injury from bites and scratches. All imaging experiments are performed under general anaesthesia. After 

imaging, animals are allowed to recover and brought back to their cage. Usually, the animals are not being 

killed after an imaging experiment, unless co-registrative histology (especially WP5) and tissue sampling for 

determination of radioactivity concentrations of organs (WP3) is to be performed. In addition to general 

anaesthetics, animals undergoing surgery receive local anaesthetics to avoid any acute post-operative 

suffering. At all times when animals are being sacrificed, psychological stress on the animal is transient and 

minimised as much as possible. Animals are killed under general anaesthesia. Death is always induced 

without producing pain or suffering by using Schedule 1 methods according to the Animals Scientific 

Procedures Act 1986. A track record in each partnering institution allows to follow-up the origin of each 

animal, the date of arrival and individual experiment, and the date and reason for death. All the procedures 

are being performed by a person with a personal licence, highly experienced with the techniques used and the 

manipulations of animals. The precise number of animals to be used by the individual partners is given in the 

individual WPs related to animal work: WP3, WP5, WP6, WP7, WP9, WP10, WP11.1, WP11.2, WP12, 

WP13. 

It should be pointed out again, that before start of DiMI-related animal work, each partner has to obtain 

permission from local ethics committee and has to provide the respective ethical permit number to the Ethical 

Management Board (EMB). 

8. Research in cooperation with developing countries 

Does not apply to the DiMI proposal. 

9. Local ethics committees opinions and authorisations of competent bodies 

Authorization of some of the proposed research has been obtained by local ethics committee from partners P7 

(WP9), P31 (WP8.1) and P26 (WP11.1). It should be pointed out that authorization for WP8.2 will be 

obtained in due course of the project and that approval by the respective ethics committees will be presented 

to the EC before start of subject recruitment.


10. Conflict of interest 

No conflicts of interest are foreseen at the current stage of the DiMI proposal. 

11. Ethical implications of research results 

The possible ethical implications of research results of DiMI are mainly related to the way of how clinical 

studies may be conducted in the future. If the proposed novel imaging technologies allow a non-invasive 

molecular phenotyping and disease classification, new drugs and therapies will always first be evaluated in 

terms of their effects on surrogate imaging end-points and not, as has been performed in the past, on clinical 

improvement alone. Therefore, by using imaging time- and resource-consuming Phase-III clinical trials may 

be postponed after a successful Phase I/II clinical trial including imaging technology. Further ethical 

implications of the research results such as the protection of dignity, autonomy, integrity and privacy of 

persons, biodiversity, protection of the environment, sustainability and animal welfare are not foreseen. 

Further ethical and safety issues 

It should be stated that all DiMI partners have extensive and specific experience in the work they are 

involved in. All safety-related issues with the various laboratory procedures, the creation and handling of 

genetically modified organisms, working with radioactivity, animal handling and working with animal and 

human tissue, blood and spinal fluid, are well recognized by all DiMI partners. Each of the partnering 

institutions have appropriate facilities and guidelines concerning the work they are performing to ensure the 

safety of personnel. They each have training programmes for new personnel to get familiar with the specific 

safety issues. All facilities are inspected by national health and safety authorities on a regular basis. All 

partners are currently working under the relevant local, national and international regulations concerning the 

respective work and will do so within their contribution in the DiMI consortium. 

With regards to stem cells, the DiMI project relates solely to studies with murine embryonic stem cells and 

excludes all work related to human embryonic stem cells. The issue of embryonic stem cells is under debate 

in the EC and EC member countries. If legislation will be modified during the course of the DiMI project, all 

partners will comply with the modified national and EC legislation. If limited use of human embryonic stem 

cells will become allowable during the course of the DiMI project, the partnership will work with its Ethical 

Advisory Committee (EAC) to formulate a request for inclusion of such work in the DiMI project to the EC 

before any such work will be contemplated. The DiMI project will not include any such modification without 

specific, written, EC approval. 

With regards to the work with HIV vectors, this work is restricted to BL-2 biosafety laboratories. All 

experiments with HIV vectors (GMO) by partners 14 and 23 are performed in agreement with the regulations 

prescribed by local, national and European laws. Partners 14 and 23 have several laboratories of BL-2 

biosafety level for HIV vector work, including animal neurosurgery rooms for stereotactic gene delivery in 

rodent and primates, PET and MRI imaging, electrophysiology, behaviour and viral vector design. There is 

NO risk of spreading genetically modified organism (GMO) to the environment.


With regards to the creation of GMO, the procedures will be carried out in research labs with experienced 

staff, in appropriate infrastructure and after permission has been obtained by the local authorities (e.g. 

Landesumweltamt Düsseldorf, Germany; or Commission de Génie Génétique, France). All experiments will 

be performed with adherence to European and the country-specific regulations (=> table above). 

With regards to application of radioactivity, the national laws will be followed, such as the 

Strahlenschutzgesetz (Germany). Moreover, the “Referral Guidelines for Imaging” adapeted by experts 

representing European Radiology and Nuclear Medicine in conjunction with the UK Royal College of 

Radiologists coordinated by the European Commission Directorate-General for the Environment (2000) will 

be adopted in experiments using human studies (=> table above). 

With regards to disposal of waste, country-specific regulations will be applied to ensure that no genetically 

modified organisms or toxic chemicals and radioactives could possible be contaminate the environment (=> 

table above). 

With regards to the safety of research staff, the specific national laws for the protection of personnel will be 

taken into account to ensure the safety and well-being of all participants in the network. New personnel will 

be appropriately trained in the specific laboratory safety issues. 

With regards to the information obtained from the DiMI project, the partnerships understands that such 

information could give rise to ethical questions that are of concern to European citizens. Where needed, the 

consortium will work together with the EAC to discuss the ethical impact of its research with ethical 

committees and patient advocacy groups. 

With regards to European competition and technology transfer, the results of the DiMi project will have a 

direct impact on European industry (bioengineering, bio-tech, imaging technology) and its international 

competitiveness, especially with regards to new diagnostic tools, test and procedures. The DiMI network will 

enable a fast transfer of probes, technology, expertise, etc. to other partners. Moreover, this type of network 

with its overall goal of achieving European leadership and international competitiveness in the field of 

molecular imaging will serve as a magnet for young researchers to stay in Europe and NOT to go to the US 

and, therefore, will prevent the current “brain drain” to the US, thus enabling a higher employment rate for 

highly educated scientists. 

DiMI Partners have agreed to comply to the following list of Ethical legal and regulatory issues 1 

National legislation 

Participants in FP6 projects must conform to current legislation and regulations in the countries where the 

research will be carried out. Where required by national legislation or rules, participants must seek the 

approval of the relevant ethics committees prior to the start of the RTD activities that raise ethical issues. 

EU legislation 

Participants will comply with relevant EU legislation such as: 

• The Charter of Fundamental Rights of the EU 

• Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the 

approximation of the laws, regulations and administrative provisions of the Member States relating to the 

1 Annex 3 to the Guide for proposers .


implementation of good clinical practice in the conduct of clinical trials on medicinal products for human 

use 

• Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection 

of individuals with regard to the processing of personal data and on the free movement of such data 

• Council Directive 83/570/EEC of 26 October 1983 amending Directives 65/65/EEC,75/318/EEC and 

75/319/EEC on the approximation laid down by law, regulation or administrative action relating to 

proprietary medicinal products 

• Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998 on the legal protection 

of biotechnological inventions 

• Directive 90/219/EEC of 23 April 1990 on the contained use of genetically modified micro-organisms 

• Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate 

release into the environment of genetically modified organisms and repealing Council Directive 

90/220/EEC 

International conventions and declarations 

Participants should respect the following international conventions and declarations: 

• Helsinki Declaration in its latest version 

• Convention of the Council of Europe on Human Rights and Biomedicine signed in Oviedo on 4 April 

1997, and the Additional Protocol on the Prohibition of Cloning Human Beings signed in Paris on 12 

January 1998 

• UN Convention on the Rights of the Child 

• Universal Declaration on the human genome and human rights adopted by UNESCO 

Opinions of the European Group on Ethics 

Participants should take into account the opinions of the European Group of Advisers on the Ethical 

Implications of Biotechnology (1991 –1997) and the opinions of the European Group on Ethics in Science 

and New technologies (as from 1998). 

Protection of Animals 

In accordance with the Amsterdam protocol on animal protection and welfare, animal experiments must be 

replaced with alternatives wherever possible. Suffering by animals must be avoided or kept to a minimum. 

This particularly applies (pursuant to Directive 86/609/EEC) to animal experiments involving species which 

are closest to human beings. Altering the genetic heritage of animals and cloning of animals may be 

considered only if the aims are ethically justified and the conditions are such that the animals’ welfare is 

guaranteed and the principles of biodiversity are respected. 

Note, that the DiMI project will introduce new in-vivo imaging techniques to follow longitudinally the course 

of molecular processes in several major diseases in animal models. Those techniques will be used to monitor 

therapy, e.g. in drug development, and will thus replace more invasive technologies such conventional 

histology. Such developments will therefore significantly reduce the number of laboratory animals. 

None of the research proposed in the DiMI JPA is related to a field excluded by the Programme.


11.1 Ethical aspects 

a) The DiMI project involves: 

Does your proposed research involve: YES NO 

• Human beings X 

Persons not able to give consent 

X 

Children 

X 

Adult healthy volunteers 

X 

• Human biological samples X 

Human embryonic stem cells in culture 

X 

Human foetal tissue/human foetuses 

X 

• Personal data or genetic information X 

• Animals (any species) X 

Transgenic animals 

X 

Non- human primates 

Dogs, pigs, cats, 

X 

X 

• Release into the environment of genetically modified 

micro-organisms or plants 

X


Appendix A – Consortium Description 

To reach the objectives of the proposed DiMI-NoE, a unique multi-disciplinary consortium of 52 

complementary partners from 13 European countries (N, S, DK, GB, NL, B, F, D, E, I, CZ, PL, EST) has 

been brought together with the critical mass and all necessary expertise and know-how spanning the fields 

of physics, instrumentation physics, bioinformatics, chemistry and radiochemistry, biochemistry, molecular 

biology, as well as various clinical specialties relating to neurosciences, cardiology, radiology and nuclear 

medicine. Already existing collaborations of some of the partners in the past (e.g. Nest-DD in 5 th FW; 

COST B12) facilitate the necessary interaction and degree of integration for the overall success of DiMI. 

All academic laboratories are active and at the tip of their discipline. Many are world leaders in a given 

domain. Many partners including the Project Coordinator have a strong background and are actively 

involved in basic research while also pursuing clinical activities guaranteeing 

• appropriate validation of experimental models and 

• efficient translation into clinical application. 

A longstanding experience and the necessary hardware, resources and infrastructure are present with 

respect to the various imaging technologies in 

• MRI (P3,4,5,7,8,9,10,17,20,22,23,24,25,26,27,29,31,32,34,37,39) 

• PET, SPECT (P1,2,4,5,7,10,12,13,14,17,18,20,22,23,24,26,29,31,33,34,36,39,40,41,42) 

• Optical imaging (P1,6,10,11,13,14,26,38,43) 

• Fluorescence microscopy (P1,8,11,25,26,32) 

• Two-photon imaging (P8,19) 

• Laser scanning microscopy (P1,8,25) 

• Ultrasound (P9,27,28) 

The other groups have been involved within the consortium because they represent highly excellent 

complementary know-how in 

• animal models (P1,4,5,10,11,14,15,16,17,21,22,23,34,37,40,43) 

• stem cell technology (P5,9,14,15,21,37) 

• basic chemistry / development of new tracers (P1,3,4,7,10,12,17,22,24,29,33,35,40). 

Moreover, six excellent SMEs (11.5 %) are directly involved from the start of DiMI with strong 

background and interest in technology related to molecular imaging. However, it should be stated that the 

involvement of further SMEs in due course of the consortium will be handled with a high degree of 

flexibility according to the specific needs and outcomes of the WPs. These activities will be under 

continuous investigation of the Board for Integrating Activities (BIA) chaired by P13. 

With regards to participation of women in the proposed DiMI it should be stated that 15 out of the 60 

representatives from 52 partnering institutions in the Governing Board (GB) and 5 out of 14 members from 

13 partnering institutions in the Scientific Management Board (SMB) are women.


Summary of expertise within DiMI and contributions to the JPA: 

No Acronym Representative Expertise Contribution to JPA 

1 MEK PD Dr. A. Jacobs (PC) 

Prof. Dr. K. Herholz 

microPET, HRRT-PET, multimodality imaging 

in neuroscience, gene therapy vectors, biosafety 

2, coordination of Nest-DD (5 th FW) 

Coordination, Steering 

(SMB), EMB, BIA, BOT, 

BODIC, BOKIM 

WPs 2, 3, 5, 6, 7, 8.1, 8.2, 

9, 10, 11.2, 12, 13, 14, 

15.1, 15.2, 16 

2 WBIC Prof. Dr. J. Clark microPET, instrumentation, quantification Steering (SMB), BOKIM 

3 UniTo Prof. Dr. S. Aime lanthanides complexes, MR-Imaging probes, 

hyperpolarized molecules, NMR, cellular biology 

4 UniTours Prof. Dr. D. Guilloteau SPECT, radiopharmaceuticals, 

neurotransmission, monoamine receptors and 

transporters 

5 AMD Prof. Dr. A. Planas animal models for human diseases, 

neurosciences, microPET 

6 UNIMI Prof. Dr. A. Maggi estrogens, hippocampus, AD, inflammation, 

animal engineering, pharmacology, optical 

imaging 

WPs 2, 11.1, 13, 16 

Steering (SMB), BOKIM 

WPs 4.1, 4.2, 7, 8.1, 12, 

16 

Steering (SMB), BOT 

WPs 1, 3, 8.1, 15.1, 16 

Steering (SMB), EMB, 

BODIC 

WPs 2, 5, 7, 9, 15.2, 16 

Steering (SMB), BODIC, 

BIA, EMB 

WPs 5, 6, 7, 14, 16 

7 NRU-DK Prof. Dr. G. Knudsen PET, MR, neurobiology, neurodegeneration Steering (SMB), BOKIM, 

EMB 

WPs 3, 5, 8.2, 9, 16 

8 UA-Imaging Prof. Dr. A. van der 

Linden 

µMRI, µCT, in vivo multimodality imaging and 

ex vivo fluorescence, confocal, two photon, 

FRET/FRAP techniques, life cell imaging (Ca++imaging) 

in experimental neurosciences 

9 IMF Prof. Dr. C. Moonen MRI, stem cells, gene expression, multi-modality 

imaging 

10 NUK_TUM PD Dr. F. Bengel 

Prof. Dr. M. Schwaiger 

PET, MRI, gene transfer, angiogenesis, 

cardiovascular molecular imaging 

Steering (SMB), BOT, 

EMB 

WPs 1, 5, 7, 8.1, 10, 15.1, 

16 

Steering (SMB), BIA, 

EMB 

WPs 4.1, 4.2, 10, 11.1, 

11.2, 12, 14, 16 

Steering (SMB), EMB, 

BODIC 

WPs 1, 8.2, 10, 11.1, 

11.2, 12, 15.2, 16 

11 UIO Dr. H. Carlson 

Prof. Dr. R. Blomhoff 

transgenic reporter mice, optical imaging in 

inflammation 

Steering (SMB), EMB 

WPs 6, 13, 16 

12 LIGE Prof. Dr. B. Tavitian PET, molecular imaging, pharmaco-imaging Steering (SMB), BOT, 

BODIC, EMB 

WPs 2, 6, 15.1, 15.2, 16 

13 Biospace Dr. M. Meynadier instrumentation, radionuclide imaging, optical 

imaging 

Steering (SMB), BIA 

WPs 1, 14, 16 

14 KULRD Prof. Dr. V. Baekelandt lentiviral vectors, gene therapy, animal models, WPs 5, 7, 10 

neurodegeneration, PD, AD 

15 ULUND-I Dr. Deniz Kirik disease models, gene transfer, stem cells, WPs 10 

Prof. Dr. A. Björklund grafting, functional recovery 

16 ULUND-II Prof. Dr. T. Blom animal models for inflammation WPs 13 

Prof. Dr. R. Holmdahl 

17 ICL I 

ICL-II 

Prof. Dr. D.J. Brooks 

Dr. H. Jones 

PET, MRI, Parkinson’s disease (PD), 

Alzheimer’s disease (AD), movement disorders 

imaging pulmonary inflammation, cell markers, 

protein profiling 

WPs 8.2, 9, 13 

18 HSP Prof. Dr. I. Carrio Radionuclide imaging of the heart WPs 11.1, 12 

19 LNNM Prof. Dr. S. Charpak two-photon imaging, neuro-vascular coupling in 2 nd period of proposal 

20 SHEFC Prof. Dr. K. Ebmeier SPECT, nicotinic receptor studies, Alzheimer’s WP 8.2 

disease, mild cognitive impairment 

21 UKB Prof. Dr. B. 

Fleischmann 

stem cells, cellular replacement therapy, 

cardiomyocytes, single cell physiology, 

WPs 5, 11.2, 12 

integrative physiology 

22 KI Prof. Dr. C. Halldin PET, preclinical and clinical neuroscience, 

neuropsychiatric disorders 

WPs 3


23 ImaGene Prof. Dr. P. Hantraye microPET focus, high field MRI/MRS, nonhuman 

In 2 nd period of proposal 

primate models of neurodegenerative 

diseases, gene transfer, cell transplantation, 

biosafety level 2+3, animal housing (rodents and 

primates, imaging and behavioural facilities) 

24 FZJ Dr. A. Bauer 

receptor imaging, clearPET Neuro, brain in 2 nd period of proposal 

Prof. Dr. H. Herzog mapping, ligand development 

25 MPIFNF Prof. Dr. M. Hoehn MRI miscroscopy, multimodal imaging in WPs 4.1, 5, 10 

neuroscience, cerebral regeneration therapy 

26 CARIM Dr. L. Hofstra cardiology, optical imaging WPs 10, 11.1, 11.2, 12, 

13 

27 CBI Prof. Dr. M. Horn MRI, MRS, myocardium, viability, plague WPs 11.1 

28 LIP Dr. L. Bridal 

ultrasound, functional and quantitative imaging, WPs 11.1, 11.2 

Prof. Dr. P. Laugier micro and nano-contrast particles 

29 AZG Prof. Dr. K. Leenders movement disorders, multimodality imaging in WPs 3, 8.2 

Prof. Dr. Vaalburg neuroscience, P-glycoprotein, blood brain barrier 

30 INP Prof. Dr. R. 

In vivo radio-quantification, tomography, WP 1 

Mastrippolito 

cerebral metabolism 

31 UNEW Dr. C.M. Morris functional genomics, dementia, diagnostic targets WP 8.1 

32 TU/e Prof. Dr. K. Nicolay microMRI, functional and molecular imaging in WPs 5, 11.1, 11.2, 12 

cardiovascular disease 

33 KII Prof. Dr. A. Nordberg PET, imaging in neuroscience, MCI, amyloid WPs 8.2, 9 

Prof. Dr. B. Langström 

34 CNR-IBB Prof. Dr. S. Pappata in vivo imaging, gene transfer, multimodality WPs 5, 8.2, 9 

Dr. A. Auricchio imaging in neuroscience, microPET 

35 DUR Prof. Dr. D. Parker new lanthanide probes, luminescence 

WPs 4.1, 4.2, 13 

microscopy 

36 UHSR Prof. Dr. D. Perani PET, SPECT multimodality imaging in 

WPs 8.2, 9 

neuroscience, neurology 

37 LVA Prof. Dr. R. Poelmann high field magnetic resonance microscopy, stem EMB, 

cell therapy, heart failure 

38 LETI Dr. P. Rizo in vivo fluorescence; fluorescence optical 

tomography; light propagation modelling; 

tomographic algorithms 

WPs 11.1, 11.2, 12 

WPs 13 

39 CRCULG Prof. Dr. E. Salmon neurosciences, radiochemistry, brain imaging WP 8.2 

40 UKM Prof. Dr. M. Schäfers ultra-high-resolution animal PET, PET/CT, WPs 5, 11.1, 11.2, 13 

PD Dr. C. Bremer arteriosclerosis imaging, multimodality imaging 

in cardiovascular diseases 

41 LMIRC Prof. Dr. K. Van Laere PET, SPECT, microPET, microSPECT imaging WPs 1, 3, 4.1, 4.2, 7, 8.2, 

Prof. Dr. A. Verbruggen in neuroscience 

11.2 

42 CYM Prof. Dr. D. Vivien PET, MRI, in vitro, in vivo, models, molecular WPs 5, 9 

tools 

43 MiceTech Dr. Harald Carlson animal models for inflammation, optical imaging WP 13 

44 Bionexis Dr. F. Russo-Marie Design of smart probes cancelled participation 

45 FIMA Dr. J. Masdeu PET imaging in neurodegeneration WP 8.2 

46 UnivTours Prof. Dr. S. Benderbous MR radiochemstry WP 4.1, 4.2 

47 Cyclopharma J. B. Deloye Radiochemistry in 2 nd period of proposal 

48 MEDRES Stefan Wecker Hardware development in 2 nd period of proposal 

49 Visgenyx Dr. S. Köks Transgenic animal models in 2 nd period of proposal 

50 Charles Uni Prof. Dr. I. Lukes MR chemistry WP 4.1, 4.2 

51 POLATOM Prof. R. Mikolajczak Radiochemistry in 2 nd period of proposal 

52 IEM ASCR Prof. Dr. E. Sykova MR imaging of stem cells WP 10 

53 IGT Dr. E. Dumont MR imaging of temperature-controlled gene 

expression 

in 2 nd period of proposal


Preexisting and future interactions within DiMI


Partner 1: Cologne (A.H. Jacobs, K. Herholz) 

MPI for Neurological Research, Department of Neurology and Center of Molecular Medicine at the University 

of Cologne, Germany 

Cologne has a local network of different institutions and laboratories which is well established in carrying out 

multidisciplinary molecular imaging research. The MPI for Neurological Research consists of various laboratories and 

working groups dealing with instrumentation physics, image coregistration, radiochemistry, neurodegenerative 

diseases, cerebral ischemia, neurooncology, and gene and stem cell-based therapies. The MPI harbors two dedicated 

high-resolution LSO-PET-scanners (Siemens ECAT HR/HRRT), a microPET (Concord, Siemens CTI), an optical 

imaging camera (Kodak), a 7T-MRI (Broker) and laser scanning microscope (Leica). Therefore, the Cologne-Group 

serves all infrastructure necessary to carry out innovative research integrating the various imaging modalities (PET, 

MRI, optical imaging). The MPI plays an essential role in neuroscience research at the University of Cologne, 

focussing on the development of potential clinically applicable new treatment strategies including gene therapy, 

phenotyping neurodegenerative disease, investigating new treatment modalities in stroke and staging and therapy 

follow-up in neurooncology. To achieve these goals, the MPI has close interactions with the Departments of 

Neurosurgery and Stereotactic Neurosurgery in the field of developing new methods for vector application and deep 

brain stimulation; Department of Radiology for co-registering molecular PET imaging data with anatomical and 

spectroscopic information obtained by MRI and MRS; Departments of Neuroanatomy and Neuropathology for 

correlation of PET data with histological findings; Center for Molecular Medicine for development of improved 

vectors and potential application of molecular imaging methods in stem cell research and phenotyping mouse models 

of human disease. Furthermore, the MPI has close collaborations with international research groups (EU-Groups 

involved in NEST-DD and EMIL-CANCER; furthermore: Molecular Neurogenetics Unit, MGH, Boston; Memorial 

Sloan-Kettering Cancer Center, New York; Institutes for Virology at the Universities in Zürich and Glasgow). 

Scientific Staff Expertise 

1. Prof. Dr. W.D. Heiss: Director of the MPI and the Department of Neurology, experimental and clinical stroke 

imaging by PET and MRI. 

2. Priv.-Doz. Dr. A. Jacobs: Neurologist, Molecular Virology and Imaging; Head of the Laboratory for Gene Therapy 

and Molecular Imaging; imaging exogenous gene expression in gene therapy by HSV-1 based vectors; founding 

member of the Society for Molecular Imaging. 

Further members of the group: Dr. A. Winkeler (biologist, development of targeted and regulated HSV-1 

vectors); Dr. M. Klein (biologist, trafficking of neural progenitor and tumor cells by PET, MRI and optical 

imaging); Dr. A. Thomas (MD; phenotyping spinocerebellar ataxias by PET); Dr. N. Galldiks (MD; 

phenotyping alzheimer mouse models by PET); Dr. A. Rüger (MD; correlation of vector-mediated gene 

expression with therapeutic efficiency); G. Schneider and C. Selbach (technicians for cell culture and 

microPET); P. Monfared, M. Ameli and M. Scheffler (doctoral students). 

3. Prof. Dr. K. Wienhard: Physics, instrumentation, hard- and software development 

Further members of the group: C. Knoess (physics; performance optimization of HRRT and microPET); S. 

Vollmar and J. Cizek (physics, informatics; software development for image coregistration; integration of 

project-specific modules into general image processing software packages) 

4. Dr. R. Wagner: Radiochemistry, probe development 

Further members of the group: Dr. B. Bauer ([ 11 C]-probes); Dr. H. Li and Dr. M. Stoeckle (chemistry, 

radiochemistry; development of new molecular imaging probes which pass blood brain barrier) 

5. Prof. Dr. K. Herholz: Physics and Neurologist; Head of Nest-DD (EU-5 th FW); image analysis; early diagnosis of 

Alzheimer’s disease and differential diagnosis from other forms of dementia by molecular imaging 

Further members of the group: Dr. L. Kracht, MD neurosciences; B. Habedank, MD neurosciences; J. Klein, 

MD neurosciences. 

6. Dr. R. Hilker: Neurologist, phenotyping inherited forms of Parkinson’s disease by imaging, differential diagnosis 

to multiple systems atrophy (MSA), imaging effects of deep brain stimulation 

7. Prof. Dr. R. Graf: Biologist; Head of the Laboratory for Experimental Cerebral Ischemia; dynamic imaging of 

pathophysiological events in stroke models of cats 

8. Prof. Dr. M. Hoehn: Physics; Head of experimental MRI; MR imaging of stroke models (rat); stem cell trafficking


References 

Instrumentation Physics 

1. Knoess C, Siegel S, Smith A, Newport D, Richerzhagen N, Winkeler A, Jacobs A, Goble RN, Graf R, Wienhard K, Heiss WD. Performance 

evaluation of the microPET R4 PET scanner for rodents. Eur J Nucl Med Mol Imaging. 2003;30:737-47 

2. Vollmar S, Michel C, Treffert JT, Newport DF, Casey M, Knoss C, Wienhard K, Liu X, Defrise M, Heiss WD. HeinzelCluster: accelerated 

reconstruction for FORE and OSEM3D. Phys Med Biol. 2002;47:2651-8. 

Imaging Gene Therapy 

1. Jacobs AH, Li H, Winkeler A, Hilker R, Knoess C, Ruger A, Galldiks N, Schaller B, Sobesky J, Kracht L, Monfared P, Klein M, Vollmar S, 

Bauer B, Wagner R, Graf R, Wienhard K, Herholz K, Heiss WD. PET-based molecular imaging in neuroscience. Eur J Nucl Med Mol 

Imaging. 2003;30:1051-65 

2. Jacobs AH, Winkeler A, Hartung M, Slack M, Dittmar C, Kummer C, Knoess C, Vollmar S, Wienhard K, Heiss WD. Improved HSV-1 

amplicon vectors for proportional coexpression of PET marker and therapeutic genes. Human Gene Therapy 2003; 14:277-297 

3. Jacobs A, Tjuvajev JG, Dubrovin M, Akhurst T, Balatoni J, Beattie B, Joshi R, Finn R, Larson SM, Herrlinger U, Pechan PA, Chiocca EA, 

Breakefield XO, Blasberg RG. PET-based imaging of transgene expression mediated by replication-conditional, oncolytic HSV-1 mutant 

vectors in vivo. Cancer Res 2001a; 61:2983-2995 

4. Jacobs A, Bräunlich I, Graf R, Lercher M, Sakaki T, Voges J, Heßelmann V, Brandau W, Wienhard K, Heiss WD. Quantitative kinetics of 

[ 124 I]-FIAU in cat and man. J Nucl Med 2001b; 42:467-475 

5. Jacobs A, Voges J, Reszka R, Lercher M, Gossmann A, Kracht L, Kaestle Ch, Wagner R, Wienhard K, Heiss WD. Non-invasive assessment of 

vector-mediated gene expression in a phase I/II clinical glioma gene therapy trial by positron emission tomography. Lancet 2001c; 358:727- 

729. 

Imaging Alzheimer’s Disease 

1. Herholz K, Schopphoff H, Schmidt M, Mielke R, Eschner W, Scheidhauer K, Schicha H, Heiss WD, Ebmeier K. Direct comparison of 

spatially normalized PET and SPECT scans in Alzheimer's disease. J Nucl Med 2002;43:21-6. 

2. Herholz K, Salmon E, Perani D, Baron JC, Holthoff V, Frolich L, Schonknecht P, Ito K, Mielke R, Kalbe E, Zundorf G, Delbeuck X, Pelati O, 

Anchisi D, Fazio F, Kerrouche N, Desgranges B, Eustache F, Beuthien-Baumann B, Menzel C, Schroder J, Kato T, Arahata Y, Henze M, Heiss 

WD. Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET. Neuroimage 2002;17:302-16. 

3. Herholz K, Lercher M, Wienhard K, Bauer B, Lenz O, Heiss WD. PET measurement of cerebral acetylcholine esterase activity without blood 

sampling. Eur J Nucl Med 2001;28:472-7. 

4. Herholz K, Bauer B, Wienhard K, Kracht L, Mielke R, Lenz MO, Strotmann T, Heiss WD. In-vivo measurements of regional acetylcholine 

esterase activity in degenerative dementia: comparison with blood flow and glucose metabolism. J Neural Transm 2000;107:1457-68. 

Imaging Parkinson’s Disease 

1. Hilker R, Voges J, Weisenbach S, Kalbe E, Burghaus L, Ghaemi M, Lehrke R, Koulousakis A, Herholz K, Sturm V, Heiss WD. Subthalamic 

nucleus stimulation restores glucose metabolism in associative and limbic cortices and in cerebellum: evidence from a FDG-PET study in 

advanced Parkinson’s disease. J Cereb Blood Flow Metab 2003 (in press) 

2. Hilker R, Voges J, Ghaemi M, Lehrke R, Rudolf J, Koulousakis A, Herholz K, Wienhard K, Sturm V, Heiss WD. Deep brain stimulation of the 

subthalamic nucleus does not increase the striatal dopamine concentration in parkinsonian humans. Mov Disord 2003;18:41-8. 

3. Hilker R, Voges J, Thiel A, Ghaemi M, Herholz K, Sturm V, Heiss WD. Deep brain stimulation of the subthalamic nucleus versus levodopa 

challenge in Parkinson's disease: measuring the on- and off-conditions with FDG-PET. J Neural Transm 2002;109(10):1257-64. 

4. Hilker R, Klein C, Hedrich K, Ozelius LJ, Vieregge P, Herholz K, Pramstaller PP, Heiss WD. The striatal dopaminergic deficit is dependent on 

the number of mutant alleles in a family with mutations in the parkin gene: evidence for enzymatic parkin function in humans. Neurosci Lett 

2002;323(1):50-4. 

5. Hilker R, Klein C, Ghaemi M, Kis B, Strotmann T, Ozelius LJ, Lenz O, Vieregge P, Herholz K, Heiss WD, Pramstaller PP. Positron emission 

tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann 

Neurol 2001;49:367-76. 

Imaging Cerebral Ischemia 

1. Dohmen C, Bosche B, Graf R, Staub F, Kracht L, Sobesky J, Neveling M, Brinker G, Heiss WD. Prediction of Malignant Course in MCA 

Infarction by PET and Microdialysis. Stroke 2003 Jul 24 

2. Toyota S, Graf R, Valentino M, Yoshimine T, Heiss WD. Malignant infarction in cats after prolonged middle cerebral artery occlusion: 

glutamate elevation related to decrease of cerebral perfusion pressure. Stroke 2002;33:1383-91. 

3. Dohmen C, Kumura E, Rosner G, Heiss WD, Graf R. Adenosine in relation to calcium homeostasis: comparison between gray and white 

matter ischemia. J Cereb Blood Flow Metab 2001;21:503-10. 

4. Heiss WD, Kracht LW, Thiel A, Grond M, Pawlik G. Penumbral probability thresholds of cortical flumazenil binding and blood flow 

predicting tissue outcome in patients with cerebral ischaemia. Brain 2001;124:20-9. 

5. Heiss WD, Thiel A, Grond M, Graf R. Contribution of immediate and delayed ischaemic damage to the volume of final infarcts. Lancet 

1999;353:1677-8. 

Imaging Stem Cells in Stroke 

1. Hoehn M, Kustermann E, Blunk J, Wiedermann D, Trapp T, Wecker S, Focking M, Arnold H, Hescheler J, Fleischmann BK, Schwindt W, 

Buhrle C. Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of 

experimental stroke in rat. Proc Natl Acad Sci U S A. 2002;99:16267-72


Partner 2: Cambridge 

Wolfson Brain Imaging Centre University of Cambridge 

The Cambridge Molecular Imaging group is a partnership of basic scientists in the Wolfson Brain Imaging Centre (John 

Clark: PET, Franklin Aigbirio: Radio-Chemistry, Tim Fryer: PET Physics, Adrian Carpenter: MRI, Guy Williams: 

computing) and the University departments of Physics (Richard Ansorge: PET/MRI) and Chemistry (F Leeper), together 

with Clinical Researchers and Biomedical scientists in the University and Clinical School. Studies range from small animals 

translating to man, with special reference to head injury and stroke (John Pickard: Neurosurgery, David Menon: 

Anaesthetics, Jean-Claude Baron: Neurology) cardiovascular disease (Peter Weissberg: Medicine, Anthony Davenport: 

Clinical Pharmacology). This highly multidisciplinary group have expertise in PET scanner modelling, reconstruction, MR 

data analysis, image fusion, lesion detection, diffusion tensor imaging, perfusion imaging, and ligand development. The 

group has access to a GE Cyclotron, GE Advance PET camera, GE PETrace chemistry, Bruker S300 3T wholebody MRI, 

Concorde MicroSystems P4 micro PE, and are constructing the first high-resolution PET/MRI scanner based on a novel 1T 

360mm bore split pair magnet. The group receives funding from the UK MRC, EPSRC, BHF, and Wellcome Trust. 

Scientific Staff 

Expertise 

1. Prof J D Pickard: Clinical Director and Chairman, Neurosurgery and acute brain injury. 

2. J C Clark, DSc: Director of PET Science Cyclotrons PET Chemistry and PET Physics, MR/PET. 

3. T A Carpenter, PhD: Director of MR and Computing, MR, MRS parallel computing and combined MR/PET. 

4. S Harding: MR and MRS Physics. 

5. T D Fryer, PhD: PET Physics, PET Kinetic Modelling and PET machine architecture modeling MR/PET. 

6. F I Aigbirhio, PhD: PET Chemistry ligand development. 

7. M Cleij, PhD: PET Chemistry ligand development. 

8. Barrett, PhD: PET Physics Monte Carlo modelling of PET machine architecture, MR/PET. 

9. R Ansorge, PhD: Imaging Physics, MR/PET and High performance computing (Cavendish Laboratory). 

10. Prof D K Menon: Anaesthetics Acute brain injury and neurointensive care. 

11. J Beech, PhD: Anaesthetics preclinical stroke models and neuroregeneration. 

12. H K Richards, PhD: Neurophysiologist and microPET experimenter. 

13. N Shaw, PhD: MR magnet design for MR/PET and high performance computing (Cavendish Laboratory). 

14. Prof PL Weissberg: Cardiovascular Medicine with special interests in atheroma imaging. 

15. AP Davenport, PhD: Human Receptor Pharmacology, Proteomics and autoradiography. 

16. P J Johnstrom, PhD: PET Chemistry and pharmacology, microPET evaluation of novel radiopharmaceuticals. 

17. Prof JC Baron: Clinical Research in Stroke medicine salvage and regeneration and Alzheimers Disease. 

18. Dr E A Warburton: Clinical Research in Stroke medicine with special interests in carotid atheroma imaging. 

19. G Williams, PhD: Computing and Image manipulation systems. 

20. F Leeper, PhD: Synthetic Organic Chemist (University Department on Chemistry). 

References 

1. P. Johnstrom, H. K. Richards, T. D. Fryer, O. Barret, J. C. Clark, J. D. Pickard, and A. P. Davenport, "In vivo imaging of enzyme conversion of 

[F-18]-Big ET-1 to [F- 18]-ET-1 and inhibition of enzyme activity using phosphoramidon - A positron emission tomography study," British 

Journal of Pharmacology 2003, 138, 57P. 

2. P. Johnstrom, N. G. Harris, T. D. Fryer, O. Barret, J. C. Clark, J. D. Pickard, and A. P. Davenport, "F-18-Endothelin-1, a positron emission 

tomography (PET) radioligand for the endothelin receptor system: radiosynthesis and in vivo imaging using microPET," Clinical Science 

2002, 103, 4S-8S. 

3. L. E. Annett, T. D. Fryer, R. M. Cummings, E. M. Torres, R. M. Ridley, H. F. Baker, S. B. Dunnett, and J. C. Clark, "Nigral grafts in 

marmosets with unilateral 60HDA lesions revealed by [F-18]Flurodopa PET," Experimental Neurology 2002, 175, 422-422. 

4. J. H. F. Rudd, E. A. Warburton, T. D. Fryer, H. A. Jones, J. C. Clark, N. Antoun, P. Johnstrom, A. P. Davenport, P. J. Kirkpatrick, B. N. Arch, 

J. D. Pickard, and P. L. Weissberg, "Imaging atherosclerotic plaque inflammation with [F-18]- fluorodeoxyglucose positron emission 

tomography," Circulation 2002, 105, 2708-2711. 

5. T. D. Fryer, M. C. Cleij, F. I. Aigbirhio, J. S. Beech, O. Barret, T. A. Carpenter, D. K. Menon, J. C. Clark, and J. C. Baron, "Imaging 

benzodiazepine receptors in the rat brain using [11C]flumazenil and microPET," Neuroimage 2002, 16, S26-S26. 

6. P. Johnstrom, N. G. Harris, T. D. Fryer, J. J. Maguire, O. Barret, H. K. Richards, J. C. Clark, J. D. Pickard, and A. P. Davenport, "In vivo 

imaging of ET-1 binding to endothelin receptors using[F-18]-ET-1 and positron emission tomography," British Journal of Pharmacology 

2002, 135, 31P. 

7. T. D. Fryer, J. H. F. Rudd, E. A. Warburton, H. Jones, J. C. Clark, P. Johnstrom, A. P. Davenport, N. Antoun, P. Kirkpatrick, J. D. Pickard, and 

P. L. Weissberg, "Imaging inflammation in carotid atherosclerotic plaque using FDG-PET," European Journal of Nuclear Medicine 2001, 28, 

OS388. 

8. K. H. J. Bockhorst, J. M. Smith, M. I. Smith, D. P. Bradley, G. C. Houston, T. A. Carpenter, L. D. Hall, N. G. Papadakis, A. A. Parsons, C. L. 

H. Huang, and M. F. James, "A quantitative analysis of cortical spreading depression events in the feline brain characterized with diffusionweighted 

MRI," Journal of Magnetic Resonance Imaging 2000, 12, 722-733. 

9. G. C. Houston, N. G. Papadakis, T. A. Carpenter, L. D. Hall, B. Mukherjee, M. F. James, and C. L. H. Huang, "Mapping of the cerebral 

response to hypoxia measured using graded asymmetric spin echo EPI," Magnetic Resonance Imaging 2000, 18, 1043-1054.


Partner 3: Torino (S. Aime) 

Unit for the development of MRI-Imaging Probes at the Department of Chemistry IFM and Centre for 

Molecular Imaging of the University of Torino, Italy. 

At the Department of Chemistry IFM there is a well established experience in the field of synthesis and physicochemical 

characterisation of Contrast Agents. Since 1986, there have been activities addressed to the development of 

paramagnetic Contrast Agents for MRI (with projects in High Relaxivity, Blood Pool, Targeting and Responsive 

Agents). In 1998, the Department of Chemistry IFM has settled a dedicated laboratory at the BioIndustry Park. This 

laboratory focuses on the improvement of the identification of targets and on the synthesis of vectors via a tight 

collaboration with biologists. In 2001, the collaboration between chemists, biologists and physicians has led to the 

foundation of the Centre for Molecular Imaging of the University of Torino. The Centre has been approved and 

supported by the Ministry of S&T and the University. The Centre coordinates the following main lines of activities: i) 

synthesis and MRI-assessment of Gd-based chelates endowed with high relaxivities (including multimeric 

derivatives); ii) synthesis and MRI-assessment of agents based on the CEST effect (CEST: Chemical Exchange 

Saturation Transfer); iii) development of 13C-hyperpolarised molecules via the formation of para-hydrogenated 

substrates; iv) labelling of cells (stem cells, leucocytes, tumor cells, etc…) with paramagnetic chelates; v) targeting 

receptors/transporters hyperexpressed/upregulated on pathological cells with paramagnetic Lanthanide chelates 

(including particles); vi) targeting thrombi, plaques with functionalised Lanthanide chelates (including particles). 

Industrial collaborations with Bracco Imaging (IT), Glaxo SK (UK), KAO (Japan), Stelar (IT). 


1. Prof. S. Aime - Chemist – UniTo - Head of NMR laboratory and of the Centre for Molecular Imaging – NMR, 

Lanthanide Complexes, MR-Imaging probes. 

Further members of the group: Dr. E. Terreno (chemist – development of CEST agents); Dr. W. Dastrù 

(chemist – NMR/MRI instrumentation); Dr. S. Geninatti Crich (chemist – cell labelling and targeting agents); 

Dr. E. Gianolio (chemist – high relaxivity and targeting agents); Dr. C. Cabella (biochemist – cell culture and 

labelling procedures, MRI); Dr. A. Barge (chemist – synthesis of metal complexes, NMR); Dr. L. Tei 

(chemist – peptide synthesis) + 5 PhD and 2 technicians. 

2. Prof. R. Gobetto – Chemist - UniTo – Professor of Chemistry – NMR, Synthesis of hyperpolarised 13C molecules. 

Further members of the group: Dr. A. Viale (chemist, synthesis, NMR); Dr. F. Reineri (chemist, synthesis, 

NMR) + 2 PhD 

3. Dr. G. Digilio – Chemist – Head of Laboratory at Bioindustry Park – NMR, Peptides and protein chemistry. 

Further members of the group: Dr. D. Corpillo (chemist – Mass Spectrometry, 2D Electrophoresis); Dr. C. 

Bracco (chemist – Bioinformatics); Dr. F. Fedeli (chemist – ligand synthesis); Dr. A. Mortillaro (chemist, 

ligand synthesis) + 2 PhD 

4. Prof. M. Botta – Chemist – University of Eastern Piedmont – NMR, Coordination chemistry, Relaxometry. 

5. Prof. G.B. Giovenzana – Chemist – University of Eastern Piedmont – Ligand synthesis 

Further members of the group: Dr. C. Cavallotti (chemist – Ligand synthesis) 

6. Prof. L. Silengo – MD – UniTo – Head of the Department of Genetics, Biology and Biochemistry - Molecular 

biology, cell targeting. 

Further members of the group: Prof. G. Tarone (biologist – cell transfection); Prof. F. Altruda (biologist – cell 

trafficking); J. Hamm (biochemist – cell targeting) 

7. Prof. G. Camussi – MD – UniTo – Department of Internal Medicine – Cell labelling, cell targeting, cell 

transplantation. 

Further members of the group: Dr. L. Biancone (MD – cell targeting, cell labelling, cell transplantation); Dr. 

B. Bussolati (MD – phage display, cell targeting) 

References 

High Sensitive Agents 

1. Aime S, Dastru W, Crich SG, Gianolio E, Mainero V. Innovative magnetic resonance imaging diagnostic agents based on paramagnetic Gd(III) 

complexes. Biopolymers 2002; 66: 419-428 

2. Aime S, Frullano L, Geninatti Crich S. Compartmentalization of a gadolinium complex in the apoferritin cavity: A route to obtain high 

relaxivity contrast agents for magnetic resonance imaging. Angew. Chemie Int. Ed. 2002; 41: 1017-1019. 

3. Aime S, Botta M, Fedeli F, Gianolio E, Terreno E, Anelli P. High-relaxivity contrast agents for magnetic resonance imaging based on multisite 

interactions between a beta-cyclodextrin oligomer and suitably functionalized Gd-III chelates. Chem. Eur. J. 2001; 7: 5262-5269. 

4. Aime S, Botta M, Fasano M, Terreno E. Prototropic and water-exchange processes in aqueous solutions of Gd(III) chelates. Acc. Chem. Res. 

1999; 32: 941-949 

5. Aime S, Botta M, Fasano M, Crich SG, Terreno E. H-1 and O-17-NMR relaxometric investigations of paramagnetic contrast agents for MRI. 

Clues for higher relaxivities. Coord. Chem Rev. 1999; 186: 321-333 

6. Aime S, Gobetto R, Canet D. Longitudinal Nuclear Relaxation in A 2 Spin System Initially Polarized through Para-hydrogen J.Am.Chem.Soc. 

1998; 120: 6770-6773. 

CEST Agents 

1. Aime S, Delli Castelli D, Terreno E . Novel pH-reporter MRI contrast agents. Angew. Chemie Int. Ed. 2002; 41: 4334-4336. 

2. Aime S, Delli Castelli D, Fedeli F, Terreno E .A paramagnetic MRI-CEST agent responsive to lactate concentration. J. Am. Chem. Soc. 2002;


124: 9364-9365. 

3. Aime S, Barge A, Delli Castelli D, Fedeli F, Mortillaro A, Nielsen FU, Terreno E. Paramagnetic lanthanide(III) complexes as pH-sensitive 

chemical exchange saturation transfer (CEST) contrast agents for MRI applications. Magn. Res. Med. 2002; 47: 639-648. 

Targeting and responsive Agents 

1. Aime S, Cabella C, Colombatto S, Crich SG, Gianolio E, Maggioni F. Insights into the use of paramagnetic Gd(III) complexes in MRmolecular 

imaging investigations. J .Magn. Res. Imag. 2002; 16 : 394-406. 

2. Lowe MP, Parker D, Reany O, Aime S, Botta M, Castellano G, Gianolio E, Pagliarin R. pH-dependent modulation of relaxivity and 

luminescence in macrocyclic gadolinium and europium complexes based on reversible intramolecular sulfonamide ligation. J. Am. Chem. Soc. 

2001; 123: 7601-7609 

3. Aime S, Botta M, Garino E, Crich SG, Giovenzana G, Pagliarin R, Palmisano G, Sisti M. Non-covalent conjugates between cationic polyamino 

acids and Gd-III chelates: A route for seeking accumulation of MRI-contrast agents at tumor targeting sites. Chem.- Eur. J. 2000; 6: 2609- 

2617. 

4. Aime S, Botta M, Gianolio E, Terreno E. A p(O-2)-responsive MRI contrast agent based on the redox switch of manganese(II/III) - Porphyrin 

complexes. Angew. Chemie Int. Ed. 2000; 39: 747-749. 

5. Aime S, Botta M, Crich SG, Giovenzana G, Palmisano G, Sisti M. A macromolecular Gd(III) complex as pH-responsive relaxometric probe 

for MRI applications. Chem. Comm. 1999; 1577-1578. 

Vectors 

1. Digilio G, Barbero L, Bracco C, Corpillo D, Esposito P, Piquet G, Traversa S, Aime S. NMR structure of two novel polyethylene glycol 

conjugates of the human growth hormone-releasing factor, hGRF(1-29)-NH2. J. Am. Chem. Soc. 2003; 125: 3458-3470 

2. Digilio G, Bracco C, Barbero L, Chicco D, Del Curto MD, Esposito P, Traversa S, Aime S. NMR conformational analysis of antide, a potent 

antagonist of the gonadotropin releasing hormone. J. Am. Chem. Soc. 2002; 124: 3431-3442. 

Cellular Biology 

1. Lupia E, Del Sorbo L, Bergerone S, Emanuelli G, Camussi G, Montrucchio G. The membrane attack complex of complement contributes to 

plasmin-induced synthesis of platelet-activating factor by endothelial cells and neutrophils. Immunology 2003; 109: 557-563. 

2. Brancaccio M, Fratta L, Notte A, Hirsch E, Poulet R, Guazzone S, De Acetis M, Vecchione C, Marino G, Altruda F, Silengo L, Tarone G, 

Lembo G. Melusin, a muscle-specific integrin beta(1)-interacting protein, is required to prevent cardiac failure in response to chronic pressure 

overload. Nat Med. 2003; 9: 68-75. 

3. Lupia E, Pucci A, Peasso P, Merlo M, Baron P, Zanini C, Del Sorbo L, Rizea-Savu S, Silvestro L, Forni M, Emanuelli G, Camussi G, 

Montrucchio G. Intra-plaque production of platelet-activating factor correlates with neoangiogenesis in human carotid atherosclerotic lesions. 

Int. J. Molec. Med. 2003; 12: 327-334. 

4. Deregibus MC, Buttiglieri S, Russo S, Bussolati B, Camussi G. CD40-dependent activation of phosphatidylinositol 3-kinase/Akt pathway 

mediates endothelial cell survival and in vitro angiogenesis. J. Biol. Chem. 2003; 278: 18008-18014. 

5. Di Cunto F, Imarisio S, Camera P, Boitani C, Altruda F, Silengo L. Essential role of citron kinase in cytokinesis of spermatogenic precursors. 

J. Cell Sci. 2002; 115: 4819-4826. 

6. Degani S, Balzac F, Brancaccio M, Guazzone S, Retta SF, Silengo L, Eva A, Tarone G. The integrin cytoplasmic domain-associated protein 

ICAP-1 binds and regulates Rho family GTPases during cell spreading. J. Cell Biol. 2002; 156: 377-387. 

7. Hirsch E, Barberis L, Brancaccio M, Azzolino O, Xu DZ, Kyriakis JM, Silengo L, Giancotti FG, Tarone G, Fassler R, Altruda F. Defective 

Rac-mediated proliferation and survival after targeted mutation of the beta(1) integrin cytodomain. J. Cell Biol. 2002; 57: 481-492.


Partner 4: Tours (D. Guilloteau) 

Unit INSERM 316, University Hospital Tours, France 

Original aspect of the group of Tours is to be based on SPECT and PET molecular imaging with the aim of 

understanding, diagnosis and treating CNS disorders, beginning with the development of new radiopharmaceutical 

products (conception, synthesis, radiosynthesis), to animal studies (evaluation of new tracers, and study of 

mechanisms guiding the choice of new molecular targets for exploration), and finally resulting in clinical applications 

(neurodevelopmental and neurodegenerative disorders). The feasibility of our scientific project is based on a 

multidisciplinary team combining complementary competence, i.e. clinical (neurologists, neuropediatric doctors), 

experimental neurobiology, imaging (nuclear physicians, radiopharmacists, chemists) and technological expertise. 

This approach uses radiopharmaceutical products (γ or β emitters) specific to the molecular targets being explored. 

The development of these tracers requires multidisciplinary competence from chemistry to medicine, and requires 

several key-steps: 1) conception, synthesis and radiolabelling of new compounds, 2) pharmacological validation 

(affinity, specificity for the molecular target) in vitro and ex vivo in animals, 3) in vivo validation in small animals, in 

normal conditions and in animal models of human disorders. Our research activity on radiopharmaceutical 

development is mainly conducted in research-dedicated premises organized in: 

- an organic synthesis unit (chemistry laboratory specially equipped with preparatory HPLC and access to NMR and 

mass spectrometry), 

- a radiosynthesis unit (“hot” laboratory authorized for 3 H, 125 I, 123 I, 99m Tc, 18 F), 

- a biology unit (equipment for micro-surgery in rodents, cryocuting, image analyzer, “phosphorimaging” system, 

HPLC with electrochemical detection, γ and β counters). 

- a in vivo imaging unit: Cameras dedicated to in vivo imaging of small animals of “ToHR” type (High Resolution 

Tomographic system) is planned for 2003. The development of a micro-imaging platform for rodents (SPECT/ 

MicroPET /MRI) is planned in these premises. Scintigraphic protocols in monkeys are performed in researchdedicated 

premises including: an animal room for non-human primates, a CERASPECT brain γ camera, an MRI 

system for animal experiments. Scintigraphic protocols in humans are undertaken in the Hospital (Nuclear 

Medicine Unit): SPECT and PET camera available. 

Tours has close collaborations with international research groups (EU-Groups involved in COST B12: Radiotracer for 

assessment of biological function. European program EUREKA Dopimag “Development of a tracer for exploration 

by scintigraphy of the dopamine transporters”. International program with University of Sydney (Australia) and 

University of California (US) “Development of ligand for Alzheimer’s disease” 

MRI probes: Our team is specialized in MRI probes validation and characterization both in vitro on cellular model 

and in vivo in animal models. These studies are conducted in a complementary way to the neurotransmission 

exploration by SPECT as described above. 


1. Prof .Dr. L. Pourcelot: Specialist of Nuclear Medicine, Professor of Biophysics, Head of Dept of Nuclear 

Medicine and Ultrasound, University-Hospital, Tours. and of the INSERM Unit 316 "Nervous system from fœtus 

to Childhood" (1988-2003); Biomedical Engineering Clinical application of functional imaging in neurology, 

cardiovascular, obstetrics, abdomen, 

Further members of the group: Prof. Dr JL Baulieu, Pr JC Besnard (Specialists of Nuclear Medicine, 

quantification and clinical applications) Dr C Prunier (Neurologist and Specialist of Nuclear Medicine, 

Imaging Parkinson’s and Alzheimer’s Diseases) 

2. Prof. Dr. D. Guilloteau : Professor of Pharmaceutical Biophysic, Radiopharmacist,Head of the team for 

radiopharmaceutical development (INSERM U316) and of the laboratory associated to CEA: Neurotransmission: 

molecular imaging and clinical aspects (LRC 21V). From 2004, will be head of the INSERM Unit” Dynamics 

and pathology of cerebral development”; development of tracers for neurotransmission exploration study of 

neurotransmission in animal models an human during normal and abnormal brain development 

Further members of the group: Pr. Y Frangin, Dr P Emond, Dr S. Mavel : chemistry, radiochemistry; 

development of new molecular imaging probes for both PET and SPET for specific for neurotransmission 

targets. 

3. Dr S. Chalon, Biologist ; Study of monoaminergic neurotransmission by molecular imaging of dopamine and 

serotonin receptors and transporters, in animal models of neurodevelopmental and neurodegenerative 

disorders.Further members of the group:J Vergote, L Garreau , biologists; In Vitro Characterization of the new 

ligands 

4. Pr Dr E. Saliba Neonatologist, Head of neonatology department of University hospital, Tours; Neurotransmission 

related to maternal/foetal infection and hypoxia/ischaemia. Further members of the group Dr P. Castelnau, 

neurologist pediatrician 

5. Pr S Benderbous , Physicist , In charge of the MRI team and probes development. Dr L Barantin, Physicist


specialist of MR sequences. 

References 

Radiopharmaceutical development 

1. Chalon S, Tarkiainen J, Garreau L, Hall H, Emond P, Vercouillie J, Farde L, Dasse P, Varnas K, Besnard JC, Halldin C, Guilloteau D. 

Pharmacological characterization of N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine as a ligand of the serotonin transporter with 

high affinity and selectivity. J Pharmacol Exp Ther. 2003 Jan;304(1):81-7. 

2. Emond P, Vercouillie J, Innis R, Chalon S, Mavel S, Frangin Y, Halldin C, Besnard JC, Guilloteau D. Substituted diphenyl sulfides as selective 

serotonin transporter ligands: synthesis and in vitro evaluation. J Med Chem. 2002 Mar 14;45(6):1253-8. 

3. Emond P, Helfenbein J, Chalon S, Garreau L, Vercouillie J, Frangin Y, Besnard JC, Guilloteau D. Synthesis of tropane and nortropane 

analogues with phenyl substitutions as serotonin transporter ligands. Bioorg Med Chem. 2001 Jul;9(7):1849-55. 

4. Chalon S, Garreau L, Emond P, Zimmer L, Vilar MP, Besnard JC, Guilloteau D.Pharmacological characterization of (E)-N-(3-iodoprop-2- 

enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)n ortropane as a selective and potent inhibitor of the neuronal dopamine transporter. J 

Pharmacol Exp Ther. 1999 Nov;291(2):648-54. 

5. Hall H, Halldin C, Guilloteau D, Chalon S, Emond P, Besnard J, Farde L, Sedvall G. Visualization of the dopamine transporter in the human 

brain postmortem with the new selective ligand [125I]PE2I. Neuroimage. 1999 Jan;9(1):108-16. 

6. Helfenbein J, Sandell J, Halldin C, Chalon S, Emond P, Okubo Y, Chou YH, Frangin Y, Douziech L, Gareau L, Swahn CG, Besnard JC, Farde 

L, Guilloteau D. PET examination of three potent cocaine derivatives as specific radioligands for the serotonin transporter. Nucl Med Biol. 

1999 Jul;26(5):491-9. 

Parkinson’s disease 

1. Prunier C., Bezard E., Montharu J., Mantzarides M., Besnard Jc., Baulieu Jl., Gros C., Guilloteau D., Chalon S.Presymptomatic diagnosis of 

experimental parkinsonism with 123I-PE2I SPECT. Neuroimage 2003,19:106-110. 

2. Prunier C, Payoux P, Guilloteau D, Chalon S, Giraudeau B, Majorel C, TafaniM, Bezard E, Esquerre JP, Baulieu JL. Quantification of 

dopamine transporter by 123I-PE2I SPECT and the non-invasive Logan graphical method in Parkinson's disease.J Nucl Med. 2003;44(5):663- 

70. 

3. Prunier C, Tranquart F, Cottier JP, Giraudeau B, Chalon S, Guilloteau D, De Toffol B, Chossat F, Autret A, Besnard JC, Baulieu JL. 

Quantitative analysis of striatal dopamine D2 receptors with 123 I-iodolisuride SPECT in degenerative extrapyramidal diseases. Nucl Med 

Commun. 2001 Nov;22(11):1207-14. 

Neurodegenerative models 

1. Fernagut PO, Chalon S, Diguet E, Guilloteau D, Tison F, Jaber M. Motor behaviour deficits and their histopathological and functional 

correlates in the nigrostriatal system of dopamine transporter knockout mice. Neuroscience. 2003;116(4):1123-30. 

2. Gouhier C, Chalon S, Aubert-Pouessel A, Venier-Julienne MC, Jollivet C, Benoit JP, Guilloteau D. Protection of dopaminergic nigrostriatal 

afferents by GDNF delivered by microspheres in a rodent model of Parkinson's disease. Synapse. 2002 Jun 1;44(3):124-31. 

3. Barc S, Page G, Barrier L, Garreau L, Guilloteau D, Fauconneau B, Chalon S. Relevance of different striatal markers in assessment of the 

MPP+-induced dopaminergic nigrostriatal injury in rat. J Neurochem. 2002 Feb;80(3):365-74. 

4. Gouhier C, Chalon S, Venier-Julienne MC, Bodard S, Benoit J, Besnard J,Guilloteau D. Neuroprotection of nerve growth factor-loaded 

microspheres on the D2 dopaminergic receptor positive-striatal neurones in quinolinic acid-lesioned rats: a quantitative autoradiographic 

assessment with iodobenzamide. Neurosci Lett. 2000 Jul 7;288(1):71-5. 

5. Chalon S, Emond P, Bodard S, Vilar MP, Thiercelin C, Besnard JC, GuilloteauD. Time course of changes in striatal dopamine transporters and 

D2 receptors with specific iodinated markers in a rat model of Parkinson's disease. Synapse. 1999 Feb; 31(2):134-9. 

MRI Probes 

1. Marchand B, Douek PC, Benderbous S, Corot C, Canet E. Pilot MR evaluation of pharmacokinetics and relaxivity of specific blood pool 

agents for MR angiography. Invest Radiol. 2000 Jan;35(1):41-9. 

2. Kroft LJ, Doornbos J, van der Geest RJ, Benderbous S, de Roos A. Infarcted myocardium in pigs: MR imaging enhanced with slow-interstitialdiffusion 

gadolinium compound P760. Radiology. 1999 Aug;212(2):467-73. 

3. Kroft LJ, Doornbos J, Benderbous S, de Roos A. Equilibrium phase MR angiography of the aortic arch and abdominal vasculature with the 

blood pool contrast agent CMD-A2-Gd-DOTA in pigs. J Magn Reson Imaging. 1999 Jun;9(6):777-85.


Partner 5: Barcelona (A. Planas) 

Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain 

We have set a local network of different institutions and laboratories that comprise well-established expertises in a variety of 

experimental animal models for human diseases, together with a new positron emission tomography center that will be operating 

from 2004. The positron emission tomography center is equipped with a micro-PET for small animals (Concorde microsystems 

Rodent 4R), a cyclotron (IBA Cyclone 18/9 with 6 targets: 18 FDG, F2, 11 C, 15 O and 13 N), and laboratories for radiosynthesis (3 

analytical HPLC systems equipped with DAD and fluorescence detectors, 1 GC-MS system, 1 LC-MS system, 2 preparative HPLC 

system, radio-TLC, ß + detectors coupled to all chromatographic systems, 1 HPLC system equipped with conductivity and 

electrochemical detectors). In addition, one of the groups of our local network has expertise in instrumentation physics and image 

analysis. The animal models that we have available are essentially for the study of neurological diseases including cerebral 

ischemia (transient or permanent focal ischemia in rats and mice by occlusion of the middle cerebral artery with intraluminal 

techniques and thrombus injection, and transient global ischemia), Alzheimer’s Disease (single APP transgenic mice, double APP 

and tau transgenic mice, and double transgenic mice overexpressing huAPP SFAD and Hu PS2 mut N1411, which develop 

amyloid-β Alzheimer-like plaques), Parkinson’s Disease (mice overexpressing α-synuclein, local lesions of the substantia nigra 

pars compacta in rodents), Huntington’s Disease (mice overexpressing huntingtin, models of excitotoxic brain lesions) and prionrelated 

diseases (non-infectious mice overexpressing PrP protein), depression and schizophrenia (examination of brain circuits 

involved in the therapeutic action of antidepressants and antipsychotic drugs), drug-addiction (cannabinoid dependence as well as 

the affective disorders, such as anxiety and depression, that could be related to drug dependence by using a biochemical and 

behavioural model of cannabinoid withdrawal in mice and knockout mice lacking different receptors -mu-opioid receptor, deltaopioid 

receptor, kappa-opioid receptor, mu/kappa-opioid receptors, D2 dopaminergic receptor, CB-1receptor- and transcription 

factors -CREM, CREBalpha/delta, inducible null CREB-), adrenomyeloneuropathy (genetically modified mice developing this 

pathology), spinal cord injury (spinal cord sectioning), epilepsy and ataxia (systemic or local administration of excitotoxins in 

rodents) and also experimental models of atherosclerosis (Apo-E knockout mice). The teams working with these animal models 

perform basic research studies on: 1) molecular aspects of the diseases including gene expression and signal transduction pathways 

involved in neuronal cell death and glial reactivity, 2) neurotransmitter alterations, and 3) therapeutics, including pharmacological 

intervention and cell transplantation (ensheating glial cells from the olfactory bulb, and stem cells). For these studies we have close 

collaborations with international research groups working on different aspects of the animal models for human diseases. The aim of 

the Barcelona local network is to take advantage of these expertises and tools in a large variety of well-developed experimental 

models of human neurological diseases and direct them towards imaging studies (positron-based imaging with micro-PET, and 

other imaging techniques in collaboration with the other partners within the European Network). This effort will allow 

investigating imaging strategies in animal models of human diseases as a pre-clinical step towards imaging in patients for 

diagnosis. 


Expertise 

1. Dr. Anna M. Planas: Neurobiologist, Head of the Laboratory for Experimental Cerebral Ischemia; expertises in the use of 

animal models of neurological diseases for studying radiotracer molecules suitable for PET imaging. 

Further members of the group: Dr. V. Petegnief (neural cell cultures, excitotoxic lesions); Dr. C. Justicia (rodent models 

of cerebral ischemia). 

2. Dr. Coral Sanfeliu: Neurobiologist, Head of the Laboratory of Cell Cultures; human and rodent cultures; cellular models of 

neurodegenerative diseases and neurotoxicity. 

Further members of the group: Dr. R. Cristòfol (neural cell cultures, brain slices). 

3. Dr. Joan Serratosa: Neurobiologist; Head of the Laboratory of Experimental Neurobiology; neural cell cultures, β-amyloid cell 

exposure, cellular and animal model of Alzheimer’s disease, myelinisation, excitotoxic lesions. 

Further members of the group: Dr. J. Saura (neurobiologist, glial reactions, experimental studies on Alzheimer’s disease); 

Dr. J. Tusell (neurochemist, microglial reactions); Dr. C. Solà (neurobiologist, microglial-astroglial cell interactions, 

alterations in Alzheimer’s disease). 

4. Prof. Francesc Artigas: Neurochemist, Head of the Department of Neurochemistry; animal models for the validation of PET 

methods to measure changes in the active fraction of 5-HT in brain using displacement of selected ligands from the main 5-HT 

receptors (5-HT 1A and 5-HT 2A ); serotoninergic and dopaminergic neurotransmission; pharmacological intervention. 

Further members of the group: Dr. A. Adell (neurobiologist; in vivo cerebral microdialysis, serotoninergic 

neurotransmission); Dr. P. Celada (neurobiologist; single unit recordings, autoradiography). 

5. Dr. Emili Martínez: Neurochemist, analytical chemistry and behavioural analysis, Head of the team Biochemical markers of 

brain damage in animal models of neurological diseases. 

Further members of the group: Dr. M L. Camón (neurobiologist, kinetic studies and immunohistochemistry); Dr. N. de 

Vera, MD, PhD (Neurobiologist, experimental surgery and biochemical techniques). 

6. Dr. Jordi Alberch: Neurobiologist, Head of the Laboratory of Neurobiology and Cellular Biology; disturbancies in the basal 

ganglia, striatal cell cultures, grafting of genetically modified cells that secrete growth factors, stem cell therapy, genetically 

modified animals as models for studying Parkinson’s and Huntington’s diseases. 

Further members of the group: Dr. E. Pérez-Navarro (neurobiologist, excitotoxic lesions in rodents and cell grafting for


the study of basal ganglia alterations, striatal neural cell cultures, signal transduction); Dr. J. Canals (neurobiologist, stem 

cell transplantation, genetically modified animals). 

7. Dr. Domènec Ros: Physicist, Head of the team on Biomedical Image Processing, Biophysics and Bioengeenering Laboratory; 

physics, software development, Monte Carlo simulation, SPECT and PET reconstruction. 

Further members of the group: Dr. C. Falcon (physicist; MRI, fMRI). 

8. Dr. Javier Pavia: Physicist, Nuclear Medicine Service; SPECT and PET instrumentation, software development, data 

processing. 

9. Dr. Pablo Garcia de Frutos: Head of the group of Experimental Cardiovascular Research; atherosclerosis, coagulation and 

inflammation. 

10. External Researchers from different Institutions in Barcelona: 

• Prof. Isidre Ferrer: MD, PhD, neuropathologist, Head of the Institut de Neuropatologia, Hospital de Bellvitge, Professor of 

Pathology at the University of Barcelona; neural cell death in neuropathological diseases, signal transduction pathways, 

animal models for neurological diseases including genetically modified mice (Parkinson’s, prion-related pathologies, 

adrenomyeloneuropathy, Alzheimer’s disease, cerebral ischemia, and others). 

• Prof. Rafael Maldonado: Neurobiologist, Head of the Laboratory of experimental drug-addiction, IMIM; opioid and 

cannabinoid dependence, affective disorders (anxiety and depression) that could be related to drug dependence, knockout 

mice lacking different receptors (mu-opioid receptor, delta-opioid receptor, kappa-opioid receptor, mu/kappa-opioid 

receptors, D2 dopaminergic receptor, CB-1receptor) and transcription factors (CREM, CREBalpha/delta, inducible null 

CREB), biochemical and behavioural model of cannabinoid withdrawal in mice, relationships between affective disorders 

and drug dependence (behavioural models of anxiety). 

• Prof. Xavier Navarro: MD, PhD, Head of the Group of Neuroplasticity and Regeneration, Institue of Neurosciences, 

Universitat Autonoma de Barcelona, Bellaterra. Repair of peripheral nerves and spinal cord injuries, glial cell cultures, 

stem cells, cell transplantation, grafting of genetically modified cells that secrete neurotrophic and neurotropic factors, 

electrophysiological analyses. 

Further members of the group: Dr. E. Verdú (PhD, ensheating glial cell therapy in experimental models of spinal cord 

injury); Dr. F.J. Rodríguez (PhD, stem cells, cell engineering, grafting of modified cells). 

References 

Cerebral ischemia 

1. Justicia C, Panés J, Solé S, Cervera A, Deulofeu R, Chamorro A, Planas AM. Neutrophil infiltration increases matrix metalloproteinase-9 in the 

ischemic brain after occlusion/reperfusion of the middle cerebral artery in rats. J Cereb Blood Flow Metab 2003; (in press) 

2. Planas AM, Justicia C, Friguls B, Solé S, Cervera A, Adell A, Chamorro A. Certain forms of matrix metalloproteinase-9 accumulate in the 

extracellular space after microdialysis probe implantation and middle cerebral artery occlusion/reperfusion. J Cereb Blood Flow Metab 2003; 

22:918-925 

3. Petegnief V, Friguls B, Sanfeliu C, Suñol C, Planas AM. Transforming growth factor-α attenuates NMDA toxicity in cortical cultures by 

preventing protein synthesis inhibition through an Erk1/2-dependent mechanism. J Biol Chem 2003; 278:29552-29559 

4. Friguls B, Petegnief V, Justicia C, Pallàs M, Planas AM. Activation of ERK and Akt signaling in focal cerebral ischemia: modulation by TGFα 

and involvement of NMDA receptor. Neurobiol Dis. 2002; 11:443-456 

Alzheimer’s Disease 

1. Ferrer I. Differential expression of phosphorylated translation initiation factor 2 alpha in Alzheimer's disease and Creutzfeldt-Jakob's disease. 

Neuropathol Appl Neurobiol. 2002 ;28, 441-51 

2. Ferrer I, Blanco R, Carmona M, Puig B. Phosphorylated mitogen-activated protein kinase (MAPK/ERK-P), protein kinase of 38 kDa (p38-P), 

stress-activated protein kinase (SAPK/JNK-P), and calcium/calmodulin-dependent kinase II (CaM kinase II) are differentially expressed in tau 

deposits in neurons and glial cells in tauopathies. J Neural Transm. 2001;108, 1397-415. 

3. Ferrer I, Blanco R, Carmona M, Puig B. Phosphorylated c-MYC expression in Alzheimer disease, Pick's disease, progressive supranuclear 

palsy and corticobasal degeneration. Neuropathol Appl Neurobiol. 2001 ;27, 343-51. 

Depression and Schizophrenia 

1. Puig MV, Celada P, Díaz-Mataix L, Artigas F. In vivo modulation of the activity of pyramidal neurons in the rat medial prefrontal cortex by 5- 

HT 2A receptors. Relationship to thalamocortical afferents Cereb Cortex 2003; 13: 870-882 

2. Artigas F, Celada P, Laruelle M, Adell A. How does pindolol improve antidepressant drug action? Trends Pharmacol Sci 2001; 22:224-228 

3. Celada P, Puig MV, Casanovas JM, Guillazo G, Artigas F. Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: 

involvement of serotonin-1A, GABA A and glutmate receptors. J Neurosci 2001; 21: 9917-9929 

4. Martín-Ruiz R, Puig MV, Celada P, Shapiro D, Roth BL, Mengod G, Artigas F. Control of serotonergic function in medial prefrontal cortex by 

serotonin-2A receptors through a glutamate-dependent mechanism. J Neurosci 2001; 21, 9856-9866 

Drug-addiction 

1. Maldonado R, Rodriguez de Fonseca F. Cannabinoid addiction: behavioral models and neural correlates. J Neurosci 2002; 22, 3326-3321. 

2. Maldonado R. Study of cannabinoid dependence in animals. Pharmacol & Therap. 2002, 95, 153-164. 

3. Berrendero F, Kieffer B L, Maldonado R. Lack of nicotine-induced antinociception, rewarding effects and dependence in mu-opioid receptor 

knockout mice. J Neurosci 2002; 22, 10935-10940. 

4. Navarro M, Carrera MRA, Fratta W, Valverde O, Cossu G, Fattore L, Chowen JA, Gomez R, Del Arco I, Villanua MA, Maldonado R, Koob 

GF, Rodriguez de Fonseca F. Functional interaction between opioid and cannabinoid systems in addiction. J Neurosci 2001; 21: 5344-50 

5. Maldonado R, Saiardi A, Valverde O, Samad TA, Roques BP, Borrelli E. Absence of opiate rewarding effects in mice lacking dopamine D2 

receptors. Nature 1997; 388, 586-589. 

Neural cell cultures : neurotoxicity assays, glial response to injury, cell therapy 

1. Verdu E, Garcia-Alias G, Fores J, Lopez-Vales R, Navarro X. Olfactory ensheathing cells transplanted in lesioned spinal cord prevent loss of 

spinal cord parenchyma and promote functional recovery. Glia 2003; 42, 275-286 

2. Sánchez-Font M.F, Sebastià J, Sanfeliu C, Cristòfol R, Marfany G, Gonzàlez-Duarte R. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, is 

under-expressed in Down Syndrome (DS) fetal brains. Cell Mol Life Sci 2003; 60, 1513-1523 

3. Saura, J, Josep Tusell JM, Serratosa J. High-Yield Isolation of Murine Microglia by mild trypsinization. Glia 2003 (in press) 

4. Pérez-Capote K, Serratosa J, Solà C.Glial activation modulates glutamate neurotoxicity in cerebelar granule cell cultures. Glia 2003 (in press)


5. Massaguer A, Perez-Del-Pulgar S, Engel P, Serratosa J, Bosch J, Pizcueta P. Concanavalin-A-induced liver injury is severely impaired in mice 

deficient in P-selectin. J Leukocyte Biol 2002; 72:262-270 

Hungtinton’s disease, Epilepsy, Ataxia 

1. Marco S, Perez-Navarro E, Tolosa E, Arenas E, Alberch J. Striatopallidal neurons are selectively protected by neurturin in an excitotoxic 

model of Huntington's disease. J Neurobiol 2002; 50, 291-304 

2. Checa N, Canals JM, Gratacos E, Alberch J. TrkB and TrkC are differentially regulated by excitotoxicity during development of the basal 

ganglia. Exp Neurol 2001; 172, 282-292 

3. Gratacos E, Perez-Navarro E, Tolosa E, Arenas E, Alberch E. Neuroprotection of striatal neurons against kainate excitotoxicity by neurotrophins 

and GDNF family members. J Neurochem 2001; 78, 1287-1296 

4. Camón L, de Vera N, Martinez E. Polyamine metabolism and glutamate receptor agonists-mediated excitotoxicity. J Neurosci Res 2001; 

66,1101-11 

5. Ferrer I, Blanco R. N-myc and c-myc expression in Alzheimer disease, Huntington disease and Parkinson disease. Mol Brain Res. 

2000;77,270-6. 


1. Saura J, Pares M, Bove J, Pezzi S, Alberch J, Marin C, Tolosa E, Marti J. Intranigral infusion of interleukin-1β activates astrocytes and protects from 

subsequent 6-hydroxydopamine neurotoxicity. J Neurochem 2003; 85, 651-661, 2003 

2. Marco S, Saura J, Perez-Navarro E, Marti MJ, Tolosa E, Alberch J. Regulation of c-Ret, GFRα1 and GFRα2 in the substantia nigra pars 

compacta in a rat model of Parkinson’s disease. J Neurobiol 2002; 52, 343-351 

3. Vivó M, Camón L, de Vera N, Martínez E. Lesion of substantia nigra pars compacta by the GluR5 agonist ATPA. Brain Res 2002; 955,104-14 

4. Ferrer I, Blanco R, Carmona M, Puig B, Barrachina M, Gomez C, Ambrosio S. Active, phosphorylation-dependent mitogen-activated protein 

kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson's disease 

and Dementia with Lewy bodies. J Neural Transm. 2001;108, 1383-96. 

5. Ferrer I, Blanco R, Cutillas B, Ambrosio S. Fas and Fas-L expression in Huntington's disease and Parkinson's disease. Neuropathol Appl 

Neurobiol. 2000;26, :424-33. 

Prion-related Diseases 

1. Ferrer I. Synaptic pathology and cell death in the cerebellum in Creutzfeldt-Jakob disease. Cerebellum 2002;1, 213-22. 

2. Ferrer I, Puig B, Blanco R, Marti E. Prion protein deposition and abnormal synaptic protein expression in the cerebellum in Creutzfeldt-Jakob 

disease. Neuroscience 2000; 97, 715-26. 

3. Ferrer I, Rivera R, Blanco R, Marti E. Expression of proteins linked to exocytosis and neurotransmission in patients with Creutzfeldt-Jakob 

disease. Neurobiol Dis. 1999;6:92-100. 

4. Ferrer I. Nuclear DNA fragmentation in Creutzfeldt-Jakob disease: does a mere positive in situ nuclear end-labeling indicate apoptosis? Acta 

Neuropathol (Berl). 1999 ;97, 5-12. 

Spinal cord injury 

1. Garcia-Alias G, Verdu E, Fores J, Lopez-Vales R, Navarro X. Functional and electrophysiological characterization of photochemical graded 

spinal cord injury in the rat. J Neurotrauma 2003; 20, 501-10. 

2. Verdu E, Garcia-Alias G, Fores J, Vela JM, Cuadras J, Lopez-Vales R, Navarro X. Morphological characterization of photochemical graded 

spinal cord injury in the rat. J Neurotrauma 2003; 20, 483-99. 

3. Navarro X, Rodríguez FJ, Cevallos D, Verdu E. Engineering an artificial nerve graft for the repair of severe nerve injuries. Med Biol Eng 

Comput. 2003;41, 220-6. 

Cardiovascular research 

1. Angelillo-Scherrer A, García de Frutos P, Aparicio C, Melis E, Savi P, Lupu F, Arnout J, Dewerchin M, Hoylaerts M, Herbert J, Collen D, 

Dahlbäck B, Carmeliet P. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against trombosis. Nature Medicine 

2001; 7, 215-221.. 

2. Espinosa-Parrilla Y, Yamazaki T, Sala N, Dahlbäck B, García de Frutos P. Protein S secretion differences in missense mutants account for 

phenotypic heterogeneity. Blood 2000; 95, 173-179. 

3. Lutgens E, Moons L, García de Frutos P, Aparicio C, Janssen A, Duimel H, Blankensteijn M, Borgers M, Dahlbäck B, Collen D, Daemen M, 

Carmeliet P. Absence of Growth Arrest Specific gene 6 (Gas6) causes increased hemorrhage in atherosclerosis, myocardial infarction and after 

LPS-footpad injection. Circulation Research, submitted. 

4. Evenäs P, Dahlbäck B, García de Frutos P. The first laminin G-type-domain in the SHBG-like region of protein S contains essential residues 

for activation of the receptor tyrosine kinase Sky. Biol Chem 2000; 381,199-209. 

Instrumentation Physics. Image analysis. 

1. Bullich S, Ros D, Cot A, Falcon C, Muxí A, Pavía J. Dynamic model of the left ventricle for use in simulation of myocardial perfusion 

SPECT and gated SPECT. Med Phys 2003; 30, 8:1968-1975. 

2. Pareto D, Cot A, Pavía J, Falcón C, Juvells I, Lomeña F, Ros D. Iterative reconstruction with correction of the spatially variant fan-beam 

collimator response in neurotransmission SPET imaging. Eur J Nucl Med Mol Imaging 2003; 30:1322-1329. 

3. Cot A, Sempau J, Pareto D, Bullich S, Pavía J, Calviño F and Ros D. Evaluation of the geometric, scatter and septal penetration components 

in fan beam colimators using Monte Carlo simulation. IEEE Trans Nucl Sci 2002; 49:12-16. 

4. Pareto D, Pavía J, Falcón C, Juvells I, Cot A, Ros D. Characterisation of fan-beam collimators. Eur J Nucl Med 2001; 28:144-149.


Partner 6: Milano (A. Maggi) 

Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan Italy 

Animal engineering 

The Center of Excellence of the University of Milan was founded by the Ministry of public Health in 2001. The aim 

of the center is to foster multidisciplinary research on the molecular basis of neurodegenerative diseases to study 

innovative diagnostic tools and therapies. The Center of Excellence has established a technological platform on 

animal and cell engineering that will be involved in the present project. In the past years the technological platform 

has been concentrating on the generation of cellular and animal models for “in vivo” detection of gene expression and 

on the development of novel concepts for animal transgenesis. Initially, we focussed on means to generate transgenes 

allowing ubiquitous expression of selected reporter genes. As a proof of principle we generated a reporter mouse to 

monitor the activity of estrogen receptors (ER) by whole mouse optical imaging . The results obtained indicate that 

the generated plasmid system is suitable for obtaining the ubiquitous expression of a selected gene marker, and using 

the technology generated we are constructing a series of mice suitable for the in vivo detection of the activity of 

intracellular receptors. We are presently generating a series of second-generation vectors (and transgenic animals) 

using reporters suitable for PET imaging analysis (dopamine D 2 receptor and thymidine kinase genes). In this secondgeneration 

vector project, by using IRES sequences, the same promoter will transcribe bicistronic mRNA coding for 

two different reporters. The expression of two reporter genes will be monitored at the same time using two different 

methodologies (e.g., by photon imaging on expressed luciferase enzyme and PET scanning on the dopamine D 2 

receptor). Most importantly, all these vectors are made with a cassette strategy in order to extend their utility to any 

transcription factor or any imaging methodology, simply by exchanging the promoter or reporter of use. 

Brain inflammation 

In the last few years we have studied the role of glia in glutamate signaling and in the mechanisms of microglia 

activation and regulation. In particular, we have discovered a TNFalpha- and prostaglandin-dependent glutamate 

release process from glial cells which is critical in normal brain communication but, when de-regulated, may also 

cause neurodegeneration. Indeed, we have directly demonstrated its relevance to the development of AIDS 

neuropathology. 

Based on this background, our group is currently investigating, by using in vitro and in vivo complementary 

approaches, whether glia actively participate to the cascade of events leading to neuronal death in amyotrophic lateral 

sclerosis (ALS) and prion diseases. In particular, mice expressing the ALS-linked mutant SOD1 G93A enzyme 

[Tg(SOD1-G93A)] are available in the lab and are presently being used either as a source of brain cell cultures for in 

vitro mechanistic studies or for crossings to various cytokines or cytokine receptor knockout animals (e.g. TNF -/- ) to 

study the impact of a null proinflammatory cytokine background on disease progression. In parallel, we plan to study 

the dynamics of astroglial alterations during disease progression by mating Tg(SOD1-G93A) animals to mice 

expressing the enhanced green fluorescent protein (eGFP) under the control of the human glial fibrillary acidic protein 

(GFAP). 

With regard to the mechanisms of microglia activation, we have recently proved that estradiol may prevent microglia 

activation and we are in the process of studying the molecular mechanisms underlying this effect and its relevance in 

neurodegenerative disorders like Alzheimer’s. disease (AD). To this aim we are utilizing APP23 transgenic mice has 

been previously described . These mice express the human APP751 cDNA with the Swedish double mutation under 

control of the neuron-specific mouse Thy-1 promoter fragment. Overexpression of the mutated form of APP leads to 

the formation of the typical neuropahtologic signs of AD, with β-amiloid deposits rich in hyperphosphorylated Tau 

proteinFor the future research we plan to generate two reporter animals to study brain inflammatory processes. The 

first will be a reporter mouse expressing ubiquitously a reporter to monitor for the activity of peroxisome proliferator 

receptors (PPAR). This will represent a valuable model for the study of drugs potentially useful in the treatment of 

adenoleukodystophy and a double reporter mouse for activation of a transcription factor associated to inflammatory 

processes. Such promoter will direct the transcription of a single transcript coding for two reporter genes with IRES 

(ribosome entry) sequences interposed between them. As reporter genes, we will utilize a gene encoding a fluorescent 

protein (GFP or its mutants) and a gene encoding a protein able to bind labelled radioligands (either viral timidine 

kinase (TK) or mutated dopamine D2 receptor lacking signal-transduction capabilities). The two reporter genes are 

suited to detect inflammatory processes by in vivo imaging with different technologies, two-photon and PET/SPECT. 

Animal PET with radioligands for either the TK or the D2 gene has been already successfully performed 

Scientific Staff Expertise


1. Prof. Dr. A.Maggi: Director of the Center of Excellence on Neurodegenerative Diseases, University of Milan 

2. Prof.A.Volterra, Professor of Pharmacology, Center of Excellence on Neurodegenerative Diseases and Dept. Of 

Pharmacological Sciences University of Milan (Pharmacologist expert in glia-neurons interaction) 

3. Prof. G.Lucignani M.D., responsible for the PET unit 

4. Dr. Giulia Chiesa, Assistant Professor in Pharmacology (responsible for the transgenic animal unit) 

5. Dr. Elisabetta Vegeto, Assistant Professor in Pharmacology (expert in cell engineering) 

6. Dr. Paolo Ciana, researcher (biologist, specialized in animal genetics, expert in vector construction) 

7. Dr.Vet. Paolo Sparaciari (M.D. Vet. Responsible for the generation and phenotyping of the transgenic animal 

colonies) 

8. Dr. Daniela Rossi, researcher (generation of transgenic mice) 

9. Dr. L. Ottobrini, Biotechnologist, construct generation 

10. M. Rebecchi, technician of the molecular biology unit 

11. C. Meda, technician of the cell biology unit 

12. Dr. Michele Raviscioni, biotechnologist expert in bioinformatics 

13. Dr. Paola Mussi, biotechnologist, expert in animal engineering 

14. Dr. Andrea Biserni, biotechnologist, expert in animal engineering 

15. Dr. S.Ghisletti, biotechnologist, expert in cell engineering 

16. Dr. S. Etteri, biotechnologist, expert in animal engineering 

References 

1. Patrone C., Cassel T.N., Petterson K., Ciana P., Maggi A., Warner M., Gustafsson J-A., Nord M. Estrogen regulates lung homeostasis via 

estrogen receptor-beta. J Mol Cell Biol, in press 

2. Maggi A., Ciana P., Belcredito S. and Vegeto E. Estrogens in the nervous system: mechanisms and non reproductive functions, Annual 

Review of Phvsiology, in press 

3. Ciana P., Raviscioni M., Mussi P., Vegeto E., Mussi P., Que I., Parker M., Lowik C. and Maggi A. In vivo imaging of transcriptionally 

active oestrogen receptor, Nature Medicine, 2003; 9: 82 – 86 

4. Flechsig E, Hegyi I, Leimeroth R, Zuniga A, Rossi D, Cozzio A, Schwarz P, Rulicke T, Gotz J, Aguzzi A, Weissmann C. Expression of 

truncated PrP targeted to Purkinje cells of PrP knockout mice causes Purkinje cell death and ataxia. EMBO J. 2003; 22(12):3095-101 

5. Vegeto E., Belcredito S., Etteri S., Ghisletti S., Brusadelli A., Meda C., Krush, Dupont, Ciana P., Chambon P., and Maggi A. Erα mediates 

the brain anti-inflammatory ativity of estradiol. Proc Natl Acad Sci U S A. 2003; 100: 9614-9. Epub 2003 Jul 23 

6. Weissman C., Eissman C., Enari M., Klohn PC, Rossi D, Flechsig E. Transmission of prions. 

Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16378-83. Epub 2002 Aug 14 

7. Ciana P., Vegeto E., Beato M., Chambon P., Gustaffsson J-Å., Parker M., Wahli W. and Maggi A. Looking at nuclear receptors from the 

hights of Erice, EMBO Reports, 2002; 31: 125-129, 2002 

8. Vegeto E., Ciana P. and Maggi A. Estrogen and inflammation: hormone generous action spreads to the brain, Mol Psychiatry, 2002; 7: 236- 

238 

9. Klotz D.M., Curtis Hewitt S., Ciana P., Raviscioni M., Lindzey J. K., Foley J., Maggi A., Diaugustine R. P. and Korach K.S. Requirement of 

estrogen receptor-α in insulin-like growth factor-1-induced uterine responses and in vivo evidence for insulin-like growth factor-1/estrogen 

receptor cross-talk, J Biol Chem 2002; 277: 8531-8537 

10. Vegeto E., Bonincontro C., Pollio G., Sala A., Viappiani S., Nardi F., Brusadelli A., Viviani B., Ciana P. and Maggi A. Estrogen prevents 

the LPS-induced inflammatory response in microglia, J Neurosci 2001; 21(6):1809-1818 

11. Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A. CXCR4- 

activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 2001; 4:702-10. 

12. Ciana P., Di Luccio G., Belcredito S., Pollio G., Vegeto E., Tatangelo L., Tiveron C. and Maggi A. Engineering of a mouse for the in vivo 

profiling of estrogen receptor activity, Mol Endocrinol, 2001; 15(7): 1104-1113 

13. Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A. Prostaglandins stimulate calcium-dependent glutamate 

release in astrocytes. Nature 1998; 391:281-5. 

14. Patent request n. MI2000A 001503 04/07/2000; extension PCT/EP 01/07622 entitled “A transgenic mouse for the screening and for the 

study of the pharmacokinetic and pharmacodinamics of ligands active throug estrogen receptor and intracellular receptors. –Methods for its 

preparation”.


Partner 7: Copenhagen (G. Knudsen) 

Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark 

Copenhagen University has a local network of different laboratories that are involved with clinical and experimental 

neuroscience research as well as brain imaging with PET, SPECT, and MRI. The university hospitals Rigshospitalet 

and Hvidovre Hospital have two high-resolution PET-scanners (GE, Advance, Advance/CT), a GE4096, two 1.5 T 

and one 3T MR-scanner. Funding for an experimental PET-scanner is currently applied for. 

Research areas include image analysis (coregistration, region-of-interest delineation, partial volume correction, 

kinetics), radiochemistry, neurodegenerative diseases, neuropsychiatric disorders (mood disorders, Tourettes 

syndrome, obsessive-compulsive disorder). 

NRU bridges between basic research and clinical neurobiology, focussing on basic pathophysiological and 

physiological aspect of, in particular, neurotransmission. NRU is a part of the Department of Neurology, the 

Neuroscience Center, and has close interactions with the PET- and Cyclotron Unit at Rigshospitalet, Hvidovre MRdepartment, 

and the Department of psychiatry, H. Lundbeck A/S, and NeuroSearch. Furthermore, NRU has close 

collaborations with international research groups (EU-Groups involved in the two European funded programs: NCI- 

MCI and PVEout; furthermore: National Cardiovascular Center Research Institute, Osaka, and Veterans Affairs San 

Diego Healthcare System, San Diego). 


1. Prof. Dr. Gitte Moos Knudsen: Neurologist and head of the NRU Molecular Imaging group, neuropsychiatric 

disorders. 

Further members of the group: Dr. Lars Pinborg (MD, evaluation of new probes, quantification); Dr. Steven 

Haugbol (MD, imaging in Tourettes syndrome by PET); Vibe Frokjaer (MD, serotonergic transmitter system 

in early AD and depression); Birgitte Rahbeck (human biologist; development of a pig model of AD); 4 

technicians. 

2. Dr. Claus Svarer: Civil engineer, Image analysis and tracer kinetics, software development. 

Further members of the group: Esben Hoegh-Rasmussen (engineer, reconstruction algorithms for PET-data 

analysis), Robin de Nijs (physicist, optimization of SPECT-methodology), Thomas Rask (engineer bachelor, 

software development for image analysis) 

3. Dr. Susana Aznar: Biologist, experimental studies of neuroreceptor anatomy and interaction, correlation of PET 

data with histological findings. 

Further member of the group: Viktorija Kostova, human biologist (animal models of depression) 

4. Prof. Dr. Olaf Paulson: Neurologist and head of the Hvidovre Hospital MR-department, clinical neurobiology. 

5. Dr. Lars Hanson: Physicist, MR-instrumentation and methodology development 

6. Dr. Nic Gillings and Dr. Jacob Madsen: Radiochemists, tracer development 

7. Dr. Steen Hasselbalch and Professor Gunhild Waldemar: Neurologists, early diagnosis of Alzheimer’s disease and 

differential diagnosis from other forms of dementia by molecular imaging 

8. Dr. Ian Rowland: Chemist, use of magnetically labelled peptides to image/target inflammatory cells, chelates with 

amino acids/peptides attached for enzyme dependent contrast in MRI, intracellular delivery of DNA etc using 

electroporation, MR guided gene therapy. 

References 

Data Analysis and Kinetics 

1. Liptrot M, Adams KH, Martiny L, Pinborg LH, Lonsdale MN, Olsen NV, Holm S, Svarer C, Knudsen GM: Cluster analysis in kinetic 

modelling of the brain: a non-invasive alternative to arterial sampling. NeuroImage (Accepted). 

2. Pinborg LH, Adams KH, Svarer C, Holm S, Hasselbalch SG, Haugbol S, Madsen J, Knudsen GM: Quantification of 5HT2A receptors in the 

human brain using [18F]altanserin-PET and the bolus/infusion approach. J Cereb Blood Flow Metabol 2003;23:985-96. 

3. Pinborg LH, Videbok C, Svarer C, Yndgaard S, Paulson OB, Knudsen GM: Quantification of [ 123 I]PE2I binding to dopamine transporters with 

SPECT. Eur J Nucl Med 2002;29:623-31. 

4. Videbok C, Toska K, Friberg L, Holm S, Angelo HR, Knudsen GM: In vivo measurement of haloperidol affinity to dopamine D2/D3 receptors 

by [ 123 I]IBZM and SPECT. J Cereb Blood Flow Metabol 2001;21:92-7 

5. Pinborg LH, Videbok C, Knudsen GM, Swahn C-G, Halldin C, Paulson OB, Lassen NA: Dopamine D2 receptor quantification in extrastriatal 

brain regions using [ 123 I]epidepride with bolus/infusion. Synapse 2000;36:322-329. 

Radiochemistry and Tracer Evaluation 

1. Madsen J, Merachtsaki P, Davoodpour P, Bergstrom M, Langstrom B, Andersen K, Thomsen C, Martiny L, Knudsen GM. Synthesis and 

biological evaluation of novel carbon-11-labelled analogues of citalopram as potential radioligands for the serotonin transporter. Bioorg Med 

Chem 2003;11:3447-3456. 

2. Elfving B, Bjornholm B, Knudsen GM: Interference of anaesthetics with radioligand binding in neuroreceptor studies. Eur J Nucl Med 

2003;30:912-5. 

3. Elfving B, Bjornholm B, Knudsen GM: Predosing with the unlabeled inactive enantiomer as a tool for improvement of the PET signal. Synapse 

2002;46:125-127. 

4. Elfving B, Bjornholm B, Ebert B, Knudsen GM: Binding characteristics of selective serotonin reuptake inhibitors with relation to emission 

tomography studies. Synapse 2001;41:203


5. Videbok C, Toska K, Scheideler MA, Paulson OB, Knudsen GM: The SPECT tracer [ 123 I]IBZM has similar affinity to dopamine D2 and D3 

receptors. Synapse 2000;38:338-42 

6. Videbok C, Ott P, Paulson OB, Knudsen GM: Blood-brain barrier transport and protein binding of flumazenil and iomazenil in the rat: 

implications for neuroreceptor studies. J Cereb Blood Flow Metabol 1999;19:948-55. 

MR Imaging Methodology 

1. Murphy PS, Rowland IJ, Viviers L, Brada M, Leach MO, Dzik-Jurasz ASK. Could assessment of the glioma methylene lipid resonance by invivo 

1H-MRS be of clinical value? Br J Radiol 2003;76:459–63 

2. Murphy PS, Leach MO, Rowland IJ. The Effects of Paramagnetic Contrast Agents on Metabolite Protons in Aqueous Solution. Phys Med Biol 

2002;47:N53-59 

3. Murphy PS, Dzik-Jurasz ASK, Leach MO, Rowland IJ. The Effect of Gd-DTPA on T 1 -Weighted Choline Signal In Human Brain Tumours. 

Magn Reson Imaging 2002;20:127-30 

4. d'Arcy JA, Collins DJ, Rowland IJ, Padhani AR, Leach MO. Applications of sliding window reconstruction with cartesian sampling for 

dynamic contrast enhanced MRI. NMR Biomed 2002;15:174-83 

Imaging Neurodegenerative Disease 

1. Pinborg LH, Videbok C, Hasselbalch SG, Sρrensen SA, Wagner A, Paulson OB, Knudsen GM: Benzodiazepine receptor quantification in 

Huntington’s disease with [ 123 I]Iomazenil and SPECT. J Neuro Neurosurg Psych 2001;70:657-61. 

Imaging Neuroreceptors by Immunohistochemistry 

1. Aznar S, Qian Z, Knudsen GM: Non-serotonergic dorsal and median raphe projection on parvalbumin- and calbindin-containing interneurons 

in hippocampus and septum. Brain Res (Accepted). 

2. Aznar S, Qian Z, Shah R, Rahbek B, Knudsen GM: The 5-HT 1A serotonin receptor is located on calbindin- and parvalbumin-containing 

neurons in the rat brain. Brain Res 2003;959:58-67. 

3. Aznar S, Knudsen GM: Serotonin induces decrease of 5-HT 1A immunoreactivity in organotypic hippocampal cultures. NeuroReport 

2001;12:3909-3912.


Partner 8: Antwerp (A. vd. Linden) 

Vision-Lab, Bio-Imaging lab, MicroTomography Lab, Laboratory of Cell Biology and Histology, and Digital 

Cell Imaging Labs, University of Antwerp, Belgium 

Various laboratories at the University of Antwerp are focussing on the following items: instrumentation physics, 

image coregistration, -analysis and -reconstruction (Vision-Lab), in vivo MRI and CT (Bio-Imaging lab and 

MicroTomography lab), microscopic in vitro and in vivo imaging: EM, LM, FM, CLSM (Laboratory of Cell 

Biology and Histology) and digital cell imaging for diagnostic automatisation (Digital Cell Imaging Labs). 

The university harbors two dedicated high-resolution micro CT scans (SkyScan, Belgium: in-vitro and in-vivo 

system), a 7T MRI system (MRRS, UK), SEM (Philips SEM515 microscope), TEM (Philips CM10 microscope 

with cryo-EM facilities), several conventional and fluorescence microscopes equipped with image analysis soft- and 

hardware (CAST-grid, AnalySIS, NeuroLucida), CLSM (Zeiss LSM410, including 3D-image reconstructie: Silicon 

Graphics, Imaris software, Huygens), multi-photon microscopy (Zeiss LSM510, upgraded with the META-system), 

Perkin Elmer UltraView microscope (specifically designed for Life cell imaging). 

Digital Cell Imaging Labs has automated scanning station for histopathological slides and cellular samples, 

Scanning software for histopathological slides, cellular samples and multi well plates (Universal Grab Software, 

DCILabs), Image analysis software (dedicated tools for cell counting, neurite outgrowth, marker estimation, 

chromatin analysis, colony counting and nerve regeneration analysis of microscopical slides and well plates). 

The Bio-Imaging lab focusses on brain research, more in particular neurodegeneration and neurogenesis. The lab 

has close collaborations with Belgian UA and KUL partners developing animal models for neurological (F. Van 

Leuven-KUL, C. Van Broeckhoven, UA, F. Kooy UA) and neuro- and cardiovascular (P. Carmeliet, KUL) diseases. 

Future collaborations with these groups involve both phenotyping and therapeutic validations mainly in AD and 

ALS models. The Bio-Imaging lab collaborates also with the Neuroscience Institute in Rotterdam (C. De Zeeuw, B. 

Oostra) on other neuropathological models (Williams and Fragile X syndrome). Concerning neurogenesis the labs 

work on bird brain models in collaboration with J. Balthazart, U Liege. 

The Laboratory of Cell Biology & Histology has many national (KUL, ULB, VUB, UG) and international 

collaborations (University of Leeds, University of Erlangen, University of Olsztyn, University of Munich, 

University of Cologne, University of Utrecht, University of Tokyo, University of St-Petersburg, University of 

Florence, University of London, …) in relation to their main research topics: the autonomic nervous system, the 

enteric nervous system, neuro-immune interactions in intestinal inflammation, cardiology (nitric oxide and oxidative 

stress in ischemic heart diseases and preconditioning), the neuroendocrine system in the lung, cerebellar circuitry 

(Golgi-cells), imaging of protein trafficking (focus on K+-channels), ecotoxicology (visualization of subcellular 

effects of heavy metals) 

The Vision lab collaborates with the Bio-Imaging lab and the Micro Tomography lab on fMRI (functional magnetic 

resonance) data processing, DT-MRI (diffusion tensor) image processing, medical image registration, tractography, 

EEG signal processing. A collaboration with the Vision Lab and Digital Cell Imaging Labs (DCILabs, a spin-off of 

the Vision Lab) ensures expertise of imaging of neurological diseases at the cellular level (e.g. measurement of 

neurite outgrowth and histopathological markers in cellular neuropathological models). 

Scientic Staff 

Expertise 

1. Prof. Dr. Annemie Van der Linden, Biologist, Head of the Bio-Imaging Lab.: Neuro MRI (7T) of anatomical, 

physiological and functional features in order to phenotype transgenic mice models for neurological diseases and 

to study neurogenesis models (songbirds). 

Further members of the group: Dr. M. Verhoye (physicist, sequence development and image processing), 

Ing. J. Van Audekerke (new developments in hard and software of MRI, simulataneous acquisition of MRI, 

EEG), G. Vanhoutte (PhD student Biomedical Sciences, neurovascular MRI studies in animal models), V. 

Van Meir, I. Tindemans and T. Boumans (PhD students Biology, neuroplasticity studies with MRI, 

Manganese Enhanced MRI and fMRI), N. Van Camp (PhD student, Biology, fMRI in animal models). 

2. Prof. Dr. Jean-Pierre Timmermans, Biologist, Head of the Laboratory of Cell Biology & Histology and Vice- 

Chair of the Department of Biomedical Sciences: morphological, pharmacological and (electro)physiological 

studies of the autonomic nervous system under normal and inflammatory conditions. 

Further members of the group: Prof. Dr. Adriaensen (biologist, intrapulmonary neuroendocrine system, 

fluorescent imaging microscopical techniques –immuno, life cell imaging, fret-techniques, two-photon 

microscopy), Prof. Dr. F. Van Meir (biologist, stereology-morphometry techniques), Dr. A. DeLaet 

(biologist, intracellular iontophoretic filling, recording and visualization), Dr. Luc Van Nassauw (biologist, 

confocal microscopy, molecular biology techniques in inflammatory models), Dr. Inge Brouns (biomedical 

sciences, confocal microscopy, life cell imaging, immunotechniques, optical recording,), Frederik De Jonge 

(PhD student Biomedical Sciences, confocal microscopy/two photon/molecular biology techniques/cell 

culturing techniques in an intestinal inflammatory model), C. Moelans (PhD student in Biomedical


Sciences, fluorescence/confocal microscopy and electrophysiology of the upper gastrointestinal tract), I. 

Pintelon (PhD student in Biomedical Sciences, Life cell imaging, immunocytochemistry of intrapulmonary 

oxygen sensing structures and their innervation under normal and pathological conditions), C. Tombeur 

(PhD student in Biomedical Sciences, morphological study of Golgi cells in relation to the cerebral cortex), 

A. Berges (PhS student in Biomedical Sciences, role of endothelial dysfunction in the decreased 

vasodilatory response after myocardial infarction), + 6 technicians. 

3. Prof. Dr. Nora De Clerck, Cardiovascular Physiologist, Research Group Microtomography : Expertise in in-vitro 

and in-vivo microtomography in bones and soft tissue. Collaborator Dr. A. Postnov, Physicist : Expertise in 

image analysis and 3D reconstructions of micro-CT data. 

4. Prof. Dr. Dirk Van Dyck, Physicist, Head of the Vision Lab: dynamical electron diffraction, image simulation, 

processing and interpretation. 

Further members of the group: Prof. Dr. Paul Scheunders (physicist, pattern recognition, wavelet analysis, 

multispectral image processing), Prof. Dr. E. Raman (physicist, thermoregulation, medical imaging), Prof. 

Dr. E. Cornelis (physicist, computer tomography, computer vision), Dr. G. Van de Wouwer (physicist, 

wavelets, texture analysis), Dr. B. Weyn (biologist, microtomography, cell-biology), Dr. J. Sijbers 

(physicist, MR image processing, statistical analysis), Dr. S. Debacker (physicist, pattern recognition, 

multispectral data analysis), Dr. A. J. den Dekker (Engineer, parameter estimation, statistics), E. 

Vandecasteele (PhD student, computer tomography, reconstruction techniques), E. Bogo (PhD student, 

computer tomography, reconstruction techniques), G. Tisson (PhD student, CT, wavelet analysis), A. 

Leemans (PhD student, Diffusion-tensor imaging, 3D image processing), D’Haes Wim (PhD student, 

Informatics, Musical synthesis algorithms), Jaber Juntu (PhD student, engineer, ultrasound, texture 

analysis), Rozema Jos (PhD student, phase contrast imaging, eye research). 

References 


1. Postnov A., De Clerck N., Sasov A., Van Dyck D. 3D in vivo x-ray microtomography of living snails. J Microsc 2002, 205(2): 201-205. 

2. De Clerck N.M., Sasov A., Van Dyck D. Visualization of biological tissues by X-ray microtomography. Eur Biophys J 2000, 29(4): 363. 

3. Boyde A., De Clerck N., Sasov A. MicroCT of bones and soft tissues. Microsc Analysis 2000, 76: 70. 

Image processing for biomedical applications 

1. Sijbers J., den Dekker A.J. Maximum Likelihood estimation of signal amplitude and noise variance from MR data. MRM 2003, submitted. 

2. Van De Casteele E., Van Dyck D., Sijbers J., Raman E. An energy-based beam hardening model in tomography. Physics Med Biol 2002, 

47(23): 4181-4190. 

3. Sijbers J., Vanrumste B., Van Hoey G., Boon P., Verhoye M., Van der Linden A., Van Dyck D. Automatic detection of EEG electrode 

markers on 3D MR data. MRI 2000, 18(4): 485-488. 

4. Sijbers J., Van Audekerke J., Verhoye M., Van der Linden A., Van Dyck D. Reduction of ECG and gradient related artifacts in 

simultaneously recorded human EEG/MRI data. MRI 2000, 18(7): 881-886. 

5. Van de Wouwer G., Weyn B., Scheunders P., Jacobs W., Van Mark E., Van Dyck D. Automated chromatine-texture based diagnosis of 

carcinoma nuclei. J Microsc 2000, 197: 25-35. 

Microscopy of neuro and cardio 

1. Van Genechten J, Brouns I, Burnstock G, Timmermans JP, Adriaensen D. Quantification of neuroepithelial bodies and their innervation in 

Fawn-Hooded and Wistar rat lungs. Am J Respir Cell Mol Biol 2003, Jun 19 [Epub ahead of print] 

2. Geuens E, Brouns I, Flamez D, Dewilde S, Timmermans JP, Moens L. A globin in the nucleus! J Biol Chem 2003, 278(33): 30417-20. 

3. Brouns I, Van Genechten J, Hayashi H, Gajda M, Gomi T, Burnstock G, Timmermans JP, Adriaensen D. Dual sensory innervation of 

pulmonary neuroepithelial bodies. Am J Respir Cell Mol Biol 2003, 28(3): 275-85. 

4. Kumar-Singh S, Cras P, Wang R, Kros JM, van Swieten J, Lubke U, Ceuterick C, Serneels S, Vennekens K, Timmermans JP, Van Marck E, 

Martin JJ, van Duijn CM, Van Broeckhoven C. Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric. Am 

J Pathol 2002, 161(2): 507-20. 

5. Hens J, Vanderwinden JM, De Laet MH, Scheuermann DW, Timmermans JP. Morphological and neurochemical identification of enteric 

neurones with mucosal projections in the human small intestine. J Neurochem 2001, 76(2): 464-71. 

MRI of animal models for neurological disorders 

1. Van Camp N., d'Hooge R., Verhoye M., Peeters R.R., De Deyn P.P., Van der Linden A. Simultaneous electroencephalographic recording 

and functional magnetic resonance imaging during pentylenetetrazol-induced seizures in rat. Neuroimage 2003, 19:627-636. 

2. Spittaels K., Van den Haute C., Van Dorpe J., Terwel D., Vandezande K., Lasrado R., Bruynseels K., Irizarry M., Verhoye M., Van Lint J., 

Vandenheede J.R., Ashton D., Mercken M., Loos R., Hyman B., Van der Linden A., Geerts H., Van Leuven F. Neonatal neuronal 

overexpression of glycogen synthase kinase-3beta reduces brain size in transgenic mice. Neuroscience 2002, 113(4): 797-808. 

3. Hoogenraad C.C., Koekkoek B., Akhmanova A., Krugers H., Dortland B., Miedema M., van Alphen A., Kistler W.M., Jaegle M., 

Koutsourakis M., Van Camp N., Verhoye M., van der Linden A., Kaverina I., Grosveld F., De Zeeuw C.I., Galjart N. Targeted mutation of 

Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice. Nature 

Genet 2002, 32: 116-127. 

4. Verhoye M., Van der Sande B., Rijken P.F.J.W., Peters H.P.W., Van der Kogel A.J., Pee G., Van Houtte G., Heerschap A., Van der Linden 

A. Assessment of the neovascular permeability in glioma xenografts by dynamic T 1 MRI with Gadomer-17. MRM 2002, 47: 305-313. 

5. Kooy F., Verhoye M., Lemmon V., Van Der Linden A. Brain studies of mouse models for neurogenetic disorders using in vivo magnetic 

resonance imaging (MRI). Eur J Hum Gen 2001, 9:153-159.


Partner 9: Bordeaux (C. Moonen) 

Molecular and Functional Imaging: From Physiology to Therapy 

Technological Research Team, ERT CNRS/Université Victor Segalen Bordeaux, Bordeaux, France 

The team “Molecular and Functional Imaging: From Physiology to Therapy” is a newly created technology 

development research laboratory (created January 1, 2003) run jointly by the National Center for Scientific Research 

and the University Victor Segalen Bordeaux. It is composed of about 25 researchers combining physicists, 

radiologists, biologists, and image processing experts. The team has a strong position in physiological imaging 

(biomarkers, functional imaging), interventional imaging (thermal therapies) and in the development of image-guided 

molecular therapies. Local drug delivery and activation is especially of interest in gene therapy, because the low 

specificity of vectors and lack of spatial and temporal control of gene expression are among the main pitfalls of gene 

therapy. The Bordeaux-group has developed a control system based on the use of the heat sensitive promoter HSP70 

and local hyperthermia generated non-invasively by an MRI guided focused ultrasound probe to control local gene 

expression. Currently, this technology is being expanded to control the transplantation and activation of stem cells. 

The team is strongly involved in the installation of a cyclotron at Bordeaux, and an association with the Nuclear 

Medicine Department has been established. The team has high level research collaborations with Philips Medical 

Systems on imaging technology, Guerbet and Amersham on the development of contrast media, Johns Hopkins 

Medical School on stem cells, and with the US National Institutes of Health on gene therapy control. 


1. Chrit Moonen, PhD, Director of Bordeaux research team: MR imaging, imaging of gene expression, 

physiological imaging. 

2. Nicolas Grenier, Professor of Radiology: interventional MRI, stem cell tracking, macrophage imaging. 

3. Michèle Allard, Professor of Nuclear Medicine: functional imaging, SPECT/PET imaging. 

4. Olivier Hauger, Radiologist: cell labelling and tracking with MRI. 

5. Clemens Bos, Postdoc physics: cell tracking with MRI. 

6. Jean Palussière, Radiologist: interventional MRI. 

7. Rares Salomir, Postdoc physics: MRI, MRI guided focused ultrasound. 

8. Franck Couillaud, staff scientist: molecular biology, cell biology. 

9. Claire Rome, Postdoc biology: molecular biology, cell biology. 

10. Baudoin Denis de Senneville, PhD student image processing. 

11. Charles Mougenot, PhD student electronics. 

12. Mathieu Lepetit-Coiffe, PhD student physics. 

References 

Image-based control of gene expression: 

1. E. Guilhon, P. Voisin, J.A. de Zwart, B. Quesson, R. Salomir, C. Maurange, V. Bouchaud, P. Smirnov, H. de Verneuil, A. Vekris, P. Canioni, 

C.T.W. Moonen. Spatial and Temporal Control of Transgene Expression in vivo using a Heat-Sensitive Promoter and MRI-Guided Focused 

Ultrasound. J Gene Med 2003; 5, 333-342. 

2. Image-guided control of transgene expression based on local hyperthermia, Guilhon E, Quesson B, Moraud-Gaudry F, de Verneuil H, Canioni 

P, Salomir R, Voisin P, Moonen CTW. J. Molecular Imaging 2003; 2, 11-17. 

Image based control of thermal therapies: 

1. Palussière J, Salomir R, Le Bail B, Fawaz R, Quesson B, Grenier N, Moonen CTW. Feasibility of MR-Guided Focused Ultrasound with Real- 

Time Temperature Mapping and Continuous Sonication for Ablation of VX2 Carcinoma in Rabbit Thigh. Magn Reson Med 2003; 49, 89-98. 

2. Automatic control of hyperthermic therapy based on real-time Fourier analysis of MR temperature maps Quesson B., Vimeux F, Salomir R., de 

Zwart J.A. and Moonen C.T.W. Magn Reson Med 2002, 47: 1065-72. 

Tracking of macrophages: 

1. Hauger, O, Delalande C, Deminiere C, Fouqueray B, Ohayon C, Garcia S, Trillaud H, Combe C, Grenier N. Nephrotoxic nephritis and 

obstructive nephropathy: evaluation with MR imaging enhanced with ultrasmall superparamagnetic iron oxide- preliminary findings in a rat 

model. Radiology 2000, 217(3): 819-26. 

Physiological Imaging: 

1. Bixente Dilharreguy B, Jones RA, Moonen CTW. Influence of fMRI data sampling on the temporal characterisation of the haemodynamic 

response. Neuroimage, in press.


Partner 10: Munich (M. Schwaiger, F. Bengel) 

Department of Nuclear Medicine, Technical University of Munich (TUM), Germany 

The Department of Nuclear Medicine of the TU Munich is equipped with a broad spectrum of in vivo imaging 

modalities (2 clinical PET scanners, a PET/CT scanner, a small animal PET scanner, 5 SPECT cameras, an 1.5T 

cardiovascular MRI scanner, an optical imaging system and access to 2 fMRI-enabled 1.5T MRT-scanners) and 

laboratories for ex vivo image validation (gamma- and beta-counters, microtome and autoradiography lab, 

biodistribution lab, PCR, HPLC etc). The department also comprises laboratories for radiochemical / 

radiopharmaceutical development (including an on-site cyclotron), PET detector and camera development, and image 

analysis software development. All necessary infrastructure for innovative and integrative research in biologic and 

molecular imaging is thus available. 

Cardiovascular imaging is a major research interest of the department. Myocardial microcirculation, metabolism, 

function and innervation are assessed in multiple clinical projects for phenotyping of heart disease and 

characterization of treatment effects. Preclinical experimental work aims at development of novel approaches for 

detection of specific molecular mechanisms such as gene and protein expression, angiogenesis and apoptosis in vitro 

as well as in vivo using various small and large animal models. For successful conduction of the broad spectrum of 

projects, close scientific cooperation exists with departments of cardiology, cardiac surgery, pediatric cardiology, 

radiology, pathology and experimental oncology & therapy research at the Technical University, but also with 

departments of cardiology, cardiac surgery, clinical chemistry and diabetology of the Ludwig-Maximilians University 

and other local centers of cardiology in Munich. Several projects are also carried out with regional, national and 

international partners, including e.g. University of Michigan, Ann Arbor, University of California, Los Angeles, and 

Cornell University, New York, USA, Turku University, Finnland, and University of Groningen, The Netherlands. 

Another major field of interest is the imaging of brain function. Using the modern infrastructure, clinical and 

preclinical studies on cerebral metabolism (F-18 FDG), brain activation (O-15 H2O, fMRI) and receptor status 

(flumazenil, diprenorphine) are being performed. Besides the characterization of cerebral processing involved in 

movement disorders, pain and epilepsy, a main focus is on early diagnosis, follow up and treatment monitoring of 

dementia. Particularly, the value of brain imaging modalities in the context of other biomarkers (spinal fluid, 

genotype) has been analyzed. First pilot studies using animal models of dementia are being performed, and novel, 

plaque-targeted molecular tracers are under development. Successful cooperations have been established with the 

local departments of neurology and psychiatry (Technische Universität München, Ludwig-Maximilians-Universität 

München) and other faculties (e.g. information technology) as well as with other national and international partners 

(e.g. University of Washington, Seattle, Georgetown University, Washington D.C., USA, Hyogo Institute of the 

Ageing Brain, Japan). 


1. Prof. Dr. M. Schwaiger: Director of the department of nuclear medicine; longstanding experience in imaging 

applications for evaluation of biologic systems. 

2. Priv.-Doz. Dr. F. Bengel: Senior nuclear physician; coordinator of nuclear cardiology research group; 

experimental and clinical cardiovascular molecular imaging. 

Further members of the group: Dr. M. Anton (PhD, molecular biologist, institute of experimental oncology 

and therapy research, development and validation of viral vectors); B. Wagner (DVM; small and large 

experimental animal models, viral vector development); Dr. M. Miyagawa (MD; experimental imaging); 

Dr. M. Simoes (MD; experimental imaging), S. Reder (technologist; biodistribution, autoradiography, PCR 

and other in vitro techniques), C. Kruschke (technologist; in vivo PET imaging), Dr. H. Bülow (MD; 

cardiovascular MRI). 

3. Dr. A. Drzezga: Senior nuclear physician; coordinator of the nuclear neuroimaging research group; clinical and 

experimental molecular imaging of neurodegenerative disorders. 

Further members of the group: PD Dr. Henning Boecker (MD, movement disorders), M. Wermke (MD, 

neurodegenerative disorders), B. Strassner (MD, neurodegenerative disorders), M. Spilker (PhD, tracer 

kinetic modelling), Dr. A. Ritzl (PhD, MRI data processing), Dr. M. Essler (MD, phage display, animal 

models), B. Dzewas (technologist, Neuro-PET). 

4. Dr. H.J. Wester: Radiochemist; development, synthesis and labelling of PET-tracers. 

Further members of the group: Dr. R. Haubner (PhD; Radiochemist, angiogenesis and nucleosides); Dr. M. 

Schottelius (PhD, Radiochemist: peptide receptors, apoptosis), Dr. G. Henriksen (PhD, Radiochemist, brain 

receptor ligands, amyloid imaging); Dr. I. Wolf (physicist; cyclotron operation). 

5. Dr. S. Nekolla: Physicist; software development for image analysis / image coregistration; integration of projectspecific 

modules into general cardiovascular processing software 

6. Dr. S. Ziegler: Physicist; Instrumentation, development and implementation of hardware, validation, quality


control and coordination of available imaging techniques / cameras. 

Further member of the group: Dr. M. Rafecas (detector technology, small animal PET). 

References 

Instrumentation / Physics 

1. Rafecas M, Boning G, Pichler BJ, Lorenz E, Schwaiger M, Ziegler SI. Inter-crystal scatter in a dual layer, high resolution LSO-APD positron 

emission tomograph. Phys Med Biol. 2003; 48: 821-48. 

2. Ziegler SI, Pichler BJ, Boening G, Rafecas M, Pimpl W, Lorenz E, Schmitz N, Schwaiger M. A prototype high-resolution animal positron 

tomograph with avalanche photodiode arrays and LSO crystals. Eur J Nucl Med. 2001; 28: 136-43. 

3. Nekolla SG, Miethaner C, Nguyen N, Ziegler SI, Schwaiger M. Reproducibility of polar map generation and assessment of defect severity and 

extent assessment in myocardial perfusion imaging using positron emission tomography. Eur J Nucl Med. 1998; 25: 1313-21. 

Tracer Development / Validation 

1. Wester HJ, Schottelius M, Scheidhauer K, Meisetschlager G, Herz M, Rau FC, Reubi JC, Schwaiger M. PET imaging of somatostatin 

receptors: design, synthesis and preclinical evaluation of a novel 18F-labelled, carbohydrated analogue of octreotide. Eur J Nucl Med Mol 

Imaging. 2003; 30:117-22. 

2. Haubner R, Wester HJ, Weber WA, Mang C, Ziegler SI, Goodman SL, Senekowitsch-Schmidtke R, Kessler H, Schwaiger M. Noninvasive 

imaging of alpha(v)beta3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res. 

2001; 61:1781-5. 

3. Brust P, Haubner R, Friedrich A, Scheunemann M, Anton M, Koufaki ON, Hauses M, Noll S, Noll B, Haberkorn U, Schackert G, Schackert 

HK, Avril N, Johannsen B. Comparison of [18F]FHPG and [124/125I]FIAU for imaging herpes simplex virus type 1 thymidine kinase gene 

expression. Eur J Nucl Med. 2001; 28:721-9. 

4. Haubner R, Avril N, Hantzopoulos PA, Gansbacher B, Schwaiger M. In vivo imaging of herpes simplex virus type 1 thymidine kinase gene 

expression: early kinetics of radiolabelled FIAU. Eur J Nucl Med 2000; 27:283-91. 

5. Wester HJ, Willoch F, Tolle TR, Munz F, Herz M, Oye I, Schadrack J, Schwaiger M, Bartenstein P. 6-O-(2-[18F]fluoroethyl)-6-Odesmethyldiprenorphine 

([18F]DPN): synthesis, biologic evaluation, and comparison with [11C]DPN in humans. J Nucl Med. 2000; 41(7): 

1279-86. 

Experimental Imaging of Cardiovascular Biology 

1. Bengel FM, Anton M, Richter T, Simoes MV, Haubner R, Henke J, Erhardt W, Reder S, Lehner T, Brandau W, Boekstegers P, Nekolla SG, 

Gansbacher B, Schwaiger M. Noninvasive imaging of transgene expression using positron emission tomography in a pig model of myocardial 

gene transfer. Circulation. 2003; 108: 2127-2133. 

2. Bengel FM, Anton M, Avril N, Brill T, Nguyen N, Haubner R, Gleiter E, Gansbacher B, Schwaiger M. Uptake of radiolabeled 2'-fluoro-2'- 

deoxy-5-iodo-1-beta-D-arabinofuranosyluracil in cardiac cells after adenoviral transfer of the herpesvirus thymidine kinase gene: the cellular 

basis for cardiac gene imaging. Circulation. 2000; 102:948-50. 

3. Egert S, Nguyen N, Schwaiger M. Contribution of alpha-adrenergic and beta-adrenergic stimulation to ischemia-induced glucose transporter 

(GLUT) 4 and GLUT1 translocation in the isolated perfused rat heart. Circ Res. 1999; 84:1407-15. 

Clinical Cardiovascular Molecular Imaging 

1. Klein C, Nekolla SG, Bengel FM, Momose M, Sammer A, Haas F, Schnackenburg B, Delius W, Mudra H, Wolfram D, Schwaiger M. 

Assessment of myocardial viability with contrast-enhanced magnetic resonance imaging: comparison with positron emission tomography. 

Circulation. 2002; 105:162-7. 

2. Ibrahim T, Nekolla SG, Schreiber K, Odaka K, Volz S, Mehilli J, Guthlin M, Delius W, Schwaiger M. Assessment of coronary flow reserve: 

comparison between contrast-enhanced magnetic resonance imaging and positron emission tomography. J Am Coll Cardiol. 2002; 39:864-70. 

3. Bengel FM, Ueberfuhr P, Schiepel N, Nekolla SG, Reichart B, Schwaiger M. Effect of sympathetic reinnervation on cardiac performance after 

heart transplantation. N Engl J Med. 2001; 345:731-8. 

4. Munch G, Nguyen NT, Nekolla S, Ziegler S, Muzik O, Chakraborty P, Wieland DM, Schwaiger M. Evaluation of sympathetic nerve terminals 

with [(11)C]epinephrine and [(11)C]hydroxyephedrine and positron emission tomography. Circulation. 2000; 101:516-23. 

5. Guethlin M, Kasel AM, Coppenrath K, Ziegler S, Delius W, Schwaiger M. Delayed response of myocardial flow reserve to lipid-lowering 

therapy with fluvastatin. Circulation. 1999; 99:475-81. 

Molecular Imaging in Neuroscience 

1. Drzezga A, Lautenschlager N, Siebner H, Riemenschneider M, Willoch F, Minoshima S, Schwaiger M, Kurz A. Cerebral metabolic changes 

accompanying conversion of mild cognitive impairment into Alzheimer's disease: a PET follow-up study. Eur J Nucl Med Mol Imaging. 

2003; 30(8): 1104-13. 

2. Boecker H, Ceballos-Baumann AO, Bartenstein P, Dagher A, Forster K, Haslinger B, Brooks DJ, Schwaiger M, Conrad B. A H (2)(15)O 

positron emission tomography study on mental imagery of movement sequences--the effect of modulating sequence length and direction. 

Neuroimage. 2002; 17(2): 999-1009. 

3. Drzezga A, Darsow U, Treede R, Siebner H, Frisch M, Munz F, Weilke F, Ring J, Schwaiger M, Bartenstein P. Central activation by 

histamine-induced itch: analogies to pain processing: a correlational analysis of O-15 H(2)O positron emission tomography studies. Pain. 

2001; 92(1-2): 295-305. 

4. Lautenschlager NT, Riemenschneider M, Drzezga A, Kurz AF. Primary degenerative mild cognitive impairment: study population, clinical, 

brain imaging and biochemical findings. Dement Geriatr Cogn Disord. 2001; 12(6): 379-86. 

5. Arnold S, Berthele A, Drzezga A, Tolle TR, Weis S, Werhahn KJ, Henkel A, Yousry TA, Winkler PA, Bartenstein P, Noachtar S. Reduction of 

benzodiazepine receptor binding is related to the seizure onset zone in extratemporal focal cortical dysplasia. Epilepsia. 2000; 41(7): 818-24.


Partner 11: Oslo (R. Blomhoff, H. Carlsen) 

Institute for Nutrition Research and Institute of Immunology, Faculty of Medicine, University of Oslo, Norway 

The Oslo group has its main interest in studying gene regulation in relation to nutrition and disease. The groups 

involved from the University of Oslo have a long-standing expertise in transgenic mice technology such as the 

production and application of luciferase based reporter mice for optical imaging and genetically altered mouse models 

for inflammatory disease and cancer rejection. Regulation of gene expression is at the center of our understanding of 

normal development as well as most, if not all types of diseases. The need to follow the temporal and spatial patterns 

of expression of individual genes in vivo is therefore obvious. One of the transgenic reporter models developed by the 

group led by Professor Rune Blomhoff is a model whose expression of luciferase is controlled by three copies of the 

binding site for the transcription factor NFkB. NFkB is central for the development of several diseases and 

inflammation in particular. Using optical imaging in living mice we have demonstrated induced NFkB activation in 

response to classical inducers and modulators such as TNFα, IL1α, LPS, UVB, and chronic inflammation, while it is 

inhibited by dexamethasone. Apparently, many research groups concentrating on different chronic and degenerative 

diseases see this transgenic mouse models as a valuable tool for their own research. The transgenic reporter model has 

been distributed to several international research laboratories. 

Previous studies in the Blomhoff group focus on transport, metabolism and function of vitamin A (retionoids). Based 

on these results we have published several invited reviews in journals like Science (1990), Physiological Reviews 

(1991), FASEB Journal (1991), Am. J. Clin. Nutr. (1992), Annual Review of Nutrition (1992), as well as the book on 

“Vitamin A in Health and Disease” (Marcel Dekker, New York, 1994) which was selected as one of the 250 best 

books in the world in medicine and health in 1994-1995. 

The laboratory of Professor Bjarne Bogen at the Institute of Immunology, University of Oslo, has over many years 

established a transgenic mouse model that is used for studies on autoimmunity and cancer. By introducing the NFkBluciferase 

transgenic mouse (Carlsen et al. 2001) into this system in collaboration between the Blomhoff lab and the 

Bogen lab, we have now established mice in which the development of autoimmunity and rejection of cancer cells can 

be studied by in vivo imaging. 

Resources within the Oslo group include optical imaging device for animal imaging (IVIS 100; Xenogen, 

luminescence and fluorescence option), core facility for production of transgenic mouse models, strong research labs 

for molecular biology, immunology and analytical chemistry. 


1. Prof. Dr. R. Blomhoff, Group leader at the Institute for Nutrition Research, University of Oslo, Nutrients and gene 

regulation, molecular imaging. Blomhoff has received several honors and awards such as Mead Johnson Award, 

American Institute of Nutrition, 1988; Anders Jahres Medical Award 1992; King Olav V’s prize for cancer 

research, 1996. 

Further members of the group: Dr. Harald Carlson (molecular biologist: transgenic animal models, molecular 

imaging of transgenic reporter mice), Dr. Harald Hauglin (physicist, fluorescence applications for imaging of 

inflammation), Dr. Kanae Ebihara (biologist, gene regulation, DNA construction, molecular imaging in 

transgenic reporter mice), Dr. George Alexander (biologist, inflammatory disease and gene regulation), Liv 

Austenaa, (PhD-student, biologist, nutrition, inflammation, molecular imaging of NFkB regulation in 

transgenic reporter mice), Lene Mathiesen, (technician, biologist, molecular imaging of reporter mice 

2. Professor B. Bogen, Group leader at The Institute of Immunology, tumor immunology, autoimmunity, animal 

disease models. The group counts 16 members. 

The members involved in the proposed projects will be Dr. Ludvig Munthe, (MD, animal models, 

inflammation), Dr. Katrin Lundin (MD, tumor immunology, animal models), Peter Hofgaard (technician, 

biologist, animal models), Dr. Alexander Corthay (biologist, inflammation), Agnete Fredriksen (PhD-student, 

biologist, molecular biology, DNA construction) 

References 

Imaging gene regulation 

1. Austenaa, L.M. I., Carlsen, H, Ertesvag. A, Alexander. G, Blomhoff. H.K., and Blomhoff. R. Abnormal NF-B activity in vitamin A 

deficiency assessed by in vivo imaging. Submitted, 2003 

2. Alexander G, Carlsen H, Blomhoff R.. Strong in vivo activation of NF-kappaB in mouse lenses by classic stressors. Invest Ophthalmol Vis 

Sci. 2003, 44(6):2683-8 

3. Carlsen.H, Moskaug,J.O., Fromm,S.H., and Blomhoff,R.. In vivo imaging of NFkB activity in transgenic mice using luminescence. J 

Immunol. 2002, 168(3):1441-6. 

Development of animal models/inflammation 

1. Lundin KU, Hofgaard PO, Omholt H, Munthe LA, Corthay A, Bogen B. Blood 2003, 102(2):605-12. 

2. Dembic, Z., Rottingen, J.A., Dellacasagrande, Schenk, K, and Bogen. Phagocytic dendritic cells from myelomas activate tumor-specific T cells 

at a single cell level. Blood. 2001; 97:2808-2814 

3. Dembic, Z., Schenk, K, and Bogen. Dendritic cells purified from myeloma are primed with tumor-specific antigen (idiotype) and activate 

CD4+ T cells. Proc Natl Acad Sci U S A. 2000; 97(6):2697-702.


Partner 12: Orsay (B. Tavitian) 

Laboratory for Imaging of Gene Expression (LIGE), Orsay, France 

The Laboratory for in vivo Imaging of Gene Expression (LIGE) is an INSERM unit in the Medical Research 

Department of the CEA and is associated with INSERM (ERM 0103) and Paris XI University. It is part of the Service 

hospitalier Frédéric Joliot (SHFJ), one of the top five European imaging centers with 100+ staff in the fields of 

molecular and functional imaging, covering most aspects of biological and clinical applications in PET, SPECT, MRI, 

and basic imaging science. The center is equipped with two cyclotrons, three PET cameras, 3 SPECT cameras and 

small animal cameras (MICROPET, GAMMA-IMAGER & PHOTO-IMAGER). LIGE has a permanent partnership 

for development of small animal imaging instruments with the SHFJ Instrumentation group and the biotech 

BIOSPACE and for radiotracer development with the SHFJ radiochemistry and radiopharmacy groups. Expertise 

covers radiophysics, radiochemistry, cellular and molecular biology, pharmacology, image analysis and patient day 

care. The SHFJ has a clinical pharmacology unit and is an authorised clinical radiopharmaceutical production center. 

Bertrand Tavitian is the coordinator of the 6 FW Network of Excellence EMIL for Molecular Imaging of Cancer. 

Contributions: 

• Radio- and fluo-labelling of biomolecules including oligonucleotides and peptides. 

• Imaging with PET, SPECT and optical methods in animals and humans. 

• Drug- and radiopharmaceutical validation and filing for exploitation. 

• Patent: Tavitian, B., Kühnast, B., and Klüssmann, S. Use of L-polynucleotides and method for labelling the same. 

AG, NOXXON Pharma and CEA. (EP 01114111.6.). 2001. European patent. 10-6-2001. 


1. B. Tavitian, MD PhD, Laboratory Director M0103 

Further members of the group: F. Duconge, PhD, researcher, molecular biology; R. Boisgar, PhD, researcher, 

in vivo imaging & cell biology; B. Kuhnast, PhD, researcher, radiopharmacy; V. Josserand, PhD, post 

doctoral student, blood-brain barrier & pharmaco-imaging; H. Boutin, PhD, post doctoral student, CNS tracer 

development; S. Guillermet, PhD, post doctoral student, pharmaco-imaging; C. Pestourie, MSc, PhD student, 

molecular biology; F. Chauveau, MSc, PhD student, CNS tracer development; N. Benzoubir, Bac, student, 

cell biology; A. Guitteny, MSc, student, imaging; B. Jego, BTS, technician, animal & cell biology; K. 

Rannou, BTS, technician, molecular biology. 

2. F. Dolle, PhD, Head of Radiochemical group 

Further members of the group: D. Roeda, PhD, researcher; B. Kuhnast, PhD, researcher; F. Hinnen, IUT, 

chemical technician; Y. Bramoulle, IUT, chemical technician; S. Demphel, IUT, chemical technician; D. 

Gouel, IUT, cyclotron technician; C. Peronne, IUT, cyclotron technician; C. Lechene, IUT, cyclotron 

technician; B. Lagnel, PhD, post-doctoral researcher; G. Roger, PhD, PhD student. 

3. R. Trebossen, PhD, Head of Instrumentation group 

Further members of the group: C. Comtat, PhD, researcher; R. Maroy, PhD, researcher; S. Jan, PhD, postdoctoral 

researcher; T. Delzesceaux, PhD, post-doctoral researcher; L. Janeiro, PhD student; J. Dauguet, PhD 

student; A. Mieville, engineer. 

References 

1. Tavitian B, Marzabal S, Boutet V, Kühnast B, Terrazzino S, Moynier M, Dollé F, Deverre JR, Thierry A. Characterization of a synthetic anionic 

vector for oligonucleotide delivery using in vivo whole body dynamic imaging. PharmRes 2002; 19(4): 367-376. 

2. Tavitian B. In vivo antisense imaging. Q. J.Nucl.Med. 2000; 44(3): 236-255. 

3. Traykov L, Tavitian B, Jobert A, Boller F, Forette F, Crouzel C, Di Giamberardino L, Pappata S. In vivo PET study of cerebral [ 11 C] methyltetrahydroaminoacridine 

distribution and kinetics in healthy human subjects. Eur.J.Neurol. 1999; 6(3): 273-278. 

4. Tavitian B, Terrazzino S, Kühnast B, Marzabal S, Stettler O, Dollé F, Deverre J, Jobert A, Hinnen F, Bendriem B, Crouzel C, Di Giamberardino 

L. In vivo imaging of oligonucleotides with positron emission tomography. Nature Med 1998; 4(4): 467-471. 

Radiochemistry 

1. M. Karramkam, F. Hinnen, Y. Bramoullé, S. Jubeau and F. Dollé, Ortho-[ 18 F]Fluoronitrobenzenes by No-Carrier-Added Nucleophilic 

Aromatic Substitution with K[ 18 F]F-K 222 - A Comparative Study. J.Label.Compounds Radiopharm. 2002, 45 (13), 1103-1113. 

2. M. Karramkam, F. Dollé, H. Valette, L. Besret, Y. Bramoullé, F. Hinnen, F. Vaufrey, C. Franklin, S. Bourg, C. Coulon, M. Ottaviani, M. 

Delaforge, C. Loc'h, M. Bottlaender and C. Crouzel, Synthesis of a Fluorine-18 Labelled Derivative of 6-Nitroquipazine, as a Radioligand for 

the In Vivo Serotonin Transporter Imaging with PET. Bioorg.Med.Chem. 2002, 10 (8), 2611-2623. 

3. B. Kühnast, F. Dollé, S. Terrazzino, B. Rousseau, C. Loch, F. Vaufrey, F. Hinnen, I. Doignon, F. Pillon, C. David, C. Crouzel and B. Tavitian, 

A General Method to Label Antisense Oligonucleotides with Radioactive Halogens for Pharmacological and Imaging Studies. Bioconjugates 

Chem. 2000, 11 (5), 627-636. 

4. F. Dollé, L. Dolci, H. Valette, F. Hinnen, F. Vaufrey, I. Guenther, C. Fuseau, C. Coulon, M. Bottlaender and C. Crouzel, Synthesis and 

Nicotinic Acetylcholine Receptor in Vivo Binding Properties of 2-Fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine : a New Positron Emission 

Tomography Ligand for Nicotinic Receptors. J.Med.Chem. 1999, 42 (12), 2251-2259. 

Instrumentation 

1. Lartizien C, Kinahan PE, Swensson R, Comtat C, Lin M, Villemagne V, Trebossen R. Evaluating image reconstruction methods for tumor 

detection in 3-dimensional whole-body PET oncology imaging. J Nucl Med. 2003; 44(2):276-90. 

2. Lartizien C, Comtat C, Kinahan PE, Ferreira N, Bendriem B, Trebossen R. Optimization of injected dose based on noise equivalent count rates


for 2- and 3-dimensional whole-body PET. J Nucl Med. 2002; 43(9):1268-78. 

3. Ferreira NC, Trebossen R, Lartizien C, Brulon V, Merceron P, Bendriem B. A hybrid scatter correction for 3D PET based on an estimation of 

the distribution of unscattered coincidences: implementation on the ECAT EXACT HR+. Phys Med Biol. 2002; 47(9):1555-71. 

4. Delforge J, Mesangeau D, Dolle F, Merlet P, Loc'h C, Bottlaender M, Trebossen R, Syrota A. In vivo quantification and parametric images of 

the cardiac beta-adrenergic receptor density. J Nucl Med. 2002; 43(2):215-26. 

5. Ferreira NC, Trebossen R, Comtat C, Gregoire MC, Bendriem B. Iterative crystal efficiency calculation in fully 3-D PET. IEEE Trans Med 

Imaging 2000; 19(5):485-92.


Partner 13: Paris (Biospace, SME) 

Biospace Mesures SA, Paris, France 

Biospace Mesures has been created in 1996 to develop and market quantitative in vitro molecular imaging equipment. 

Biospace’s µ IMAGER and Beta IMAGER instruments are now sold worldwide for medical research, genomics, 

biology and pharmaceutical development. Biospace has experienced since its creation a continuous growth leading to 

an equipment base of more than 100 instruments in 12 different countries. Since 2000, Biospace Mesures has been 

heavily involved in in vivo molecular imaging research through several R&D projects funded internally and/or carried 

out within collaborations with academic institutions. In 2001 and 2002, this strong R&D effort has made possible the 

marketing of a new high resolution gamma camera dedicated to in vivo imaging and of a breakthrough instrument for 

the local kinetic measurement of a PET radiotracer, the β MICROPROBE. With 3 PhDs and a team of more than 10, 

Biospace Mesures keeps investing more than 10% of its turnover in instrumentation research on in vivo small animal 

high resolution imaging. Biospace Mesures mother company, Biospace Instruments, has been awarded the award in 

the category Health, Safety and Quality of Life at the 2002 SME technology days (Leeds, 2002), and is currently 

successfully demonstrating the value of low dose radiology within an FP5 RTD project, EOS. Biospace Mesures has a 

portfolio of about 20 patents and has filed in 2002 a new patent on detection technologies applicable to these 

developments. Biospace Mesures is currently involved in collaborations with numerous academic centers (SHFJ 

Orsay, IN2P3 Nantes and Marseille, CEA-LETI, INSERM Paris, Tours and Grenoble). 


Expertise 

1. Marie Meynadier, PhD, CEO, 5 years of research experience at ATT Bell Labs, has carried successfully 2 research 

programmes in FP4 and 5. 

2. Serge Maîtrejean, PhD, R&D manager, over 20 publications, 6 patents. 

3. Sébastien Teysseyre, engineer. 

4. Philippe Cuscito, engineer. 

5. Pascal Asselin, engineer. 

6. Pascal Désauté, engineer. 

7. Olivier Levrey, engineer. 

Instrumentation customers 

Academic: Institute Pasteur, INSERM, CNRS, Karolinska Institute, DKFZ, Max Planck Institute, IRLS Hammersmith Hospital, Sloan Kettering 

Memorial Center, Univ. Washington/St Louis, National Institute for Drug Abuse, CEA Orsay, CEA/LETI, CERMEP, Univ. Toronto, Kyoto PET 

center, Univ. Jülich, Brookhaven Nal Lab. 

Private: Merck, Pharmacia, Pfizer, Novartis, Sanofi, GSK, BASF, Organon, Memory Pharmaceuticals, Syngenta, L’Oréal, Knoll, Janssen, Roche, 

Elli Lilly, Renasci.


Partner 14: Leuven (V. Baekelandt) 

Molecular Virology and Gene Therapy project group, K.U. Leuven, Belgium 

The Molecular Virology and Gene Therapy project group of the K.U.Leuven is the result of a close collaboration 

between the Laboratory for Molecular Virology and Gene Therapy and the Laboratory for Experimental Neurosurgery 

and Neuroanatomy. The research project centers around HIV-1 derived lentiviral vectors for gene transfer with gene 

therapeutic purposes on the one hand and to create new neurodegenerative disease models on the other hand. Lentiviral 

vector-mediated local over-expression of disease-associated genes in the brain of laboratory animals is a novel 

technology to create animal models that differs from classical transgenesis. The animal models offer numerous 

technological advances and are useful for basic research into the pathogenesis of neurodegeneration, for the 

development of (gene) therapeutics and diagnostics and for functional genomics in the central nervous system (CNS). 

The Laboratory for Molecular Virology and Gene Therapy is responsible for the lentiviral vector core facility. Dr. 

Debyser has about 15 years of experience with antiviral research and molecular virology of HIV. He was one of the first 

to successfully introduce lentiviral vector technology in Belgium at the end of 1997. Research is carried out in 

specifically designed and approved biosafety BL-2 laboratories (BL-2 vector production core facility, BL-2 cell 

culture, BL-2 experimentation with animals). Dr. Baekelandt of The Laboratory for Experimental Neurosurgery and 

Neuroanatomy is responsible for the in vivo gene transfer experiments within the consortium. The research focuses on 

the development of animal models and gene therapy for Parkinson’s and Alzheimer’s disease. Expertise of the group 

consists of stereotactic neurosurgery on small rodents and optimization of in vivo gene transfer and analysis in rats and 

mice. The Molecular Virology and Gene Therapy project group of the K.U.Leuven is coordinator of an EU-based 

project of FP5 (NEUROPARK or European Network to Develop New Therapeutic Strategies for Parkinson’s Disease 

using Lentiviral vector technology) together with the Telethon Institute for Gene Therapy, Milano, Italy and the 

Laboratory for Alzheimer’s and Parkinson’s Disease Research, Ludwig-Maximilians-University of Munich, Germany. 


1. Prof. Dr. V. Baekelandt, PhD: Laboratory for Experimental Neurosurgery and Neuroanatomy, in vivo gene transfer 

module. Animal models and gene therapy for Parkinson’s and Alzheimer’s disease. 

Further members of the group: Dr. C. Van den Haute (PhD, biologist, gene therapy for Alzheimer’s disease), 

E. Lauwers (PhD student, biochemist, animal models and gene therapy for Parkinson’s disease); L. 

Vercammen (PhD student, biologist, animal models and gene therapy for Parkinson’s disease); V. Reumers 

(PhD student, biomedical sciences, animal models for PD and optical imaging); K. Eggermont, L. Luyts and 

A. Van der Perren (technicians for stereotactic neurosurgery and histology). 

2. Prof. Dr. B. Nuttin, MD PhD: Neurosurgeon, Laboratory for Experimental Neurosurgery and Neuroanatomy and 

University Hospitals of Leuven. Expert advice on clinical applications of technology and therapies. 

3. Prof. Dr. Z. Debyser, MD PhD: Laboratory for Molecular Virology and Gene Therapy, Rega Institute for Medical 

Research. Production and optimisation of lentiviral vectors. Molecular virology of HIV. 

Further members of the group: Dr. R. Gijsbers (PhD, bioengineer, Production and optimisation of lentiviral 

vectors); W. Pluymers (PhD, biologist, Proteomics); M. Geraerts (PhD student, biomedical sciences, 

transduction of neural progenitor cells); J. De Rijck (PhD student, biologist, vectorology); K. 

Bartholomeeusen (PhD student, biomedical sciences, optimisation of lentiviral vectors); M. Michiels, S. 

Willems, C. Duportail, L. Desender (technicians: production of lentiviral vectors, molecular biology). 

References 

Publications 

1. Van den Haute, C., Eggermont, K., Nuttin, B., Debyser, Z. and Baekelandt, V. Lentiviral vector-mediated delivery of short-hairpin RNA 

results in persistent knock-down of gene expression in mouse brain. Human Gene Therapy 2003, in press. 

2. Baekelandt, V., Eggermont, K., Michiels, M., Nuttin, B. and Debyser, Z. Optimized lentiviral vector production and purification procedure 

prevents immune response after transduction of rodent brain. Gene Therapy 2003, 10, 1933-1940. 

3. Lauwers, E., Debyser, Z., Van Dorpe, J., De Strooper, B., Nuttin, B. and Baekelandt, V. Neuropathology and neurodegeneration in rodent brain 

induced by lentiviral vector-mediated overexpression of α-synuclein. Brain Pathology 2003,13, 364-372. 

4. Baekelandt V., Claeys A., Eggermont K., Lauwers E., De Strooper B., Nuttin B. and Debyser Z. Characterization of lentiviral vector mediated 

gene transfer in adult mouse brain. Human Gene Therapy 2002, 13 (7), 841-853 (6.8) 

5. Tenenbaum L., Chtarto A., Lehtonen E., Blum D., Baekelandt V., Velu T., Brotchi J. and Levivier M. Neuroprotective Gene Therapy for 

Parkinson’s disease. Current Gene Therapy 2002, 2 (4), 451-483. 

6. Baekelandt V., De Strooper B., Nuttin B. and Debyser Z. Gene therapeutic strategies for neurodegenerative diseases. Current Opinion in 

Molecular Therapeutics 2000, 2 (5), 540-554. (0.5) 

7. Baekelandt V., Claeys A., Cherepanov P., De Clercq E., De Strooper B., Nuttin B. and Debyser Z. DNA-dependent protein kinase is not 

required for efficient lentivirus integration. Journal of Virology 2000, 74 (23), 11278-11285. (5.9) 

Patent applications 

1. UK provisional patent application (GB0031054.0) : Baekelandt V., Debyser, Z., Lauwers, E., De Strooper, B., Nuttin, B. (2000) Method to 

create disease models in animals using stereotactic vector-mediated gene transfer: Rodent model for Parkinson’s disease by locoregional 

overexpression of alpha-synuclein in the brain. 

2. UK provisional patent application: Van den Haute C., Debyser Z. and Baekelandt V. (2002) Lentiviral vector-based system for RNA 

interference.


Partner 15: Lund (D. Kirik, A. Bjorklund) 

Section of Neurobiology, Department of Physiological Sciences at Lund University, Sweden 

The Section of Neurobiology at the Wallenberg Neuroscience Center is specialized on studies on neurodegeneration 

and repair in the central nervous system. The section consists of 5 groups with a total of about 40 scientific and 

administrative staff, with the undersigned as director. Drs. Kirik and Bjorklund's research groups collectively 

comprise 20 people (4 post-docs, 6 PhD students, 1 research engineer, 4 technicians, and 3 adminstrative staff). 

The current research in our groups is focused on (i) isolation, propagation and characterization of neural stem and 

progenitor cells for use in brain repair; (ii) cell replacement and functional recovery in animal models of 

neurodegenerative disease; (iii) gene delivery to the central nervous system using recombinant AAV and lentiviral 

vectors; (iv) targeted delivery of neurotrophic factors (especially GDNF) for neuroprotection and functional recovery 

in the brain; (v) development of a new rodent model of Parkinson's disease based on vector-mediated overexpression 

of α-synuclein in the nigrostriatal system (vi) novel theraputic strategies in transgenic mouse models of HD. 

The speciality of the lab is in vivo studies in rodent models of Parkinson's disease, Huntington's disease and dementia. 

This involves a battery of tests of rodent behaviours, techniques for neuroanatomical studies, including 

immunohistochemistry, tract tracing and in situ hybridization methods, and biochemical assays. The section has also 

state-of-the art cell culture facilities and an active vector core for development and production of viral vectors for in 

vivo use. Our center is one of the Marie-Curie training sites for where several PhD students from different EU 

countries have visited and worked as part of thesis projects. We plan and execute frequent lunch seminars (every 1-2 

weeks) that are held jointly between different research groups within the center, most often with graduate students and 

post-docs as presenters. The Lund Neurobiology Club presents monthly seminars in the Neuroscience Center with 

prominent speakers, often invited from abroad. The group leaders have organised multiple international conferences 

over the past years, and any visiting scholar will be invited to participate in future conferences. Finally, we are 

actively involved in the leading European clinical cell transplantation program aimed at the development of cell based 

therapies for patients with Parkinson's disease. 


1. Deniz Kirik, Assistant Professor, MD, PhD; in vivo models of Parkinson’s disease, transplantation of primary 

fetal, progenitor and stem cells, viral vector construction for in vivo gene transfer, characterization of new animal 

models and neuroprotective treatment strategies (project coordinator). 

2. Anders Bjorklund, Professor, PhD; cell transplantation in animal models of neurodegenerative diseases. 

3. Lachlan Thompson, Post-doc, PhD; transplantation of isolated progenitors and cell lines into the adult and 

developing rodent brain. 

4. Dwain Morris-Irvin, Post-doc, PhD; endogeneous neurogenesis in the adult rodent brain following injury to the 

dopaminergic cells. 

5. Malin Parmar, Post-doc, PhD; epigenetic and genetic procedures for generation of forebrain neuronal cells and cell 

lines. 

6. Perrine Barraud, Post-doc, PhD; isolation, expansion and sorting of progenitor and stem cells from rodent and 

human fetal brains, grafting into neonatal rodent brain for in vivo survival studies. 

7. Marina Romero-Ramos, Post-doc, PhD; generation of new models of PD based on overexpression of disease 

causing genes, interaction with oxidative stress. 

8. Biljana Georgievska, PhD student; delivery of neurotrophic factors for neuroprotection/repair in rodetn models of 

Parkinson’s disease. 

9. Elin Andersson, PhD student; epigenetic and genetic procedures for generation of dopaminergic cell lines from 

neural stem cell lines. 

10. Simon Stott, PhD student; in utero injections of cells and viral vectors for studies on development of dopaminergic 

system in the rodent brain. 

11. Josephine Jensen, PhD student; forebrain development and determination of cell fate. 

12. Thomas Carlsson, PhD student; restoration of motor function by viral vector mediated repair in PD models. 

13. Matthew Maingay, PhD student; viral vector delivery for generation of animal models of PD. 

References 

1. Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Bjorklund A. Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated 

overexpression of human alpha-synuclein: a new primate model of Parkinson's disease. Proc Natl Acad Sci U S A, 2003. 100(5): p. 2884-9. 

2. Kirik D, Bjorklund A. Modeling CNS neurodegeneration by overexpression of disease-causing proteins using viral vectors. Trends Neurosci, 

2003. 26(7): p. 386-92. 

3. Bjorklund A, Dunnett SB, Brundin P, Stoessl AJ, Freed CR, Breeze RE, Levivier M, Peschanski M, Studer L, Barker R., Neural transplantation 

for the treatment of Parkinson's disease. Lancet Neurol, 2003. 2(7): p. 437-45. 

4. Parmar, M, Skogh C, Bjorklund A, Campbell K. Regional specification of neurosphere cultures derived from subregions of the embryonic 

telencephalon. Mol Cell Neurosci, 2002. 21(4): p. 645-56.


5. Kirik, D., et al., Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene 

transfer. Proc Natl Acad Sci U S A, 2002. 99(7): p. 4708-13. 

6. Kirik, D., et al., Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J 

Neurosci, 2002. 22(7): p. 2780-91. 

7. Englund, U., et al., Grafted neural stem cells develop into functional pyramidal neurons and integrate into host cortical circuitry. Proc Natl 

Acad Sci U S A, 2002. 99(26): p. 17089-94. 

8. Kirik, D., C. Winkler, and A. Bjorklund, Growth and functional efficacy of intrastriatal nigral transplants depend on the extent of nigrostriatal 

degeneration. J Neurosci, 2001. 21(8): p. 2889-96. 

9. Dunnett, S.B., A. Bjorklund, and O. Lindvall, Cell therapy in Parkinson's disease - stop or go? Nat Rev Neurosci, 2001. 2(5): p. 365-9. 

10. Brundin, P., et al., Transplanted dopaminergic neurons: more or less? Nat Med, 2001. 7(5): p. 512-3. 

11. Piccini, P., et al., Delayed recovery of movement-related cortical function in Parkinson's disease after striatal dopaminergic grafts. Ann Neurol, 

2000. 48(5): p. 689-95. 

12. Lindvall, O. and A. Bjorklund, First step towards cell therapy for Huntington's disease. Lancet, 2000. 356(9246): p. 1945-6. 

13. Lee, C.S., et al., Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson's disease. Brain, 

2000. 123 ( Pt 7): p. 1365-79. 

14. Kirik, D., et al., Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson's model: intrastriatal but not intranigral transduction 

promotes functional regeneration in the lesioned nigrostriatal system. J Neurosci, 2000. 20(12): p. 4686-700. 

15. Brundin, P., et al., Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease. Brain, 

2000. 123 ( Pt 7): p. 1380-90. 

16. Bjorklund, A. and O. Lindvall, Cell replacement therapies for central nervous system disorders. Nat Neurosci, 2000. 3(6): p. 537-44. 

17. Bjorklund, A. and O. Lindvall, Self-repair in the brain. Nature, 2000. 405(6789): p. 892-3, 895. 

18. Bjorklund, A. and O. Lindvall, Parkinson disease gene therapy moves toward the clinic. Nat Med, 2000. 6(11): p. 1207-8.


Partner 16: Lund (R. Holmdahl, T. Blom) 

Medical Inflammation Research (MIR) at the Biomedical Center, Lund University Medical Faculty, Sweden 

Our laboratory is specialized in studies of human disease models with a chronic inflammatory process such as 

rheumatoid arthritis and multiple sclerosis. MIR is a part of the Biomedical Center, which contains numerous research 

groups with expertise in immunology, tumor immunology, connective tissue research, molecular signaling, molecular 

biology and cell biology. The institute is well integrated with the benefit of having availability of methodology and 

expertise in many fields of biology. The institute is a part of the medical faculty of Lund University, the largest 

University in Scandinavia. MIR has a lab space of 850 m 2 and an animal house with a space of 650 m 2 . The animal 

house contains 15000 mice and rats. A large number (>200) of unique mouse and rat strains are bred, genetically 

monitored and analyzed here. These are selected (appropriate genomes) or made (transgenics) specifically for studies 

on models for RA and other inflammatory diseases. Mice are only incorporated via embryo transfer. The animal 

technicians work integrated in the research group. Beside this there is a well equipped laboratory containing a modern 

histopathology lab with computerized image analyses, a molecular biology lab including robotics and a 

microcappillary (Megabace) work station and microarray reading and spotting equipments, a biochemical lab and a 

cellular immunology lab. The Medical Inflammation Research lab is an EU granted Marie Curie training lab on 

animal models for inflammatory diseases which involve training program for PhD students from all over Europe. 

Our first goal will be to characterize the inflammatory disease process in selected animal models like pristane induced 

arthritis in the rat, collagen induced arthritis and collagen antibody induced arthritis in mice. These diseases will be 

characterized using non-invasive technology to determine both hard tissue destruction as well as the distribution of 

tracers of immune adjuvant and tissue antigens that are known to play a crucial role in these diseases. The second goal 

will be to use the non-invasive technology in phenotyping of strains in which genes of importance for specific parts of 

the inflammatory process has been isolated. We will also use mice with known generated mutations (for example 

osteopontin, ncf1, c9 genes) affecting the disease process. In addition we will use genetically segregated crosses to 

study the importance of gene interaction producing the phenotype analyzed by non-invasive technology. 


1. Prof. Rikard Holmdahl, head of MIR: principal investigator and partner in the cooperation. Direction of research 

and consulting functions 

2. Assistant Prof. Thomas Blom, director of animal technology and phenotyping at MIR. Responsible to establish the 

unit of noninvasive technology application on animal models for chronic inflammation and joint destruction at 

MIR. 

3. Associate Prof. Shohreh Issazadeh, immunologist. Expertise in experimental animal techniques and immunology. 

Consulting functions. 

4. Associate Prof. Åsa Andersson, immunologist and geneticist. Expertise in experimental animal techniques, 

immunology and animal genetics. Consulting functions. 

5. Anna Karin Lindqvist, postdoc. Expertise in mouse models and genetic analysis. Research supervising and 

training/teaching functions. 

6. Lena Wester, postdoc. Expertise in rat arthritis models. Research supervising and training/teaching functions. 

References 

1. Olofsson P, Holmberg J, Tordsson J, Lu S, Åkerström B, Holmdahl R: Positional identification of ncf1 as an arthritis severity regulating gene 

in rats. Nat Gen 2003, 33: 25-32. 

2. Bäcklund J, Carlsen S, Höger T, Holm B, Fugger L, Kihlberg J, Burkhardt H, Holmdahl R: Predominant selection of T cells specific for 

glycosylated collagen type II peptide (263-270) in humanized transgenic mice and in rheumatoid arthritis. Proc Natl Acad Sci USA 2002, 

9960-9965. 

3. Madsen LS, Andersson EC, Jansson L, Krogsgaard M, Andersen CB, Engberg J, Strominger JL, Svejgaard A, Hjorth JP, Holmdahl R, 

Wucherpfennig KW, Fugger L: A humanized model for multiple sclerosis using HLA-DR2 and a human T- cell receptor. Nat Genet 1999; 23: 

343-347. 

4. Vingsbo-Lundberg C, Nordquist N, Olofsson P, Sundvall M, Saxne T, Pettersson U, Holmdahl R. Genetic control of arthritis onset, severity 

and chronicity in a model for rheumatoid arthritis in rats. Nat Genet 1998, 20: 401-404. 

5. Sundvall M, Jirholt J, Yang H-T, Jansson L, Engström Å, Pettersson U, Holmdahl R. Identification of murine loci associated with susceptibility 

to chronic experimental autoimmune encephalomyelitis. Nat Genet 1995, 10: 313-317.


Partner 17a: London (D.J. Brooks) 

Neurology Group, MRC Clinical Sciences Centre, Hammersmith Hospital, Imperial College London, UK 

The MRC Clinical Sciences Centre has well established laboratories for carrying out molecular imaging research in 

humans and animals along with programmes in genomics, proteomics, and immunology. The Cyclotron Building, 

Hammersmith Hospital, has working groups dealing with PET instrumentation physics, image coregistration, 

radiochemistry, neurodegenerative diseases, cerebral ischemia, psychiatry, oncology, and gene and stem cell-based 

therapies. The Cyclotron Building houses three dedicated high-resolution PET scanners (Siemens ECAT HR+, HR++, 

and 953B), a small animal PET (Siemens CTI), and a quad HIDAC camera. The NMR unit houses 3T human and a 7T 

animal MRIs (Phillips). The Hammersmith Group, therefore, has all infrastructure necessary to carry out innovative 

research integrating PET, MRI, and molecular medicine. 

The MRC Clinical Sciences Centre plays an essential role in neuroscience research at Imperial College London, 

translating gene and stem cell therapy into the clinic, phenotyping neurodegenerative disease, investigating new 

treatment modalities in neurodegenerative disease and therapies in oncology. The MRC CSC has close interactions with 

the Division of Neuroscience, ICL, which runs disease orientated clinics and provides deep brain stimulation and 

neuropathology for correlation of PET data with histological findings. The MRC CSC has a close collaboration with the 

Neurorestoration Programme at Lund University (Olle Lindvall and Anders Bjorklund). It has held an EC Biomed 5 

Shared Cost Grant – “Microglial activation in neurodegeneration in Alzheimer’s disease: A therapeutic target?” 

(£102,090 to this site) Jan 2000 – Dec 2002 and an EC Biomed2 Shared Cost Grant - BMH4-CT95-0341 “Development 

of a cell transplantation therapy for patients with Parkinson’s Disease” (450,000 ECU) Jan 1996 - June 1999. 


1. Prof. Dr. D.J. Brooks: Head of Neurology, MRC Clinical Sciences Centre, Imperial College London. Imaging of 

Parkinson’s and Alzheimer’s diseases with PET and MRI. 

2. Dr. P. Piccini: Senior Lecturer in Neurology, Imperial College London. Imaging of Parkinson’s disease with PET and 

MRI. Further members of the group: Dr. N Pavese, MRC Clinical Research Associate, MRC Clinical Sciences 

Centre, Imperial College London. Imaging of Parkinson’s disease with PET and MRI. 12 clinical research fellows. 

3. Physicists, kinetic modellers, and Radiochemists at Cyclotron Building, Hammersmith; Imanet PLC 

References 

Imaging transplantation function 

1. Piccini P, Brooks DJ, Bjorklund A, Gunn RN, Grasby PM, Rimoldi O, Brundin P, Hagell P, Rehncrona S, Widner H, Lindvall O. Dopamine 

release from nigral transplants visualised in vivo in a Parkinson’s patient. Nat Neurosci 1999; 2: 1137-1140. 

2. Hagell P, Schrag AE, Piccini P, Jahanshahi M, Brown R, Odin P, Wenning G, Morrish P, Rehncrona S, Widner H, Brundin P, Rothwell JC, 

Gustavii B, Bjorklund A, Brooks DJ, Marsden CD, Quinn NP, Lindvall O. Sequential bilateral transplantation in Parkinson’s disease: Effects of 

the second graft. Brain 1999; 122: 1121-1132 

3. Wenning GK, Odin P, Morrish PK, Rehncrona S, Widner H, Brundin P, Rothwell JC, Brown R, Gustavii B, Hagell P, Jahanshahi M, Sawle GV, 

Bjorklund A, Brooks DJ, Marsden CD, Quinn NP, Lindvall O. Short- and long-term survival and function of unilateral intrastriatal dopaminergic 

grafts in Parkinson’s disease. Ann Neurol 1997; 42: 95-107 

4. Lindvall O, Sawle G, Widner H, Rothwell JC, Bjorklund A, Brooks DJ, Brundin P, Frackowiak R, Marsden CD, Odin P, Rehncrona S. Evidence 

for long term survival and function of dopaminergic grafts in progressive Parkinson’s disease. Ann Neurol 35: 172-180 


1. Doder M, Rabiner EA, Turjanski N, Lees AJ, Brooks DJ. Tremor in Parkinson’s disease and serotonergic dysfunction: An 11 C-WAY 100635 PET 

study. Neurology 2003; 60: 601-605 

2. Gill SS, Patel NK, Hotton GR, O’Sullivan K, McCarter R, Bunnage M, Brooks DJ, Svendsen CN, Heywood P. Direct brain infusion of glial cell 

line-derived neurotrophic factor (GDNF) in Parkinson’s Disease. Nat Medicine 2003; 9: 589-595 

3. Piccini P, Pavese N, Brooks DJ. An in vivo study of striatal and cortical endogenous dopamine release following pharmacological challenges in 

Parkinson's disease. Ann Neurol 2003; 53: 647-653 

4. Whone AL, Watts RL, Stoessl J, Davis M, David M, Reske S, Nahmias C, Lang AE, Rascol O, Ribeiro MJ, Remy P, Poewe WH, Hauser RA, 

Brooks DJ for the REAL-PET Study Group. Slower progression of PD with ropinirol versus L-dopa: the REAL-PET study. Ann Neurol 2003; 54: 

93-101 

Imaging microglial activation 

1. Gerhard A, Banati RB, Goerres GB, Cagnin A, Myers R, Gunn RN, Turkheimer F, Good CD, Mathias CJ, Quinn NP, Schwarz J, Brooks DJ. 

[ 11 C](R) PK11195 PET imaging of microglial activation in multiple system atrophy. Neurology 2003; 61: 686-689 

2. Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, Jones T, Banati RB. In vivo measurement of microglial activation in 

dementia. Lancet 2001; 358: 461-467. 

3. Banati RB, Cagnin A, Brooks DJ, Gunn RN, Myers R, Jones T, Birch R, Anand P. Long-term trans-synaptic glial responses in the human thalamus 

after peripheral nerve injury. Neuroreport 2001; 12: 3439-3442. 

4. Banati RB, Goerres GW, Brooks DJ, Myers R, Gunn RN, Turkheimer FE, Jones T, Duncan J. PK11195 positron emission tomography imaging of 

activated microglia in Rasmussen’s encephalitis. Neurology 1999; 53: 2199-2203.


Partner 17b: London (H.A. Jones) 

Medicine, Imperial College London, UK 

We have been pursuing research into the non-invasive measurement of pulmonary inflammation using Positron 

Emission Tomography. Using the facilities in the Cyclotron Unit on site, formerly MRC, now Hammersmith Imanet, 

we have carried out a number of studies on animal models of inflammation, using markers to monitor different 

components of the inflammatory process. We have validated these using ex vivo and in vitro techniques. The 

methodology has now been successfully transferred to humans and we have measured inflammation in patients with 

different lung diseases and compared the data with that from normal subjects. We have also carried out studies in 

additional groups of patients in collaboration with the University of Cambridge Clinical School using the facilities in 

the Wolfson Brain Imaging Centre (WBIC). We are planning further clinical research studies at Hammersmith and 

Cambridge and animal studies using microPET in collaboration with WBIC at Cambridge. Our aim is to continue to 

apply the methodology we have already developed, to study progression and natural history of disease in humans 

while identifying, developing and validating new markers for monitoring specific cellular and biochemical 

components of lung disease. These studies will include protein profiling of tissues and biofluids to identify candidate 

targets for imaging. 


1. Dr HA Jones: Research Fellow, development and application of non-invasive methods to assess discrete and 

specific features of inflammation in human lung disease. 

2. Dr PW Ind: Senior Lecturer, Hon Consultant Physician. Bronchial pharmacology of asthma, COPD, cough, use of 

induced sputum techniques, study of labelled platelets and white cells by gamma camera and beta receptors and 

drug deposition using PET. 

3. Prof AR Boobis: Professor of Biochemical Pharmacology. Non-invasive methods for assessing toxicity, 

mechanistic toxicology, protein profiling, in vitro systems, kinetics and drug metabolism 

References 

Pulmonary inflammation and scarring 

1. Jones HA, Marino PS, Shakur BS, Morrell NW. In vivo assessment of lung inflammatory cell activity in patients with COPD and asthma. 

Eur.Respir J. 2003; 21:567-73. 

2. Jones HA, Valind SO, Clark IC, Bolden GE, Krausz T, Schofield JB, Boobis AR, Haslett C. Kinetics of lung macrophages monitored in vivo 

following particulate challenge in rabbits. Toxicol. and Appl. Pharmacol. 2002; 183: 46-54. 

3. Rudd JHF, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, Johnstrom P, Davenport AP, Kirkpatrick PJ, Arch BN, Pickard JD, 

Weissberg PL. Imaging atherosclerotic plaque inflammation with [18F]- fluordeoxyglucose Positron Emission Tomography. Circulation 2002; 

105: 2708 – 2711. 

4. Jones HA, Cadwallader KA, White JF, Uddin M, Peters AM, Chilvers ER. Dissociation between respiratory burst activity and deoxyglucose 

uptake in human neutrophil granulocytes: implications for interpretation of 18 F-FDG PET images. J. Nucl. Med. 2002; 43 652 – 657. 

5. Jones HA, Schofield JB, Krausz T, Boobis AR, Haslett C. Pulmonary fibrosis correlates with duration of tissue neutrophil activation. Am J 

Respir Crit Care Med 1998. 158: 620 - 628. 

6. Jones HA, Sriskandan S, Peters AM, Pride NB, Boobis AR, Haslett C. Dissociation of neutrophil emigration and metabolic activity in lobar 

pneumonia and bronchiectasis. Eur.Respir J 1997 10: 795-803 

7. Qing F, Rahman SU, Rhodes CG, Hayes MJ, Sriskandan S, Ind PW, Jones T, Hughes JMB. Pulmonary and cardiac beta-adrenoceptor density 

in vivo in asthmatic subjects. Am J Respir Crit Care Medicine. 1997 ; 155(3):1130-1134. 

8. Taylor IK, Hill AA, Hayes M, Rhodes CG, O'Shaunessy KM, O'Connor BJ, Jones HA, Hughes JMB, Jones T, Pride NB, Fuller RW. Imaging 

allergen-invoked airway inflammation in atopic asthma with [ 18 F]-fluorodeoxyglucose and positron emission tomography. Lancet. 1996. 347: 

937-940. 

9. Hayes MJ, Qing F, Rhodes CG, Rahman SU, Ind PW, Sriskandan S, Jones T, and Hughes JMB. In vivo quantification of human pulmonary β- 

adrenoceptors: effect of β-agonist therapy. Am. J. Respir. Crit. Care Med. 1996 ; 154:1277-1283. 

10. Mason GR, Peters AM, Myers MJ, Ind PW, Hughes JMB. The effect of inhalation of Platelet activating factor on the pulmonary clearance of 

Tc-99m DTPA aerosol. Am Rev Resp Dis Critical Care Med 1995 ; 151: 1621-1624. 

11. Jones HA, Clark RJ, Rhodes CG, Schofield JB, Krausz T, Haslett C. In vivo measurement of neutrophil activity in experimental lung 

inflammation. Am J Respir Crit Care Med 1994; 149: 1635-1639. 

12. Tam FWK, Clague J, Dixon CMS, Stuttle AWJ, Henderson BL, Peters AM, Lavender JP, Ind PW. Inhaled platelet activating factor causes 

pulmonary neutrophil sequestration in normal humans. Am Rev Respir Dis 1992; 146: 1003-08. 

13. Ind PW, Peters AM, Malik F, Lavender JP. Pulmonary platelet kinetics in asthma. Thorax 1985; 40: 412-417.


Partner 18: Barcelona (I. Carrio) 

Department of Nuclear Medicine, Hospital Sant Pau and CETIR Foundation, Autonomous University of 

Barcelona, Spain 

The group in Barcelona has the following equipment available for research: Cyclotron (CETIR Foundation) GE PET 

Trace and Radiochemistry / Radiopharmacy Laboratory currently producing several radioligands for molecular 

imaging in research using PET. There is one PET scanner (GE Advance) for human use and a MicroPET system 

(Argus, Suinsa) for small animal imaging (CETIR Foundation). Three gamma cameras, including one combined with 

a low dose CT scanner are available for research. The group is currently engaged in several national and EU research 

programs on molecular imaging in clinical and basic research in the field of cardiovascular molecular imaging and 

PET: EUREKA FIT0700002000693, PROPET (EU-2604), IBEROEKA FIT0700002001811. Main research interests 

are focused on the fields of cardiovascular imaging and oncology, evaluated by nuclear medicine techniques, 

including gamma camera imaging and PET. 


1. Ignasi Carrio: Director of Department of Nuclear Medicine at Hospital Sant Pau and Professor of Nuclear 

Medicine at Autonomous University of Barcelona. Molecular Imaging in cardiovascular diseases, targeting of 

myocardial necrosis and apoptosis and characterization of vulnerable plaque. 

2. Montserrat Estorch (MD). Associate Professor of Nuclear Medicine. Molecular Imaging in cardiovascular 

diseases. Myocardial innervation and function. 

3. Albert Flotats (MD). Associate Professor of Nuclear Medicine. Characterization of myocardial metabolism and 

function. Cardiac PET. 

4. Valle Camacho (MD). Nuclear Medicine Physician. Molecular imaging in cardiovascular diseases. Small animal 

imaging. 

5. Gregori Valencia (PhD). Chemist. Established investigator (CSIC). Design of molecular probes for molecular 

imaging. 

6. Carlos Piera (PhD). Chemist and Radiopharmacist. Cyclotron products. Production of molecular probes for PET. 

7. Angels Hernandez (Pharmacist). Production of cyclotron products. Laboratory testing of new radioligands. 

References 

1. Udelson JE, Schafer CD, Carrió I. Radionuclide imaging in heart failure: assessing etiology and outcomes and implications for management. J 

Nucl Cardiol 2002; 9(5): 40S-52S. 

2. Pons G, Ballester M, Borrás X, Carreras I, Carrio I. Myocardial Cell Damage in Human Hypertension. J Am Coll Cardiol 2000; 36: 2198- 

2203. 

3. Flotats A, Domingo P, Carrió I. Dilated Cardiomyopathy in HIV-Infected Patients. N Engl J Med 1999; 340(9): 669-744. 

4. Estorch, M.Campreciós, I.Carrió et al. Sympathetic reinnervation of cardiac allografts evaluated by 123I-MIBG imaging. J Nucl Med 1999; 

40: 911-916. 

5. Carrió I, Pieri PL, Narula J, Prat L, Riva P, Pedrini L, Pretolani E, Caruso G, Sarti G, Estorch M, Berna L, Riambau V, Matias-Guiu X, Pak C, 

Ditlow C, Chen F, Khaw BA. Noninvasive localization of human atherosclerotic lesions with indium-labeled monoclonal Z2D3 antibody 

specific for proliferating smooth muscle cells. J Nucl Cardiol 1998; 6: 551-557.


Partner 19: Paris (S. Charpak) 

EPI 0002 Inserm, ESPCI, Paris, France 

The EPI 0002 Inserm is a laboratory composed of neurophysiologists and physicists whose goal is to use and develop 

new optical tools dedicated to functional imaging of neuronal and vascular activity in vivo, with micrometer and 

millisecond time resolutions. The laboratory is now currently using 3 custom-built two-photon microscopes to analyse 

i) calcium dynamics in olfactory bulb neurons, ii) odor-evoked vascular responses in olfactory bulb glomeruli and iii) 

intrinsic signals with new types of imaging. Part of the laboratory is also specialised in single-cell RT-PCR and 

electrophysiology in vitro and in vivo. 


1. Prof. Dr. S. Charpak: Director of the laboratory of neurophysiology and EPI0002. Two-photon imaging and 

electrophysiology in vivo. 

2. Dr. E. Audinat: Electrophysiology and single-cell RT-PCR in vitro. 

References 

Two-photon imaging and olfactory bulb physiology 

1. Chaigneau, E., Oheim, M., Audinat, E., and Charpak , S. Two-photon imaging of the vascular flow in the rat olfactory bulb. Proc. Natl. Acad. 

Sci. U. S. A. 2003; in press 

2. Leobon, B., Garcin, I., Menasché. P, Vilquin, J. T, Audinat, E., and Charpak, S. Myoblasts transplanted into infarcted myocardium are 

functionally isolated from their host. Proc. Natl. Acad. Sci. U. S. A 2003; 100, 7808-7811. 

3. Debarbieux, F., Audinat, E., and Charpak, S. Action potential propagation in dendrites of rat mitral cells in vivo. J. Neurosci. 2003; 23, 5553- 

5560. 

4. Charpak, S., Mertz, J., Beaurepaire, E., Moreaux, L., & Delaney, K.. Odor-evoked calcium signals in dendrites of rat mitral cells. Proc. Natl. 

Acad. Sci. U. S. A 2001; 98, 1230-1234. 

5. Moreaux, L., Sandre, O., Charpak, S., Blanchard-Desce, M., & Mertz, J.. Coherent scattering in multi-harmonic light microscopy. Biophys. J. 

2001; 80, 1568-1574. 

Electrophysiology coupled to single-cell RT-PCR 

1. Christophe, E., Roebuck, A., Staiger, J.F., Lavery, D.J., Charpak, S., & Audinat, E.. Two types of nicotinic receptors mediate an excitation of 

neocortical layer I interneurons. J. Neurophysiol. 2002; 88, 1318-1327. 

2. Cauli B, Porter JT, Tsuzuki K, Lambolez B, Rossier J, Quenet B, Audinat E.. Classification of fusiform neocortical interneurons based on 

unsupervised clustering. Proc Natl Acad Sci U S A. 2000; 97, 6144-6149. 

3. Gallopin T, Fort P, Eggermann E, Cauli B, Luppi PH, Rossier J, Audinat E, Muhlethaler M, Serafin M.. Identification of sleep-promoting 

neurons in vitro, Nature 2000; 404, 992-995.


Partner 20: Edinburgh – Glasgow (K.P. Ebmeier) 

SHEFC Brain Imaging Centre for Scotland, West of Scotland Radionuclide Dispensary and Institute of 

Neurological Sciences, Glasgow. 

Edinburgh and Glasgow, only divided by 45km, have a strong history of collaboration in the imaging field. The Brain 

Imaging Centre for Scotland, established by the Scottish Higher Education Funding Council in Edinburgh in 1999, has 

a good record of accomplishment in collaborative structural and functional MRI, MRS and SPECT. Its scientific 

committee includes scientists from Edinburgh, Glasgow, St Andrews, Stirling and Dundee (Chair: Ebmeier). The 

Institute of Neurological Sciences in Glasgow, in collaboration with the West of Scotland Radionuclide Dispensary, 

has been at the forefront of radionuclide development for SPECT for the last 10 years. The Institute has 3 Tesla MRI 

exclusively for brain imaging. The Radionuclide Dispensary has a development facility for novel ligands and in the 

past five years has produced 8 compounds that have been used in in-vivo human studies. Both Edinburgh and 

Glasgow have Neurofocus SPECT cameras. These are state-of-the-art imaging systems with high sensitivity and depth 

independent resolution of between around 5mm. 

The combined expertise of Edinburgh and Glasgow has been recognised by a major donation from the Sackler 

Foundation (€ Mio) to provide an infrastructure to coordinate research between both centres and a donation from the 

Gordon Small Charitable Trust (€ Mio) to establish an eponymous centre for old age psychiatry, emphasising the 

collaboration between north British sites. Apart from funding by the UK Research Councils, there is also now a major 

centre for schizophrenia research funded by the Stanley Foundation. While there is expertise and facilities for MRIrelated 

modalities, there is a long history of SPECT research focussed on the dementias using blood flow and receptor 

ligand tracers. 


1. K P Ebmeier, M.D.: Professor of Psychiatry and Chair of the SHEFC Brain Imaging Centre for Scotland 

Scientific Committee. General and Old Age Psychiatry, SPECT with Blood Flow and Receptor Ligands (Clinical 

and Research Licences for SPECT, issued by the Administration of Radioactive Substances Advisory 

Committee), Coordinator of “SPECT in Dementia”, BMH4 98 3130 (Framework 4). 

2. D Wyper BSc PhD: Professor of Medical Physics, Department of Clinical Physics, Institute of Neurological 

Sciences, South Glasgow University Hospitals NHS Trust, Southern General Hospital. SPECT with Blood Flow 

and Receptor Ligands in dementia, schizophrenia, depression and glioma 

3. J Owens, BSc., PhD: Senior Clinical Scientist, West of Scotland Radionuclide Dispensary, North Glasgow 

University Hospitals NHS Trust, Western Infirmary. Radiochemistry of I-123-labelled SPECT Ligands 

4. J Patterson BSc PhD: Head of Neuro-SPECT, Department of Clinical Physics, Institute of Neurological 

Sciences, South Glasgow University Hospitals NHS Trust, Southern General Hospital. SPECT with Blood Flow 

and Receptor Ligands in neuro-oncology, neuro-psychiatry, and neurology 

5. D Hadley MD PhD: Professor of Neuroradiology, Department of Neuroradiology, Institute of Neurological 

Sciences, South Glasgow University Hospitals NHS Trust, Southern General Hospital. Clinical SPECT and MRI 

6. J Cavanagh MPhil MD: Senior Lecturer in Psychiatry, University of Glasgow, Department of Psychological 

Medicine, Gartnavel Royal Hospital. Use of perfusion SPECT and molecular imaging [DAT, SERT and 

nicotinic receptor] in major depression. 

7. D Grossett MD: Consultant Neurologist, Department of Neurology, Institute of Neurological Sciences, South 

Glasgow University Hospitals NHS Trust, Southern General Hospital. Dopamine transporter imaging with 

SPECT in the diagnosis of movement disorders 

8. D Brown MD: Consultant in Old Age Psychiatry, Greater Glasgow Primary Care NHS Trust, Gartnavel Royal 

Hospital. SPECT perfusion and cholinergic receptor imaging in dementia 

9. R Hunter MD FRCPsych: R&D Director and Consultant Psychiatrist, Greater Glasgow Primary Care NHS Trust, 

Gartnavel Royal Hospital, Glasgow. SPECT perfusion imaging in dementia and schizophrenia 

10. S Pimlott BSc: Radiochemist and neuro-scientist, West of Scotland Radionuclide Dispensary, North Glasgow 

University Hospitals NHS Trust, Western Infirmary. Radiochemistry of I-123-labelled SPECT ligands 

11. M Dempsey BSc: Clinical Physicist specialising in neuro-imaging, Department of Clinical Physics, Institute of 

Neurological Sciences, South Glasgow University Hospitals NHS Trust, Southern General Hospital. Image 

analysis in SPECT and MRI. 

12. D Brennan BSc: Clinical Physicist specialising in neuro-imaging, Department of Clinical Physics, Institute of 

Neurological Sciences, South Glasgow University Hospitals NHS Trust, Southern General Hospital. Image 

fusion and computer analysis 

13. J Lonie BA (hons.) Psychology, Master in Clinical Neuropsychology: Clinical Neuropsychologist, specialising 

in neuropsychological assessment of the elderly, esp. dementia; Lothian Primary Care NHS Trust, Care of the 

Elderly Services, Division of Psychiatry, University of Edinburgh.


14. N Dougall BSc Physics: Research Fellow in Neuroimaging, specialising in functional neuroimaging of the 

elderly, esp. dementia Division of Psychiatry, University of Edinburgh. 

15. J Best, FRCR: Professor of Radiology, Division of Psychiatry, University of Edinburgh. 

References 


1. Pimlott SL, Piggott M, Owens J, Greally E, Court JA, Jaros E, Perry RH, Perry EK, Wyper D. Nicotinic Acetylcholine Receptor Distribution in 

Alzheimer's Disease, Dementia with Lewy Bodies, Parkinson's Disease, and Vascular Dementia: In Vitro Binding Study Using 5-[(125)I]-A- 

85380. Neuropsychopharmacology. 2003 Sep 3 

2. Piggott MA, Owens J, O'Brien J, Colloby S, Fenwick J, Wyper D, Jaros E, Johnson M, Perry RH, Perry EK. Muscarinic receptors in basal 

ganglia in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease. J Chem Neuroanat. 2003 Mar;25(3):161-73. 

3. Piggott M, Owens J, O'Brien J, Paling S, Wyper D, Fenwick J, Johnson M, Perry R, Perry E. Comparative distribution of binding of the 

muscarinic receptor ligands pirenzepine, AF-DX 384, (R,R)-I-QNB and (R,S)-I-QNB to human brain. J Chem Neuroanat. 2002 

Sep;24(3):211-23. 

Nuclear Medicine and Physics of SPECT 

1. Erlandsson K, Bressan RA, Mulligan RS, Gunn RN, Cunningham VJ, Owens J, Wyper D, Ell PJ, Pilowsky LS. Kinetic modelling of 

[123I]CNS 1261--a potential SPET tracer for the NMDA receptor. Nucl Med Biol. 2003 May;30(4):441-54. 

2. Stamatakis EA, Wilson JT, Hadley DM, Wyper DJ. SPECT imaging in head injury interpreted with statistical parametric mapping. J Nucl 

Med. 2002 Apr;43(4):476-83. 

3. Stamatakis EA, Wilson JT, Wyper DJ. Spatial normalization of lesioned HMPAO-SPECT images. Neuroimage. 2001 Oct;14(4):844-52. 

SPECT Imaging in Neurological and Psychiatric Disease 

1. Herholz K, Schopphoff H, Schmidt H, Mielke R, Eschner, W., Scheidhauer K, Schicha H, Heiss W-D, Ebmeier K. Direct comparison of 

spatially normalized PET and SPECT scans in Alzheimer disease. Journal of Nuclear Medicine 2002; 43, 21-26. 

2. MacHale, S.M., Lawrie, S.M., Cavanagh, J.T., Glabus, M.F., Murray, C.L., Goodwin, G.M., Ebmeier, K.P.. Cerebral perfusion in chronic 

fatigue syndrome and depression. British Journal of Psychiatry 2000; 176, 550-556. 

3. Semple, D., Ebmeier, K.P., Glabus, M.F., O'Caroll, R.E., Johnstone, E.C.. Reduction of in vivo binding to the serotonin transporter in the 

cerebral cortex of MDMA (ecstasy) users. British Journal of Psychiatry 1999; 174, 63-69. 

4. Ebmeier, K.P., Glabus, M.F., Prentice, N., Ryman, A., Goodwin, G.M. A voxel based analysis of cerebral perfusion in dementia and depression 

of old age. NeuroImage 1998; 7, 199-208. 

5. Shah, P.J., Ogilvie, A., Goodwin, G.M., Ebmeier, K.P. Clinical and psychometric correlates of dopamine D2 binding in depression. 

Psychological Medicine 1997; 27, 1247-1256.


Partner 21: Bonn (B.K. Fleischmann) 

Institute of Physiology I, University of Bonn 

Bonn has a local network of different institutions and laboratories that are well established in the field of 

cardiovascular research carrying out multidisciplinary stem cell research including the molecular and integrative 

physiological analysis of cells prior and after transplantation. 

The Institute of Physiology I consists of several working groups performing single cell and molecular analysis on 

different types of stem cells. For molecular and functional assessment of the efficacy of transplanting cells for the 

treatment heart failure the group has established novel injury models in mouse. Researchers at the Institute are also 

investigating the mechanism of gas exchange using animal models and performing analysis on humans. 

The unique expertise of the group is the combination of molecular- and cell biological aspects of stem cell biology, 

single cell physiology as well as integrative physiology. Thus, we are investigating engraftment and differentiation of 

transplanted cells at different time points after transplantation starting from integrative physiology (ultrasound of the 

heart, left ventricular catheterization, isometric force measurements) down to the single cell level. In particular ion 

channel expression, sub-cellular Ca 2+ homeostasis and cellular signalling are sensitive read-outs of cell differentiation 

and therefore very helpful for the analysis. 

The Institute of Physiology serves as the center for the cardiovascular research program at the University of Bonn. In 

close collaboration with the Departments of Cardiac Surgery, Cardiology and Anaesthesiology all the necessary 

expertise is available to evaluate the efficacy of different cellular replacement therapies in small and large animals and 

long term to try to bring these novel therapeutic approaches into clinics. 

Furthermore, the Institute of Physiology has close collaborations with international research groups (Stem Cell Center, 

University of Lund (Sweden), Department of Therapeutics, University of Nottingham (UK), Department of Animal 

Physiology, University of Torino (Italy), Department of Animal Biology, University of Pennsylvania (USA)). 


1. Prof. Dr. B.K. Fleischmann: Chairman of the Institute of Physiology I. 

Further members of the group: Dr. Brandt (M.D.): Molecular biologist, establishment of transgenic ES cell 

lines for the identification of early genes participating at cardiac commitment; L. Xia (M.D.): Microsurgery, 

differentiation and characterization of ES cell-derived neurones; Y. Duan (M.D.): Functional characterization 

of early embryonic cardiomyocytes, molecular analysis of gene expression (quantitative and single cell PCR); 

Toktam Hashemi (M.D.): Functional role of bone marrow-derived cells for treatment of heart disorders; M. 

Breitbach (Ph.D. student): In vitro differentiation of stem cells, transdifferentiation of adult stem cells, single 

cell imaging. 

2. Prof. Dr. A. Welz, Dr. W. Röll and Dr. O. Dewald, Department of Cardiac surgery, University of Bonn: Micro- and 

macrosurgery on mice and rats. Functional analysis using ultrasound, Doppler-echocardiography, left ventricular 

catheterization. 

3. Prof. Lüderitz and Dr. K. Tiemann, Department of Cardiology of the University of Bonn: Development of novel 

ultrasound probes for mice, stress echocardiography on mice 

References 

Single Cell Physiology 

1. Liu,Q.H., Fleischmann,B.K., Hondowicz,B., Maier,C.C., Turka,L.A., Yui,K., Kotlikoff,M.I., Wells,A.D., and Freedman,B.D. Modulation of 

Kv channel expression and function by TCR and costimulatory signals during peripheral CD4(+) lymphocyte differentiation. J. Exp. Med. 

2002; 6, 897-909. 

2. Adda,S., Fleischmann,B.K., Freedman,B.D., Yu,M., Hay,D.W., and Kotlikoff,M.I. Expression and function of voltage-dependent potassium 

channel genes in human airway smooth muscle. J. Biol. Chem. 1996; 271 , 13239-13243. 

3. Freedman,B.D., Fleischmann,B.K., Punt,J.A., Gaulton,G., Hashimoto,Y., and Kotlikoff,M.I. Identification of Kv1.1 expression by murine 

CD4-CD8- thymocytes. A role for voltage-dependent K+ channels in murine thymocyte development. J. Biol. Chem. 1995; 70, 22406-22411. 

Cellular signalling 

1. Murakami,M., Fleischmann,B., De Felipe,C., Freichel,M., Trost,C., Ludwig,A., Wissenbach,U., Schwegler,H., Hofmann,F., Hescheler,J., 

Flockerzi,V., and Cavalie,A.. Pain perception in mice lacking the beta3 subunit of voltage-activated calcium channels. J. Biol. Chem. 2002; 

277, 40342-40351. 

2. Bloch,W., Fan,Y., Han,J., Xue,S., Schoneberg,T., Ji,G., Lu,Z.J., Walther,M., Fassler,R., Hescheler,J., Addicks,K., and Fleischmann,B.K.. 

Disruption of cytoskeletal integrity impairs Gi-mediated signaling due to displacement of Gi proteins. J. Cell Biol. 2001; 154, 753-761. 

3. Bloch,W., Fleischmann,B.K., Lorke,D.E., Andressen C, Hops,B., Hescheler J, and Addicks K. Nitric oxide synthase expression and role during 

cardiomyogenesis. Cardiovasc. Res. 1999 ; 43, 675-684. 

4. Ji,G.J., Fleischmann,B.K., Bloch,W., Feelisch,M., Andressen,C., Addicks,K., and Hescheler,J.. Regulation of the L-type Ca2+ channel during 

cardiomyogenesis: switch from NO to adenylyl cyclase-mediated inhibition. FASEB J 1999; 13, 313-324. 

Stem Cell Biology 

1. Lenka,N., Lu,Z.J., Sasse,P., Hescheler,J., and Fleischmann,B.K.. Quantitation and functional characterization of neural cells derived from ES 

cells using nestin enhancer-mediated targeting in vitro. J. Cell Sci. 2002; 115, 1471-1485. 

2. Kazemi, S, Wenzel, D, Kolossov, E, Lenka, N., Raible, A, Sasse, P., Hescheler J, Addicks K, Fleischmann B.K., and Bloch, W. Differential 

role of bFGF and VEGF for vasculogenesis. Cellular Physiology and Biochemistry. 2002; 12, 55-62.


3. Kolossov,E., Fleischmann,B.K., Liu,Q., Bloch,W., Viatchenko-Karpinski,S., Manzke,O., Ji,G.J., Bohlen,H., Addicks,K., and Hescheler,J.. 

Functional characteristics of ES cell-derived cardiac precursor cells identified by tissue-specific expression of the green fluorescent protein. J. 

Cell Biol. 1998; 143, 2045-2056 

Cellular replacement 

1. Roell, W, Fan, Y., Xia Y, Stoecker E, Sasse, P., Kolossov E., Bloch, W., Metzner H, Schmitz, C., Addicks K, Hescheler J, Welz, A., and 

Fleischmann B.K. Cellular cardiomyoplasty in a transgenic mouse model. Transplantation 2002; 73, 462-465. 

2. Roell,W., Lu,Z.J., Bloch,W., Siedner,S., Tiemann,K., Xia,Y., Stoecker,E., Fleischmann,M., Bohlen,H., Stehle,R., Kolossov,E., Brem,G., 

Addicks,K., Pfitzer,G., Welz,A., Hescheler,J., and Fleischmann,B.K.. Cellular cardiomyoplasty improves survival after myocardial injury. 

Circulation 2002; 105, 2435-2441. 


1. Hoehn,M., Kustermann,E., Blunk,J., Wiedermann,D., Trapp,T., Wecker,S., Focking,M., Arnold,H., Hescheler,J., Fleischmann,B.K., 

Schwindt,W., and Buhrle,C.. Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging 

investigation of experimental stroke in rat. Proc. Natl. Acad. Sci. 2002; 99, 16267-16272.


Partner 22: Stockholm (C. Halldin) 

Karolinska Institute, Department of Clinical Neuroscience, Psychiatry Section, Stockholm, Sweden 

The Karolinska Institute is a governmental organisation for research and education in the field of medicine. The PETand 

MRI-centres at the Karolinska Hospital are organized within the Department of Clinical Neuroscience. The 

Karolinska PET-center started in the 70’s and was one of the first in the world. The early activities were characterized 

by strong technical development of PET-systems within industrial collaborations. The group was among the pioneers 

in the development of quantitative studies on neurotransmission systems and its application to the diagnosis and 

treatment of neuropsychiatric disorders. The MRI-center was inaugurated in 1992. The activities are focused on 

development of methods for all major aspects of MRI including spectroscopy and a dedicated system for animal 

research including monkey studies. The laboratory for Neuropsychiatric PET-research has about 30 members and is 

located at the psychiatric clinic adjacent to the Karolinska PET-center. The research activities follow three major lines 

i.e. the development of new radioligands for PET-imaging of neuroreceptors, the use of PET in drug development, and 

applied studies in major psychiatric disorders such as schizophrenia and depression. The group received highest 

recommendations at a recent international hearing of neuroscience at the Karolinska Institute and has received a series 

of prestigious international awards during recent years. At the international level, the laboratory is supported by the 

NIMH (USA) and participates in collaborative programs with centres in Europe, USA and Japan. 


1. Prof. Dr. L. Farde: Professor of Psychiatry at the Department of Neurology, 20 years of experience in PETresearch, 

one of the pioneers at brain imaging of neuroreceptors, modelling, pharmacology, and clinical research 

2. Prof. Dr. C. Halldin: Professor of Medicinal Radiochemistry, more than 25 years of contribution of radioligands 

used world-wide, radioligand development and characterization 

3. Ass. Prof. B. Gulyas: neurologist, image analysis, animal studies 

4. Ass. Prof. A-L. Nordström: psychiatrist, Head of the Psychiatry Section, clinical studies 

5. Ass. Prof. H. Hall: neurobiologist, post-mortem human autoradiography 

6. Dr. Bengt Andree: psychiatrist, clinical pharmacology 

Further members of the group: Dr. Per Karlsson, image analysis, Dr. Mirjam Talvik, psychopharmacoloy, Dr. 

Evgeny Shchukin, radiochemist, Dr. Judith Sovago, animal pharmacology, Dr Zsolt, Cselenyi, image analysis 

References 

Neuroscience 

1. Varnäs K., Halldin C., Pike VW, Hall H. Distribution of 5-HT4 receptors in the postmortem human brain – an autoradiographic study using 

[125I]SB 207710. Eur Neuropsychopharm 2003;13:228-234. 

2. Halldin C., Erixon-Lindroth N., Pauli S., Chou Y-H, Okubo Y., Karlsson P., Lundkvist C., Olson H., Guilloteau D., Emond P, Farde L. 

[11C]PE2I – a highly selective radioligand for PET-examination of the dopamine transporter in monkey and human brain. Eur J Nucl Med 

Mol Imaging 2003;30:1220-1230. 

3. Suhara T., Okubo Y, Yasuno F., Halldin C, Farde L. Decreased dopamine D2 receptor binding in the anterior cingulate cortex in schizophrenia. 

Arch Gen Psych 2002;59:25-30. 

4. Karlsson P., Farde L., Halldin C., Sedvall G. D1-dopamine receptor binding in neuroleptic naive patients with schizophrenia – a PET-study. A 

J Psychiatry 2002;159,761-767 

5. Farde L, Hall H, Ehrin E, Sedvall G. Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science 

1986;231:258-261.


Partner 23: Orsay (P. Hantraye) 

The ImaGene Program, CEA centre, Fontenay-aux-Roses / Orsay, France 

The ImaGene program is an integrated centre dedicated to pre-clinical trials in gene and cell therapy for 

neurodegenerative, cardiac and hepatic diseases. Based in the CEA centre at Fontenay-aux-Roses, operating in close 

association with the Service Hopsitalier Frédéric Joliot at Orsay (a clinical PET center specialised in brain imaging 

and Molecular Imaging), the ImaGene program gathers research units from various National Research Institutes 

(CEA, INSERM, CNRS) with complementary expertises in various fields concerned by the present Network 

(neurodegenerative disorders such as Parkinson’s, Huntington’s, prion’s diseases, AIDS, cardiac and hepatic 

disorders). This facility comprises very high performance imaging tools: magnetic resonance imaging and NMR 

spectroscopy (4.7T Bruker), positron emission tomograph for primates (microPET Focus, Concord Microsystem), 

level 3 and level 2 microbiologically safe laboratories and animal houses for non-human primates (macaques, 

baboons) and rodents (mice and rats), and laboratories specialised in electrophysiological, behavioural and anatomical 

studies operating under both L2 and L3 biosafety security levels. By bringing together, on a unique site, 

multidisciplinary teams of physicians, physicists, neurobiologists, virologists and imaging specialists, in close 

collaboration with other research bodies in universities, in particular the University of Paris-Sud and the hospitals of 

Île-de-France Sud (Pitié-Salpétrière in Paris, Henri Mondor in Créteil), the ImaGene platform ensure the coordination 

of research, the networking of skills and the optimisation of regional resources in the area of experimental 

neuroscience and therapeutics. 

The ImaGene program focuses on the development of new animal models of human disorders and the development, 

validation and in vivo monitoring of clinically applicable new therapeutic strategies for neurodegenerative diseases, 

cardiac and hepatic disorders. These include interventional surgery, high frequency stimulation, gene therapies and 

cell based therapies. To achieve these goals, ImaGene has close interactions with the Departments of Neurology, 

Neurosurgery and Stereotactic Neurosurgery of Henri Mondor and Pitié-Salpétrière hospitals in the field of neural 

grafting, high frequency stimulation and gene therapy ; Department of Neuroradiology of Henri Mondor Hospital for 

co-registering molecular PET imaging data with anatomical and spectroscopic information obtained by MRI and MRS 

inpatients. Furthermore, ImaGene has close collaborations with many national institutes such as the GVPN (Gene 

Vector Production Network), the Pitié-Salpétrière Hospital, the Henri Mondor Hospital, the Antoine Béclère Hospital; 

many European partners such as The Ecole Polytechnique Fédérale and The Physiology Institute of Lausanne, 

Switzerland, the University of Dundee, Scotland, the Instituto Superiore de Sanita of Rome, Italy, as well as ongoing 

collaborations with international research bodies in the US: Burnham Institute at La Jolla, Cornell University in New 

York; Rush Presbyterian Hospital in Chicago and the Massachusetts Institute of Technology in Boston. 


1. Philippe Hantraye PhD: Neurobiologist Responsible for the ImaGene program, Head of the URA CEA CNRS 

2210 Unit (funding unit of the ImaGene Program), Head of the Isotopic Imaging Unit, at Service Hospitalier 

Frédéric Joliot ; pre-clinical and clinical imaging by PET and MRI/MRS. 

2. Nicole Déglon PhD: Neurobiologist, Molecular Virology; Co-responsible for the ImaGene program; gene transfer 

and gene therapy by HIV based vectors; member of the Society …... 

Further members of the group: E. Brouillet PhD (animal models of neurodegenerative diseases); G. Bonvento 

(neurone-glia interactions); KL Moya (axonal transport and synaptic activity). 

3. Régine Trébossen PhD: Physicist, PET instrumentation, hard- and software development 

Further members of the group: C. Comtat (physics; performance optimization of HRRT and microPET); T. 

Delcescaux and R. Maroy (informatics; software development for image coregistration; integration of projectspecific 

modules into general image processing software packages). 

4. Frédéric Dollé PhD: Radiochemistry, probe development 

Further members of the group: B Kunatz PhD, D. Roeda PhD, (chemistry, radiochemistry; development of new 

molecular imaging probes including macromolecules, peptides). 

5. Philippe Remy MD: Neurologist; PET specialist for Huntington’s and Parkinson’s diseases; in vivo monitoring of 

neuroprotection and neural grafting by PET and MRI/MRS. 

6. Stéphane Palfi MD, PhD: Neurosurgeon, PET imaging of experimental therapeutics (high frequency cortical 

stimulation in Parkinson, neural grafting in Parkinson and Huntington’s patients.


References 

1. Whone AL, Watts RL, Stoessl AJ, Davis M, Reske S, Nahmias C, Lang AE, Rascol O, Ribeiro MJ, Remy P, Poewe WH, Hauser RA, Brooks 

DJ; REAL-PET Study Group. Slower progression of Parkinson's disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol. 

2003 Jul;54(1):93-101. 

2. Thobois S, Ribeiro MJ, Lohmann E, Durr A, Pollak P, Rascol O, Guillouet S, Chapoy E, Costes N, Agid Y, Remy P, Brice A, Broussolle E; 

French Parkinson's Disease Genetics Study Group. Young-onset Parkinson disease with and without parkin gene mutations: a fluorodopa F 18 

positron emission tomography study. Arch Neurol. 2003 May;60(5):713-8. 

3. Bizat N, Hermel JM, Boyer F, Jacquard C, Creminon C, Ouary S, Escartin C, Hantraye P, Kajewski S, Brouillet E. Calpain is a major cell 

death effector in selective striatal degeneration induced in vivo by 3-nitropropionate: implications for Huntington's disease. J Neurosci. 2003 

Jun 15;23(12):5020-30. 

4. Henry PG, Lebon V, Vaufrey F, Brouillet E, Hantraye P, Bloch G. Decreased TCA cycle rate in the rat brain after acute 3-NP treatment 

measured by in vivo 1H-[13C] NMR spectroscopy. J Neurochem. 2002 Aug;82(4):857-66. 

5. Pain F, Besret L, Vaufrey F, Gregoire MC, Pinot L, Gervais P, Ploux L, Bloch G, Mastrippolito R, Laniece P, Hantraye P. In vivo 

quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal-resolution beta +-sensitive 

microprobe. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10807-12. 

6. Palfi S, Leventhal L, Chu Y, Ma SY, Emborg M, Bakay R, Deglon N, Hantraye P, Aebischer P, Kordower JH. Lentivirally delivered glial cell 

line-derived neurotrophic factor increases the number of striatal dopaminergic neurons in primate models of nigrostriatal degeneration. J 

Neurosci. 2002 Jun 15;22(12):4942-54. 

7. Mittoux V, Ouary S, Monville C, Lisovoski F, Poyot T, Conde F, Escartin C, Robichon R, Brouillet E, Peschanski M, Hantraye P. 

Corticostriatopallidal neuroprotection by adenovirus-mediated ciliary neurotrophic factor gene transfer in a rat model of progressive striatal 

degeneration. J Neurosci. 2002 Jun 1;22(11):4478-86. 

8. Ribeiro MJ, Vidailhet M, Loc'h C, Dupel C, Nguyen JP, Ponchant M, Dolle F, Peschanski M, Hantraye P, Cesaro P, Samson Y, Remy P. 

Dopaminergic function and dopamine transporter binding assessed with positron emission tomography in Parkinson disease. Arch Neurol. 

2002 Apr;59(4):580-6. 

9. Poyot T, Conde F, Gregoire MC, Frouin V, Coulon C, Fuseau C, Hinnen F, Dolle F, Hantraye P, Bottlaender M. Anatomic and biochemical 

correlates of the dopamine transporter ligand 11C-PE2I in normal and parkinsonian primates: comparison with 6-[18F]fluoro-L-dopa. J Cereb 

Blood Flow Metab. 2001 Jul;21(7):782-92. 

10. Henry PG, Dautry C, Hantraye P, Bloch G. Brain GABA editing without macromolecule contamination. MRM. 2001 Mar;45(3):517-20. 

11. Beal MF, Hantraye P. Novel therapies in the search for a cure for Huntington's disease. Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):3-4. 

12. Bachoud-Levi AC, Remy P, Nguyen JP, Brugieres P, Lefaucheur JP, Bourdet C, Baudic S, Gaura V, Maison P, Haddad B, Boisse MF, 

Grandmougin T, Jeny R, Bartolomeo P, Dalla Barba G, Degos JD, Lisovoski F, Ergis AM, Pailhous E, Cesaro P, Hantraye P, Peschanski M. 

Motor and cognitive improvements in patients with Huntington's disease after neural transplantation. Lancet. 2000 Dec 9;356(9246):1975-9. 

13. Kordower JH, Emborg ME, Bloch J, Ma SY, Chu Y, Leventhal L, McBride J, Chen EY, Palfi S, Roitberg BZ, Brown WD, Holden JE, 

Pyzalski R, Taylor MD, Carvey P, Ling Z, Trono D, Hantraye P, Deglon N, Aebischer P. Neurodegeneration prevented by lentiviral vector 

delivery of GDNF in primate models of Parkinson's disease. Science. 2000 Oct 27;290(5492):767-73. 

14. Mittoux V, Joseph JM, Conde F, Palfi S, Dautry C, Poyot T, Bloch J, Deglon N, Ouary S, Nimchinsky EA, Brouillet E, Hof PR, Peschanski M, 

Aebischer P, Hantraye P.Restoration of cognitive and motor functions by ciliary neurotrophic factor in a primate model of Huntington's 

disease. Hum Gene Ther. 2000 May 20;11(8):1177-87. 

15. Dautry C, Vaufrey F, Brouillet E, Bizat N, Henry PG, Conde F, Bloch G, Hantraye P. Early N-acetylaspartate depletion is a marker of neuronal 

dysfunction in rats and primates chronically treated with the mitochondrial toxin 3-nitropropionic acid. J Cereb Blood Flow Metab. 2000 

May;20(5):789-99. 

16. Palfi S, Conde F, Riche D, Brouillet E, Dautry C, Mittoux V, Chibois A, Peschanski M, Hantraye P. Fetal striatal allografts reverse cognitive 

deficits in a primate model of Huntington disease. Nat Med. 1998 Aug;4(8):963-6.


Partner 24: Juelich (A. Bauer, H. Herzog) 

Institute of Medicine (Molecular Neuroimaging Laboratory), Forschungszentrum Juelich (FZJ), Juelich, 

Germany. 

The Institute of Medicine (IME) is part of the Forschungszentrum (Research Center) Juelich (FZJ), the largest of the 

15 Helmholtz Research Centres in Germany (staff of 4200) and characterized by a multidisciplinary research 

approach. The FZJ has recently inaugurated a neuroscience program. To cover all levels of scientific and 

methodological complexity, four institutes (Institute of Medicine, IME; Institutes of Biological Information, IBI-1 & 

2; Institute of Nuclear Chemistry, INC; Central Laboratory of Electronics, ZEL) concentrate their efforts in this 

programme. Thematically, the competences of the groups span from molecular biology to cellular neuroscience, 

human brain mapping, regional and cellular transmitter receptor imaging to functional human brain imaging. 

Methodologically, the participants cover all techniques from the structural analysis of single molecules to nuclear 

chemistry, electronics, MEG (magnetic encephalography), MRI (magnetic resonance imaging), and PET (positron 

emission tomography). This concentration of various competences in one programme integrates neuroscientific with 

technological expertise, molecular/cellular with systemic approaches, and basic with clinically oriented research in the 

neurosciences. 

The IME consists of nine work groups. Its mission is to analyze the relationship of cerebral structure and function, and 

to discover the organization of the living human brain with modern imaging techniques. Research foci are the cerebral 

representation of cognitive and motor functions as well as the role of transmitters and receptors in cerebral 

neurotransmission. The IME is equipped with a high-resolution PET and a SPECT scanner, two MRI scanners (1.5T, 

4T) as well as a MEG whole brain detector. With regard to animal investigations laboratory facilities for all types of 

molecular analysis (autoradiography, in situ hybridization, immunohistochemistry, cell culture etc.) are in place. A 

9.4T dedicated animal MRT will soon be installed. The IME has a history of animal PET scanning, since the first 

animal PET scanner built in Germany, the TierPET, was developed and evaluated at the FZJ. At present, a secondgeneration 

scanner (ClearPET Neuro) is being installed. It is a high-sensitivity, high-resolution small animal PET 

scanner dedicated for receptor PET and the first scanner that has jointly been developed and evaluated by the 

European Crystal Clear Collaboration (CCC). CCC represents a network of world-wide leading experts in detectors, 

based on inorganic scintillators, for basic research and applications to develop small animal PET scanners based at 

VUB Brussels, IHPE Lausanne, CERMEP/ Unipe Lyon, CERN, Geneva. 

With regard to clinically oriented research the IME has been elected as a “Center of Excellence for Imaging in 

Clinical Neurosciences” by the German Federal Ministry of Education and Research. A dedicated research ward for 

neurologic and psychiatric patients is currently under construction. The IME has multiple collaborations with national 

and international research groups (National programmes, e. g. SFB 194, 575, DFG programmes for “Klinische 

Forschergruppen”, “Forschergruppen”, VW-grant programme, DFG-supported programme for high-field MRI. 

International collaborative programmes, e. g. MRC Neuropsychology Programme, Oxford, Human Brain Mapping 

group in the “International Consortium of Human Brain Mapping” funded by the National Institute of Mental Health, 

National Institute of Neurological Disorders and Stroke, National Institute on Drug Abuse, and the National Cancer 

Institute, USA; EU-funded Role of the parietal cortex in sensorimotor interaction programme, Parma, Italy. Crystal 

Clear Collaboration (R&D project, CERN, Geneva, Switzerland) etc. 


1. Dr. A. Bauer (speaker): Neurologist; Laboratory for Molecular Neuroimaging; receptor pharmacology/imaging in 

vitro (autoradiography, immunohistochemistry) and in vivo (PET, animal PET, high-field MRT). 

Further members of the group: Dr. C. Boy, D. Elmenhorst, Dr. R. Hurlemann, Dr. V. Labrovic, Dr. P. T. 

Meyer, physicians; Dr. M. Dehnhardt, Dr. N. Palomero-Gallagher, P. Reiprich, biologists; A. Börner, M. 

Cremer, S. Herzig, S. Krause, S. Wilms, technicians. 

2. Prof. Dr. K. Zilles: Director of the IME and of the C. & O. Vogt Institute of Brain Research, Düsseldorf, Germany, 

autoradiography, brain mapping, integrative neuroscience. 

3. Prof. Dr. H. H. Coenen: Nuclear Chemist, ligand development. 

Further members of the group: Dr. M. Holschbach, Dr. D. Bier, Dr. K. Hamacher, B. Krebs, W. Sihver, J. 

Ermert, chemists; B. Palm, S. Grafmüller, E. Wabbals, technicians. 

4. Prof. Dr. H. Herzog: PET-Physics, instrumentation, hard- and software development. Group members: Dr. E. Rota- 

Kops, physicist; L. Tellmann, S. Schaden, E. Theelen, technicians. 

5. Dr. N. J. Shah: MR physics, instrumentation, hard- and software development. Group members: Dr. T. Dierkes, Dr. 

H. Neeb, Dr. R. Huang, Dr. O. Poznansky, Dr. S. Romanzetti, Dr. A. Oros, Dr. T. Stoecker, physicists; B. 

Elghahwagi, G. Oeffler, P. Engels, technicians.


References 

Receptor Imaging 

1. Bauer, A.; Holschbach, M.H.; Meyer, P.T.; Boy, C.; Herzog, H.; Olsson, R.A.; Coenen, H.H.; Zilles, K.: In vivo imaging of adenosine A1 

receptors in the human brain with [18F]CPFPX and positron emission tomography. Neuroimage 2003; 19, 1760-1769. 

2. Bauer, A.; Holschbach, M.H.; Cremer, M.; Weber, S.; Boy, C.; Shah, N.J.; Olsson, R.A.; Halling, H.; Coenen, H.H.; Zilles, K.; Evaluation of 

18 F-CPFPX, a Novel Adenosine A 1 Receptor Ligand: In Vitro Autoradiography and High Resolution Small Animal PET. J Nucl Med 2003; 44, 

1682-1689. 

3. Meyer, P.T.; Bier, D.; Holschbach, M.H.; Cremer, M.; Tellmann, L.; Bauer, A.: In vivo imaging of rat brain A1 adenosine receptor occupancy 

by caffeine. Eur J Nucl Med Mol Imaging 2003; 30(10), 1440. 

4. von Hörsten, S.; Schmitt, I.; Nguyen, H.P.; Holzmann, C.; Schmidt, T.; Walther, T.; Bader, M.; Pabst, R.; Kobbe, P.; Krotova, J.; Stiller, D.; 

Kask, A.; Vaarmann, A.; Rathke-Hartlieb, S.; Schulz, J.B.; Grasshoff, U.; Bauer, A.; Li, X.J.; Riess, O.: Transgenic rat model of Huntington’s 

disease. Hum Mol Gen 2003; 12(6), 617-624. 

5. Härtig, W.; Bauer, A.; Brauer, K.; Grosche, J.; Hortobagyi, T.; Penke, B.; Schliebs, R.; Harkany, T.: Functional recovery of cholinergic basal 

forebrain neurons under disease conditions: Old problems, new solutions? Rev Neurosci 2002; 13, 95-165. 

Ligand Development 

1. Holschbach,M. H.; Wutz,W.; Olsson,R. A. Synthesis of 2-benzyl-2H-pyrazole-3,4-diamine dihydrochloride. Tetrahedron 2003; 44, 41 – 43. 

2. Holschbach,M.H.; Wutz,W.; Schüller,M.; Bier,D.; Coenen,H. H. Tritium-labelled 8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine 

([3H]CPFPX), a potent and selective antagonist for the A1 adenosine receptor. J labelled compd rad 2003; 46: 365-372. 

3. Holschbach,M. A.; Olsson,R. A. Applications of adenosine receptor ligands in medical imaging by positron emission tomography Curr pharm 

design 2002; 8, 26: 2345 – 2352. 

4. Holschbach,M.H.; Olsson,R. A.; Bier,D.; Wutz,W.; Schüller,M.; Palm,B.; Coenen,H. H. Radiosynthesis and evaluation of n.c.a. 8-cyclopentyl- 

3-(3-[18F]fluoroprophyl)-l-propylxynthine ([18F]CPFPX), a potent and selective A1-adenosine receptor antagonist J med chem 2002; 45: 

5150 – 5156. 

Instrumentation Physics PET 

1. Buchholz, H. G., Herzog, H., Förster, G. J., Reber, H., Nickel, O., Rösch, F., Bartenstein, P. PET imaging with yttrium-86: comparison of 

phantom measurements acquired with different PET scanners before and after applying background subtraction. Eur J Nucl Med Mol Imaging 

2003; 30:716-720. 

2. Herzog H, Tellman L, Qaim SM, Spellerberg S, Schmid A, Coenen HH. PET quantitation and imaging of the non-pure positron-emitting 

iodine isotope 124I. Appl Radiat Isot. 2002; 56(5):673-9. 

3. Kemna LJ, Posse S, Tellmann L, Schmitz T, Herzog H. Interdependence of regional and global cerebral blood flow during visual stimulation: 

an O-15-butanol positron emission tomography study. J Cereb Blood Flow Metab. 2001; 21(6):664-70. 

4. Weber, S.; Bauer, A.; Herzog, H.; Kehren, F.; Mühlensiepen, H.; Vogelbruch, J.; Coenen, H. H.; Zilles, K.; Halling, H. Recent results of the 

TierPET scanner IEEE T Nucl Sci 2000; 47, 4, 1665 – 1669. 

5. Weber S, Terstegge A, Herzog H, Reinartz R, Reinhart P, Rongen F, Muller-Gartner HW, Halling H. The design of an animal PET: flexible 

geometry for achieving optimal spatial resolution or high sensitivity. IEEE Trans Med Imaging. 1997 Oct; 16(5):684-9. 

Instrumentation Physics MRT 

1. Shah NJ, Neeb H, Zaitsev M, Steinhoff S, Kircheis G, Amunts K, Häussinger D, Zilles K. Quantitative T1 Mapping of Hepatic Encephalopathy 

using Magnetic Resonance Imaging. Hepatology (in press) 

2. Shah NJ, Zaitsev M, Steinhoff S, Zilles K. A new method for fast multislice T(1) mapping. Neuroimage. 2001;14(5):1175-85. 

3. Steinhoff S, Zaitsev M, Zilles K, Shah NJ. Fast T(1) mapping with volume coverage. Magn Reson Med. 2001;46(1):131-40. 

4. Zaitsev M, Zilles K, Shah NJ. Shared k-space echo planar imaging with keyhole. Magn Reson Med. 2001;45(1):109-17. 

5. Shah NJ, Unlu T, Wegener HP, Halling H, Zilles K, Appelt S. Measurement of rubidium and xenon absolute polarization at high temperatures 

as a means of improved production of hyperpolarized (129)Xe. NMR Biomed. 2000;13(4):214-9.


Partner 25: Cologne (M. Hoehn) 

MPI for Neurological Research, In-vivo-NMR-Laboratory, Germany 

The In-vivo-NMR-Laboratory at the Max-Planck-Institute for Neurological Research houses two dedicated experimental high-field 

MR scanners (4.7T and 7.0T BioSpecs; Bruker BioSpin, Germany) and a high-resolution 300 MHz NMR spectrometer (Bruker, 

Germany). It has a laboratory for invasive multimodal imaging techniques such as autoradiography, bioluminescence, fluorescence, 

immunohistochemistry and histology. Immunohistochemistry is applied to brain slices in conjunction with confocal laser scanning 

microscopy (Leica). Through the close cooperation within the MPI, access to a microPET (Concord, Siemens CTI), and to an 

optical imaging camera (Kodak) exists for the integration of the various imaging modalities (PET, MRI, optical imaging), 

prerequisite for cutting-edge multimodal imaging. The In-vivo-NMR-Laboratory has an international key position in physiologybased 

experimental MRI. The Laboratory has a leading function in combining the non-invasive imaging technique with various 

other complementary measurements such as electrophysiological recording in the magnet. In the emerging field of in vivo MRI 

microscopy the In-vivo-NMR-Laboratoy has an internationally unrivaled position tracking cell dynamics in the host brain tissue. 

With this broad range of expertise the Laboratory plays an active role in neuroscience research at the University of Cologne, and 

beyond. With the research focus on the investigation of new treatment strategies in stroke and other cerebral lesions, and on stem 

cell based regeneration the In-vivo-NMR-Laboratory has close interactions with the Departments of Neurosurgery and Stereotactic 

Neurosurgery concerning stroke and brain tumor investigations and deep brain stimulation; with the Department of Radiology for 

fiber tracking to image functional and structural connectivities in the brain; with the Department of Neurophysiology for the 

investigation of mechanisms of interaction between stem cells and host tissue. With the Laboratory of Gene Transfer and Molecular 

Imaging at MEK (Priv.-Doz. Dr. Andreas Jacobs) there is close interaction aiming at the synergistic application of PET and MR 

microscopy for molecular imaging of stem cell treatment for cerebral lesions. Finally, the In-vivo-NMR-Laboratory has close 

collaborations with international research groups (e.g. EU-Groups involved in EMIL-CANCER; Molecular Imaging Laboratory at 

NINDS, Bethesda). 


1. Prof. Dr. M. Hoehn: Physics; Head of In-vivo-NMR-Laboratory; physiology-based MR imaging of stroke models; MR 

microscopy for stem cell trafficking, multimodal imaging of regeneration after cerebral lesions 

Further members of the group: S. Weber (pathophysiology; animal models; behavior studies); S. Wegener 

(pathophysiology; cell implantation; fMRI); D. Wiedermann (chemistry; NMR specialist; methodological development 

for MR microscopy); K. Kandall (veterinarian; cell culture and cell labeling strategies); U. Himmelreich (physics; MR 

microscopy applications and stem cell dynamics); S. Wecker (physics; MR hardware developments for sensitivity 

optimization; cryo-detectors); C. Sprenger (technician for immunohistochemistry); U. Uhlenküken and M. Diedenhofen 

(technicians for software development of image postprocessing and image data analysis) 

2. Priv.-Doz. Dr. A. Jacobs: Neurologist, Molecular Virology and Imaging; Head of the Laboratory for Gene Therapy and 

Molecular Imaging; imaging exogenous gene expression in gene therapy by HSV-1 based vectors; founding member of the 

Society for Molecular Imaging. 

References 


1. Wecker S, Hörnschemeyer T, Hoehn M. Investigation of insect morphologyby MRI: assessment of spatial and temporal resolution. Magnetic 

Resonance Imaging 2002; 20:105-111 

2. Franke C, Van Dorsten FA, Olah L, Schwindt W, Hoehn M. Arterial spin tagging perfusion imaging of rat brain. Dependency on magnetic 

field strength. Magnetic Resonance Imaging 2000; 18:1109-1113 


1. Niessen F, Hilger T, Hoehn M, Hossmann K-A. Thrombolytic treatment of clot embolism in rat: comparison of intra-arterial and intravenous 

application of recombinant tissue plasminogen activator. Stroke 2002; 33:2999-3005 

2. Fiehler J, Fiebach JB, Gass A, Hoehn M, Kucinski T, Neumann-Haefelin T, Schellinger P, Siebler M, Villringer A, Röther J.Diffusionweighted 

imaging in acute stroke - a tool of uncertain value? Cerebrovascular Diseases 2002 ; 14 : 187-196 

3. Neumann-Haefelin C, Brinker G, Uhlenküken U, Pillekamp F, Hossmann K-A, Hoehn M. Prediction of hemorrhagic transformation after 

thrombolytic therapy of clot embolism: an MRI investigation in rat brain. Stroke 2002; 33:1392-1398 

4. Hilger T, Niessen F, Diedenhofen M, Hossmann K-A, Hoehn M. MR-angiography of thromboembolic stroke in rats: indicator of recanalization 

probability and tissue survival after rt-PA treatment. J Cereb Blood Flow Metab 2002; 22:652-662 

5. Van Dorsten FA, Olah L, Schwindt W, Grüne M, Uhlenküken U, Pillekamp F, Hossmann KA, Hoehn M. Dynamical changes of ADC, 

perfusion and NMR relaxation parameters in transient brain focal ischemia of rat brain. Magnetic Resonance in Medicine 2002; 46: 97-104 


1. Erdö F, Bührle C, Blunk J, Hoehn M, Xia Y, Fleischmann B, Föcking M, Küstermann E, Kolossov E, Hescheler J, Hossmann K-A, Trapp T. 

Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J. Cereb Blood Flow Metab 2003; 20:780-785 

2. Hoehn M. Regeneration potential of embryonic stem cells in experimental infarct: in vivo MRI investigation of stem cell dynamics. Restorative 

Neurology and Neuroscience 2003; 20:227 

3. Hoehn M, Küstermann E, Blunk J, Wiedermann D, Trapp T, Wecker S, Föcking M, Arnold H, Hescheler J, Fleischmann BK, Schwindt W, 

Bührle C. Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of 

experimental stroke in rat. Proc Natl Acad Sci U S A. 2002;99:16267-72


Partner 26: Maastricht (L. Hofstra) 

Netherlands Molecular Imaging Center, Maastricht, Netherlands 

Maastricht’s molecular imaging program ranges from conjugation technology of novel probes to biological imaging in patients with 

a variety of diseases, including cardiovascular disease and cancer. The mission of our center is to deliver cutting edge research 

through a combination of novel image technologies and molecular biological knowledge, with a focus on cardiovascular molecular 

imaging. The program is driven by the fact that for a number of cardiovascular diseases, such as the unstable atherosclerotic plaque 

and heart failure, insufficient diagnostic and therapeutic means exist to fulfill the needs of our patients. The molecular imaging 

center relies on a strong experimental program (Hofstra/Reutelingsperger), which drives a clinical program focused on biological 

imaging of disease (Hofstra/Heidendaal). The experimental program is based on innovative optical imaging methodology, which 

has been developed in our own lab (Nature Medicine 2001). This strategy has resulted in a rapid translation of biological and 

experimental findings into the clinic, which will be of immediate benefit to our patients. The ability of our research team to translate 

basic research finding into clinical studies is reflected by a number of studies in patients with cardiovascular disease (e.g. Lancet 

2000, JAMA 2001). The main assets of our program are: 1. One of the major strengths of our set-up is the fact that in the 

combination of the Reutelingsperger lab and the Hofstra lab all necessary key elements for molecular imaging are present, including 

discovery of novel targets, the development of novel probes, the evaluation of probes in vitro, the evaluation of probes in vivo and 

the clinical application of the probes (in collaboration with the department of nuclear medicine). 2. In the Reutelingsperger lab 

extensive expertise on conjugation technology is present, which is vital for the development of novel probes. 3. We have an in 

house developed molecular imaging platform, which allows for the rapid translation of basic research findings to experimental and 

clinical applications in a variety of model systems. 4. We have extensive experience in molecular imaging in patients (n=100) with a 

variety of diseases, using Annexin-A5 based technology. 5. We have state of the art clinical imaging technology, including a high 

resolution PET-CT (Siemens) and state of the art MRI scanners (Phillips). 


Expertise 

1. Dr. C.P.M. Reutelingsperger, director of the preclinical molecular imaging program, discovered the ability of Annexin-A5 to 

detect apoptotic cells, expert on conjugation technology and apoptosis biology. 

2. Dr. L. Hofstra, cardiologist, expert in translational medicine and molecular imaging, head of the optical imaging laboratory, 

published the first paper on cell death detection in patients using Annexin-A5 based molecular imaging technology. 

Further members of the group: Prof Dr J Narula, Chief of Cardiology, University of California Irvine, Director of the 

Cardiovascular Research Program, expert in cardiovascular molecular biology, and molecular imaging. 

3. Prof Dr P. Lambin, head of the radiation therapy department, expert on Pet-CT imaging, director of the Maestro Institute. 

4. Prof Dr J Van Engelshoven, head of the Radiology department, expert in MRI imaging of unstable atherosclerotic lesions and 

MRA 

5. Prof Dr G Heidendal, head of the Nuclear Medicine department, expert in clinical molecular imaging. 

6. Dr H. Boersma, nuclear pharmacist, expert in conjugation of molecular imaging probes to radiopharmaceuticals, expert on 

pharmacokinetic and bio-distribution studies. 

References 

1. Dagmar D., J. Verjans, C. Reutelingsperger, L.Hofstra, N. Narula, J. Narula. Targeting of Apoptotic Macrophages in Experimental Atheroma 

with Radiolabeled Annexin-V for Noninvasive Imaging of Vulnerable Plaques. Circulation 2003. 

2. Thimister P.W.L., L. Hofstra, I.H. Liem, H.H. Boersma, G.J. Kemerink, C.P.M. Reutelingsperger, G.A.K. Heidendal. In vivo detection of cell 

death in the area at risk in acute myocardial infarction. J Nucl Med 2003; 44: 391-396. 

3. Boersma H.H., I.H. Liem, G.J. Kemerink, P.W.L. Thimister, L. Hofstra, L.M.L. Stolk, W.L. van Heerde, M-T. W. Pakbiers, D. Janssen, T. 

Beysens, C.P.M. Reutelingsperger, G.A.K. Heidendal. Comparison between human pharamcokinetics and imaging properties of two 

conjugation methods for 99m Tc-Annexin A5. Br J Radiol 2003; 76: 1-8. 

4. Reutelingsperger CP, Dumont E, Thimister PW, van Genderen H, Kenis H, van de Eynde and Hofstra,L. Visualization of cell death in vivo 

with the annexin A5 imaging protocol. J Immunol Methods 2002; 265(1-2):123-132. 

5. Imanishi T, Han DK, Hofstra L, Hano T, Nishio I, Conrad LW et al. Apoptosis of vascular smooth muscle cells is induced by Fas ligand 

derived from monocytes/macrophage. Atherosclerosis 2002; 161(1):143-151. 

6. Dumont EA, CP Reutelingsperger, JFM Smits, MJAP Daemen, PA Doevendans and L Hofstra. Detection of apoptotic cell membrane changes 

at the single cell level in the beating murine heart. Nature Med 2001; 7: 1352-1355. 

7. Hofstra L, EA Dumont, PW Thimister, GA heidendal, AA DeBruine, TW Elenbaas, HH Boersma, WL van Heerde en CPM Reutelingsperger. 

In vivo detection of apoptosis in an intracardiac tumor. JAMA 2001; 285: 1841-1822. 

8. Kemerink GJ, Boersma HH, Thimister PW, Hofstra L, Liem IH, Pakbiers MT et al. Biodistribution and dosimetry of 99mTc-BTAP-annexin-V 

in humans. Eur J Nucl Med 2001; 28(9):1373-1378. 

9. Kemerink GJ, IH Liem, L Hofstra, HH Boersma WC Buijs, CPM Reutelingsperger, and GA Heidendaal Patient dosimetry of intravenously 

administered 99mTc-Annexin-V. J Nucl Med 2001; 42: 382-387. 

10. Hofstra L, IH Liem, EA Dumont, HH Boersma, WL van Heerde, PA Doevendans, E DeMuinck, HJ Wellens, GJ Kemerink, CP 

Reutelingsperger, GA Heidendal.Visualisation of cell death in vivo in patients with acute myocardial infarction. Lancet 2000; 356: 209-212. 

11. Hofstra L, E Dumont WL van Heerde, S Van Den Eynde, PA Doevendans, E DeMuinck, MA Daemen, JF Smits, P Frederik, HJ Wellens, MJ 

Daemen, CP Reutelingsperger. Cardiomyocyte Death induced by myocardial ischemia and reperfusion. Detection with human recombinant 

Annexin-V in a mouse model. Circulation 2000, 102: 1536-1543.


Partner 27: Göteburg (M. Horn) 

Center for Bio-Imaging, Sahlgrenska Akademin, Göteborg Universitet, Sweden 

Göteborg University established a core facility (Center for Bio-Imaging, CBI) for the imaging of small rodents. The unit is equipped 

with state-of the-art systems to acquire images in high spatial and temporal resolution. Currently available are magnetic resonance 

imaging (MRI) and spectroscopy (MRS, Bruker 7, multichannel), ultrasound (US, ATL HDI 5000 SonoCT), computer tomography 

(CT, XCT Research M), double energy X-ray absorption (DEXA, pDEXA Sabre ® ) and a gamma camera (GE systems, modified). 

All systems are adapted for the in-vivo use in small animals. The image modalities at CBI serve as infrastructure for research groups 

from different universities in Sweden (Lund, Gothenburg, Stockholm, Uppsala, Umeå) and enable them to perform non-invasive 

investigation of genetically engineered animals. CBI is driven by researchers with a mixed background from cardiology, clinical 

physiology, endocrinology, chemistry and radiophysics; all of them are located at Gothenburg university and are imbedded into 

different research groups in Gothenburg. A tight cooperation exists between the Department of Neuroscience in Lund and CBI for 

the development of high resolution MRI and usage of the techniques in degenerative diseases. The researchers in CBI do have 

collaborations with international research groups within Europe (Oxford, Basel, Rotterdam, Würzburg) and the USA (Missouri, 

Boston, Chicago, Washington). 


Expertise 

1. Prof. Dr. C. Ohlsson: Scientific Manager of CBI, Endocrinology, experimental and clinical research: Bone density, body 

composition by DEXA and CT 

Further members of the group: Dr. M. Garcia (chemist, body composition); Dr. N. Andersson (MD, bone density/hormone 

therapy) 

2. Assoc. Prof. Dr. M. Horn: Chemist, head of the MR unit at CBI, myocardial viability, plaque imaging 

Further members of the group: Dr. S. Skrtic (MD, SPIO contrast agents); Dr. E. Bollano (MD, myocardial metabolism and 

growth hormone); Dr. F. Tian (MD; long time hypoxia) 

3. Assoc. Prof. Dr. G. Bergström: Clinical physiology, head of US unit at CBI: vessel imaging, myocardial motion 

Further members of the group: Dr. A. Wickman (aortic flow), Dr. L.M. Gan (vessel US) 

4. Prof. E. Forssell-Aronsson: Radiophysics, head of gamma camera unit at CBI 

Further members of the group: Dr. M. Ljungberg ( 31 P-spectroscopy), Å. Carlsson (mouse imaging/cancer); Dr. A. Larsson 

(development collimator), Dr. S. B. Orström (development biomarkers) 

References 

CT 

1. Moverare S, Venken K, Eriksson AL, Andersson N, Skrtic S, Wergedal J, Mohan S, Salmon P, Bouillon R, Gustafsson JA, Vanderschueren D, 

Ohlsson C. Differential effects on bone of estrogen receptor {alpha} and androgen receptor activation in orchidectomized adult male mice. Proc 

Natl Acad Sci U S A. 2003. 

2. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO. Interleukin-6-deficient mice develop matureonset 

obesity. Nat Med. 2002;8:75-9. 

DEXA 

1. Sjogren K, Hellberg N, Bohlooly YM, Savendahl L, Johansson MS, Berglindh T, Bosaeus I, Ohlsson C. Body fat content can be predicted in 

vivo in mice using a modified dual-energy X-ray absorptiometry technique. J Nutr. 2001;131:2963-6. 

2. Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly M, Rudling M, Lindberg MK, Warner M, Angelin B, Gustafsson JA. Obesity and 

disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice. Biochem Biophys Res Commun. 2000;278:640-5. 

Gamma camera 

1. Bernhardt P, Kolby L, Johanson V, Nilsson O, Ahlman H, Forssell-Aronsson E. Biodistribution of 111in-DTPA-D-Phe1-octreotide in tumorbearing 

nude mice: influence of amount injected and route of administration. Nucl Med Biol. 2003;30:253-60. 

2. Carlsson J, Forssell Aronsson E, Hietala SO, Stigbrand T, Tennvall J. Tumour therapy with radionuclides: assessment of progress and 

problems. Radiother Oncol. 2003;66:107-17. 

MR 

1. Ljungberg M, Sunnerhagen KS, Vikhoff-Baaz B, Starck G, Forssell-Aronsson E, Hedberg M, Ekholm S, Grimby G. 31P MRS evaluation of 

fatigue in anterior tibial muscle in postpoliomyelitis patients and healthy volunteers. Clin Physiol Funct Imaging. 2003;23:190-8. 

2. Horn M, Weidensteiner C, Scheffer H, Meininger M, de Groot M, Remkes H, Dienesch C, Przyklenk K, von Kienlin M, Neubauer S. Detection 

of Myocardial Viability Based on Measurement of Sodium Content: A 23 Na NMR study. Magn Reson Med, 2001; 45: 756-764 

3. Horn M, Remkes H, Strömer H, Dienesch C, Neubauer S. Chronic phosphocreatine depletion by the creatine analogue -guanidino propionate 

is associated with increased mortality and loss of ATP in rats post-myocardial infarction. Circulation, 2001; 104: 1844-1849 

4. Horn M, Remkes H, Schnackerz K, Hu K, Ertl G, Neubauer S. Chronic high-dose creatine feeding does not attenuate left ventricular 

remodeling in rat hearts post-myocardial infarction. Cardiovasc Res 1999; 43: 117-124. 

5. Von Kienlin M, Rösch C, Le Fur Y, Behr W, Roder F, Haase A, Horn M, Illing B, Hu K, Ertl G, Neubauer S. Three-dimensional 31 P magnetic 

resonance spectroscopic imaging of regional high-energy phosphate metabolism in injured rat heart. Magn Reson Med 1998; 39: 731-741 

US 

1. Johansson EM, Wickman A, Fitzgerald SF, Gan L, Bergström G. Angiotensin II influences distribution of atherosclerosis independent of the 

type 2 receptor, but does not affect plaque morphology. XIIIth International Symposium on Atherosclerosis, Kyoto, Japan, September 2003. 

2. Wikstrom J, Hägg-Samuelsson U, Johansson M, Wickman A, Bergström G, Gan LM. Study of local atherosclerosis-related hemodynamic 

changes in ApoE-/- mice using high-resolution echocardiography. XIIIth International Symposium on Atherosclerosis, Kyoto, Japan, 

September 2003. 

3. Nyström H, Lindblom P, Wickman A, Andersson I, Norlin J, Lindahl P, Bjarnegard M, Fitzgerald S, Gan LM, Betzholtz C, Bergström G. The 

PDGF-B retention motif knockout mouse shows primary conduit vessel and renal dysfunction together with eccentric cardiac hypertrophy. 

XIIIth International Symposium on Atherosclerosis, Kyoto, Japan, September 2003.


Partner 28: Paris (L. Bridal, P. Laugier) 

Targeted and Functional Ultrasound, Laboratoire d’Imagerie Paramétrique – UMR 7623 CNRS/Université 

Paris VI, France 

The Laboratoire d’Imagerie Paramétrique (LIP) is a public laboratory affiliated with the University Pierre et Marie 

Curie of Paris 6 and the CNRS (National Center of Scientific Research). The research activities are focused in the 

areas of biomedical applications of ultrasound and medical imaging sciences. It is currently composed of 15 faculty 

and 10 PhD students organized in three multidisciplinary research teams. The principal research axes can be 

categorized under three basic headings: 

- Quantitative ultrasonography spanning a range of frequencies from less than 1 MHz to more than 100 MHz with 

applications to clinical investigations of bone, cartilage, eye and skin. 

- Quantitative and functional ultrasonic imaging: from man to mouse. 

- Ultrasonic characterization of microscopic biological systems, including modelization of cell membranes (inverse 

micelles) and living cells cultures. 

LIP, with an established reputation for advanced knowledge and skill in medical ultrasound signal, image processing 

and high frequency ultrasound, has been recognized as a world leader in the field of quantitative ultrasonography. LIP 

has recently strongly contributed to the field of quantitative ultrasonography for osteoporosis. The first ultrasound 

bone densitometer with an image was developed at LIP, and the UBIS (Ultrasound Bone Imaging scanner) device, is 

now included in the bone densitometers products sold throughout the world. LIP has also produced remarkable 

developments in the field of ultrasound biomicroscopy applied to several biomedical problems, including atheroma, 

osteoarthritis, and eye diseases. One team is active in the field of ultrasonic contrast agents, looking for new agents 

that are more stable in time, modelling their response in the ultrasonic field and testing various imaging sequences 

using both in vitro and in vivo protocols. 


1. Lori Bridal, PhD: senior researcher, quantitative and functional ultrasonic imaging. 

2. Wladimir Urbach, PhD: professor of physics, physical properties of nano and micro particles. 

3. Laugier P, PhD: director of Paris research team, ultrasonic quantitative imaging. 

4. Jean-Michel Correas, radiologist: clinical use of ultrasonic contrast agents. 

5. Monica Spisar, postdoc physics: physical properties of ultrasonic contrast agents. 

6. Azzdine Ammi, PhD student: ultrasonic contrast agents: modelization and experimentation. 

7. Erol Kurtisovski, PhD student: physics, new targeted ultrasonic contrast agents. 

References 

1. Bridal L, Correas J-M, Saïed A, Laugier P. Milestones on the road to higher resolution, quantitative and functional ultrasonic imaging. 

Proceedings of the IEEE Special Issue on Emerging Medical Technology 2003, 91(10): 1543-1561. 

Contrast agents 

1. O. Lucidarme, S. Franchi-Abella, J.-M. Correas, S. L. Bridal, E. Kurtisovski and G. Berger. Blood flow quantification with contrast-enhanced 

US: 'Entrance in the section' phenomenon- Phantom and rabbit study. Radiology 2003, 228: 473-479. 

2. J.-M. Correas, E. Kurtisovski, S. L. Bridal, A. Amararene, O. Hélénon and G. Berger. Optimizing an ultrasound contrast agent's stability using 

in vitro attenuation measurements. Invest Radiol 2002, 37: 672-679. 

3. J.-M. Correas, A. R. Meuter, E. Singlas, D. R. Dessler, K. Worah and S. C. Quay. Human pharmacokinetics of a perfluorocarbon ultrasound 

contrast agent evaluated with gas chromatography. Ultrasound Med Biol 2001, 27: 565-570. 

4. O. Lucidarme, J.-M. Correas, S. L. Bridal and G. Berger. Quantification of ultrasound contrast agent response: Comparison of continuous wave 

Doppler and power Doppler to backscattered radiofrequency data. Ultrasound Med Biol 2001, 27: 1379-1386. 

5. J.-M. Correas, X. Lai, X. Qi and P. N. Burns. Infusion vs. bolus of an ultrasound contrast agent: In vivo dose response measurements of BR1. 

Investigative Radiology 2000, 35: 72-79. 

Agent binding 

1. N. Taulier, M. Waks, T. Gulik-Krzywicki and W. Urbach. Interaction between transmembrane proteins embedded in lamellar phase stabilised 

by steric interactions. Europhys.Lett. 2002, 59: 142-148. 

2. N. Taulier C.Nicot, M. Waks, R. Ober, T. Gulik-Krzywicki, R.S Hodges and W. Urbach. Unbinding-Binding Transition induced by molecular 

snaps in model memebranes. Biophys. J. 2000, 78: 857-865. 

Atheroma plaque 

1. Waters KR, Bridal SL, Cohen-Bacrie C, Levrier C, Fornès P, Laugier P, Parametric analysis of carotid plaque using a clinical ultrasound 

imaging system, Ultrasound in Medicine and Biology 2003, 29 (11).


Partner 29a: Groningen (K. Leenders) 

Department of Neurology and Neuroimaging centre (postgraduate school BCN) at the University of Groningen, 

Netherlands 

The research program of the Neurology department is part of the University post-graduate School BCN (Behavioural 

and Cognitive Neuroscience) with as main research topics: cognitive organisation of the brain (language, memory, 

attention); the motor organisation of the brain (emotional motor system, spatio-temporal organisation; 

pathophysiology in movement disorders); neurodegenerative diseases (Parkinson’s disease (PD), Huntington’s 

disease, ALS, Alzheimer’s disease). A wide spectrum of human protocols is being performed involving mainly the 

clinical departments of Neurology, Psychiatry, Neurosurgery, Oncology and the University departments of Anatomy, 

Physiology, Pharmacy and others. A close connection with animal experimental groups is maintained. PET monkey 

studies are being performed on a regular basis in connection with the University of Nijmegen, particularly concerning 

the restorative potency of neurotrophic factors and apoptotic inhibitors in MPTP monkey parkinsonian models. 

The PET unit at the Groningen University Hospital is since 12 years fully equipped as a research unit and has 

performed many protocols in parallel to performing clinical diagnostic scans. Both new tracers have been developed 

and existing tracers like F-DOPA, FDG, H 2 O, Raclopride and new tracers like Verapamil are being used in protocols 

investigating pathophysiology in brain diseases. 

Recently long-term studies in PD patients comparing the potential neuroprotective effect of a dopaminergic agonist 

(pergolide), a glutamate inhibiting substance (riluzole) have been tested and an experimental neurotrophic factor and 

the influence of chronic STN stimulation is currently under study in prospective longitudinal studies in combination 

with F-DOPA PET scanning. The cerebral glucose pathophysiology in the various forms of parkinsonisms is also 

being studied. Activation programs using reward paradigms are applied in the context of fMRI and Raclopride PET 

studies. Motor learning and sequencing paradigms are being studied using a 3Tesla MRI scanner. Dystonia is being 

studied using rTMS and multichannel EEG in combination with 3Tesla MRI scanning. 


1. Professor Leenders, clinical neurologist: head of the movement disorders clinic at the Neurology Department of 

the Groningen University Hospital, co-chair of the Neurology Department. The imaging projects are performed in 

close collaboration with the University Neuroimaging centre. The research group of the Neurology Department 

contributes 4 staff researchers apart from PhD students and supporting staff. 

2. Dr R.P. Maguire, physicist: expert in PET and MRI methodology, has worked in PET instrumentation research 

and in tracer modelling for 14 years next to recent work in MRI data analysis. 

3. Dr. B.M. de Jong, neurologist: expert in cerebral organisation of movement, has carried out many activation 

studies in healthy controls and patients. 

4. Dr. R. Kortekaas: neuropharmacologist, has worked with experimental monkey PET tracer studies for four years 

and participates in the human reward activation project. 

5. Dr M van Beilen: neuropsychologists, involved in cognitive testing of subjects using fMRI. 

References 

1. Curt A, Bruehlmeier M, Leenders KL, Roelcke U, Dietz V. Differential effect of spinal cord injury and functional impairment on human brain 

activation. Journal of Neurotrauma 2002; 19:43-51. 

2. Jong BMd, Leenders KL, Paans AM. Right parieto-premotor activation related to limb-independent antiphase movement. Cerebral Cortex 

2002; 12:1213-1217 

3. Cutts DA, Spyrou NM, Maguire RP, Leenders KL. Hierarchical clustering of Alzheimer and "normal" brains using elemental concentrations 

and glucose metabolism determined by PIXE, INAA and PET. Journal of Radioanalytical and Nuclear Chemistry 2001; 249:455-460. 

4. Martin-Soelch C, Leenders KL, Chevalley A-F et al. Reward mechanisms in the brain and their role in dependence: evidence from 

neurophysiological and neuroimaging studies. Brain Research Reviews 2001; 36:139-149. 

5. Antonini, A., Leenders, K.L., Vontobel, P., Maguire, R.P., Missimer, J., Psylla, M., and Gunther, I., Complementary PET studies of striatal 

neuronal function in the differential diagnosis between multiple system atrophy and Parkinson's disease. Brain 1997; 120, 2187-2195. 

6. Leenders, K.L., Salmon, E.P., Tyrrell, P., Perani, D., Brooks, D.J., Sager, H., Jones, T., Marsden, C.D., and Frackowiak, R.S., The nigrostriatal 

dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease. 

Arch. Neurol. 1990; 47, 1290-1298.


Partner 29b: Groningen (W. Vaalburg) 

Groningen PET-center, Groningen, The Netherlands 

The PET center has a lot of experience in the preparation of new radiopharmaceuticals and their evaluation in animals 

as well as the implementation of several of these radiopharmaceuticals in clinical protocols, such as [ 11 C]verapamil for 

multidrug resistance, ganciclovir and uracil derivatives for gene therapy, FDG, FLT, [ 11 C]choline and [ 11 C]tyrosine for 

tumor imaging, various radioligands for dopamine D 2 -receptors, several progesterone derivatives for the progestin 

receptor and potent ligands for the sigma, muscarinic and ß-adrenergic receptors. The present clinical research lines 

include neurology (brain stimulation by measuring regional cerebral blood flow, serotonergic receptors, receptor status 

in patients with parkinsonism), psychiatry (studies with schizophrenics), cardiology (cardiomyopathy and vitality 

studies), lung diseases (asthma/COPD) and oncology (therapy evaluation and tumor detection). The PET center has 

gained experience with tracer kinetic modelling of the binding of (S)-[ 11 C]CGP 12177 to β-adrenergic receptors, and 

of the incorporation of [ 11 C]tyrosine into tissue proteins. The PET center has the latest generation PET cameras 

(Siemens Exact HR+) and therefore state of the art PET images with maximal resolution can be generated. Regarding 

the research on sigma receptors, a collaboration has been established with the Department of Neurology of the 

Groningen University Hospital and the Tokyo Metropolitan Institute of Gerontology, Hamamatsu Photonics, and M’s 

Science. With respect to the work on P-glycoprotein, the PET-center collaborates with the Departments of Medical 

Oncology and Neurology, and the University of Washington, Seattle, USA. 


1. Prof. Dr. W. Vaalburg. Director of the PET-center. 

2. Dr. P.H. Elsinga. Radiopharmaceutical chemist. Head of the Radiochemistry Laboratory. Development of 

radiotracers for receptor imaging (β-adrenoceptors, 5-HT1A, dopamine and sigma), tumor detection (FLT, choline, 

amino acids, P-gp substrates). 

3. Dr. N.H. Hendrikse. Hospital pharmacist-pharmacologist. Development and evaluation of radiotracers to image 

multidrug resistance in vivo (P-glycoprotein, verapamil, carvedilol). 

4. Dr. A. van Waarde. Biochemist. Evaluation of radiotracers for receptor and tumor imaging (β-adrenoceptors, 5- 

HT1A, dopamine and sigma). 

5. Dr. A.T.M. Willemsen. Medical Physicist. Mathematical modelling, kinetic analysis, software development. 

References 

1. Bart J, Groen HJ, Hendrikse NH, van der Graaf WT, Vaalburg W, de Vries EG. The blood-brain barrier and oncology: new insights into 

function and modulation. Cancer Treat.Rev 2000; 26.6: 449-62. 

2. Doze P, Van Waarde A, Elsinga PH, Hendrikse NH, Vaalburg W. Enhanced cerebral uptake of receptor ligands by modulation of P- 

glycoprotein function in the blood-brain barrier. Synapse 2000; 36.1: 66-74. 

3. Elsinga PH, Franssen EJ, Hendrikse NH, Fluks L, Weemaes AM, van der Graaf WT, de Vries EG, Visser GM, Vaalburg W. Carbon-11-labeled 

daunorubicin and verapamil for probing P-glycoprotein in tumors with PET. J Nucl Med. 1996; 37.9: 1571-75. 

4. Elsinga PH, Kawamura K, Kobayashi T, Tsukada H, Senda M, Vaalburg W, Ishiwata K. Synthesis and evaluation of [(18)F]fluoroethyl 

SA4503 as a PET ligand for the sigma receptor. Synapse 2002; 43.4: 259-67. 

5. Eriks-Fluks E, Elsinga PH, Hendrikse NH, Franssen EJ, Vaalburg W. Enzymatic synthesis of [4-methoxy-11C]daunorubicin for functional 

imaging of P-glycoprotein with PET. Appl.Radiat.Isot. 1998; 49.7: 811-13. 

6. Hendrikse NH, Bart J, de Vries EG, Groen HJ, van der Graaf WT, Vaalburg W. P-glycoprotein at the blood-brain barrier and analysis of drug 

transport with positron-emission tomography. J.Clin.Pharmacol. Suppl 2001: 48S-54S. 

7. Hendrikse NH, de Vries EG, Eriks-Fluks L, van der Graaf WT, Hospers GA, Willemsen AT, Vaalburg W, Franssen EJ. A new in vivo method 

to study P-glycoprotein transport in tumors and the blood-brain barrier. Cancer Res 1999; 59.10: 2411-16. 

8. Hendrikse NH, de Vries EG, Franssen EJ, Vaalburg W, van der Graaf WT.In vivo measurement of [11C]verapamil kinetics in human tissues. 

Eur.J.Clin.Pharmacol. 2001; 56.11: 827-29. 

9. Hendrikse NH, Franssen EJ, van der Graaf WT, Vaalburg W, de Vries EG.Visualization of multidrug resistance in vivo. Eur.J.Nucl.Med 

1999; 26.3: 283-93. 

10. Hendrikse NH, Schinkel AH, de Vries EG, Fluks E, Van der Graaf WT, Willemsen AT, Vaalburg W, Franssen EJ. Complete in vivo reversal 

of P-glycoprotein pump function in the blood-brain barrier visualized with positron emission tomography. Br.J.Pharmacol. 1998; 124.7: 1413- 

18. 

11. Hendrikse NH, Vaalburg W. Dynamics of multidrug resistance: P-glycoprotein analyses with positron emission tomography. Methods 2002; 

27.3: 228-33. 

12. Kawamura K, Elsinga PH, Kobayashi T, Ishii S, Wang WF, Matsuno K, Vaalburg W, Ishiwata K. Synthesis and evaluation of 11C- and 18Flabeled 

1-[2-(4-alkoxy-3-methoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazines as sigma receptor ligands for positron emission tomography 

studies. Nucl.Med.Biol. 2003; 30.3: 273-84. 

13. Passchier J, van Waarde A, Doze P, Elsinga PH, Vaalburg W. Influence of P-glycoprotein on brain uptake of [18F]MPPF in rats. Eur J 

Pharmacol. 2000; 407:273-80.


Partner 30: Paris (R. Mastrippolito) 

Institute of Nuclear Physics (INP), University of Paris Sud, France 

Our group in the Nuclear Physics Institute is involved in research at the frontier between physics and biology for 15 

years. Our work has led to the development of tools for autoradiographic quantification ex vivo and in vivo. These 

tools have been transferred to Biospace and their commercial names are MicroImager and BetaMicroprobe. 

We are now developing an original tomograph with sub-milimeter resolution. 


1. Hirac Gurden (PhD. Neurobiology) 

2. Philippe Lanièce (PhD, Physics) 

3. Françoise Lefèbvre (PhD, Informatics) 

4. Roland Mastrippolito (PhD, Physics) 

5. Frédéric Pain (PhD, Physics) 

6. Laurent Pinot (Ingeneer, electronics) 

7. Luc Valentin (PhD, Physics) 

References 

1. L. Ploux, R. Mastrippolito. In vivo Radiolabel quantification in small-animal models. Nucl. Med. & Biol 1998; 25, 737-742. 

2. R.M. Allemand, R. Pomet, S. Papillon, A. Richard, R. Mastrippolito. Un nouveau concept d’utilisation du Fluorure de Baryum pour la 

tomographie d’émission de positons en oncologie". Revue de l’ACOMEN 1999; 5-2,160-164 

3. F. Pain, P. Lanièce, R. Mastrippolito, Y. Charon, D. Comar, V. Leviel, J.F. Pujol, L. Valentin. Sic, an intracerebral radiosensitive probe for in 

vivo neuropharmacology investigations in small laboratory animals : theoretical considerations and physical characteristics. IEEE 

Transactions on Nuclear Science 2000; 47-1 25-32. 

4. Zimmer L, Hassoun W, Pain F, Bonnefoi F, Lanièce P, Mastrippolito R, Pinot L, Pujol JF, and Leviel V, .SIC, an intracerebral Beta range 

sensitive probe for radiopharmacology investigations in small laboratory animals : binding studies with [11C]-Raclopride. J Nucl Med 2002; 

43(1), p 227-233. 

5. G. Cleon, R. Allemand, S. Papillon, L. Pinot, A. Richard, Y. Charon, P. Lanièce, L. Ménard, L. Valentin, R. Mastrippolito. Design of a new 

BaF2 PET module concept and preliminary evaluation results. IEEE Transactions on Nuclear Science 2002; 

6. Pain F, Lanièce P, Mastrippolito R, Charon Y, Comar D, Leviel V, Pujol JF, and Valentin L, SIC, an Intracerebral Radiosensitive Probe for in 

vivo Neuropharmacology Investigations in Small Laboratory Animals: first prototype design characterisation and in vivo evaluation. IEEE 

Transactions Nuclear Science 2002; 49 (3), p822-826. 

7. Pain F, Besret L, Vaufrey F, Grégoire MC, Pinot L, Gervais P, Ploux L, Bloch G, Mastrippolito R, Lanièce P, and Hantraye P, In vivo 

quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal resolution Beta-sensitive 

MICROPROBE, PNAS 2002; 99(16), p 10807-10812. 

8. Zimmer L, Pain F, Mauger G, Plenevaux A, Le Bars D, Mastrippolito R, Pujol JF, Renaud B, and Lanièce P. The potential of the Beta- 

MICROPROBE, an intracerebral radiosensitive probe, to monitor the [18F]-MPPF binding in the rat dorsal raphe nucleus. Eur J Nucl Med 

2002; 29(9), p 1237-1247. 

9. L. Pinot, R. Sellem, J.C. Cuzon, A. Lesage, R. Mastrippolito, L. Valentin. A compact data acquisition system for TOHR multi-detectors: time 

encoding for both time and energy measurements. Transactions on Nuclear Science 2002; 50-2: 272-277.


Partner 31: Newcastle (C.M. Morris) 

Institute for Ageing and Health, Wolfson Research Centre, University of Newcastle, Newcastle General 

Hospital, Newcastle upon Tyne, Tyne and Wear, United Kingdom 

The Institute for Ageing and Health (IAH), Newcastle represents a key grouping of various departments and groups 

and was established to promote interdisciplinary research on the major causes of ill health and disability in later life, 

with the goal of improving diagnosis and treatment and, ultimately, preventing such conditions. A major scientific 

focus is diagnosis and characterisation of dementia with Lewy Bodies (DLB) and vascular dementia, conditions that 

overlap extensively with Alzheimer’s disease (AD), using a range of different techniques. The Depts of Old Age 

Psychiatry and Geriatric Medicine are undertaking prospective studies of patients with dementia and stroke with 

detailed clinical, neuropsychiatric, neurological and computer based psychometric testing to identify regions of the 

brain which are affected by disease. This is correlated with blood flow and ligand SPECT imaging (IGE CamStar 

XR/T) and serial structural MRI (1.5T Philips machine with 3T Unit to be operational by 2005) in association with the 

Department of Regional Medical Physics who are developing methods of co-registering images. Neuropathological 

assessment (Department of Neuropathology) of cases coming to autopsy provides a final validation of clinical and 

imaging modalities and correlation with findings. An extensive bank of post mortem human tissues is being used to 

identify neurochemical targets which may be of use in the detection of disease changes pre-mortem. In order to 

identify biological markers and determinants of neurodegenerative disease we are using state of the art functional 

genomic and proteomic methods of analysis. The IAH benefits greatly from increased involvement with the Institute 

for Human Genetics which has state of the art facilities (advanced cell culture suites, transgenics/gene targeting 

facility), microarray gene expression imaging (Affymetrix GeneChip analysis suite) and bioinformatics support. 

Newcastle has also a dedicated proteomics facility for the Faculty of Medicine (Applied Biosystems Voyager DESTR 

MALDI mass spectrometer, ABI/Sciex QTrap LC/MS/MS electrospray Triple-Stage Quadripole / Ion-Trap Mass 

Spectrometry instrument, Genomic Solutions Proms, Progest, Propic robotic proteomics workstation, Typhoon 9400 

multimodal imager, Bruker Autoflex MALDI TOF/TOF). The proposals build on previous studies in dementia, but 

will also develop new areas of proteomics and considerable added value also derives from the established 

collaborations with industrial partners (Amersham Bioscience, Amersham Health) who are at the forefront of the new 

technologies used. 


1. Prof. JT O’Brien: Professor of Old Age Psychiatry, experimental and clinical dementia imaging by SPECT and 

MRI. 

Further members of the group: Dr. Michael Firbanks (Medical Physics, development of MR co-registration, 

spectroscopy and DTI), Dr. Emma Burton (voxel based image analysis), Mr Sean Colloby (statistical 

parametric mapping of SPECT) 

2. Prof I G McKeith: Professor of Old Age Psychiatry, Clinical Diagnostic instruments of dementia subtypes, 

clinical trials. 

Further members of the group: Dr Urs Mossiman (visuocognitive processing), Dr D Burn (Movement 

disorder) 

3. Prof RN Kalaria: Professor of Cerebrovascular Pathology, Cerebrovascular disease, prospective study of dementia 

following stroke. 

Further members of the group: Prof R A Kenny (cardiovascular disease and dementia), Dr Tuomo Polvikoski 

(cerebrovascular neuropathology), Dr A Thomas (depression after stroke) 

4. Prof. RH Perry: Professor of Neuropathology, correlative neuropathology of dementia 

Further members of the group: Dr. E Jaros (Clinical Scientist, analysis of neuroanatomical correlates of 

dementia) 

5. Prof. EK Perry: Professor of Neurochemistry neurochemical analysis of neurodegenerative disease, 

neurochemistry of autism. 

Further members of the group: Dr. JA Court (nicotinic receptor pharmacology in dementia), Dr M A Piggott 

(neurochemistry of movement disorders). 

6. Dr. CM Morris: MRC Scientist, genetic analysis of neurodegenerative disease, development of transgenic and non 

transgenic models of neurodegenerative disease, gene expression and proteomics based analysis of 

neurodegenerative disease. 

Further members of the group: Prof JA Edwardson (proteomic analysis), AB Keith (inflammatory 

mechanisms).


References 

Clinical Diagnosis 

1. Burn DJ, Rowan EN, Minett T, Sanders J, Myint P, Richardson J, Thomas A, Newby J, Reid J, O'Brien JT, McKeith IG Extrapyramidal 

features in Parkinson's disease with and without dementia and dementia with Lewy bodies: A cross-sectional comparative study. Mov Disord. 

2003, 18:884-9. 

2. McKeith IG, Ballard CG, Perry RH, Ince PG, O'Brien JT, Neill D, Lowery K, Jaros E, Barber R, Thompson P, Swann A, Fairbairn AF, Perry 

EK Prospective validation of consensus criteria for the diagnosis of dementia with Lewy bodies. Neurology. 2000, 54:1050-8. 

Imaging in Dementia 

1. Firbank MJ, Colloby SJ, Burn DJ, McKeith IG, O'Brien JT. Regional cerebral blood flow in Parkinson's disease with and without dementia. 

Neuroimage. 2003, 20:1309-19. 

2. Colloby SJ, Fenwick JD, Williams ED, Paling SM, Lobotesis K, Ballard C, McKeith I, O'Brien JT. A comparison of (99m)Tc-HMPAO SPET 

changes in dementia with Lewy bodies and Alzheimer's disease using statistical parametric mapping. Eur J Nucl Med Mol Imaging. 2002, 

29:615-22. 

Cerebrovascular Disease 

1. Ballard C, Rowan E, Stephens S, Kalaria R, Kenny RA.Prospective follow-up study between 3 and 15 months after stroke: improvements and 

decline in cognitive function among dementia-free stroke survivors >75 years of age. Stroke. 2003, 34:2440-4. 

2. Thomas AJ, O'Brien JT, Davis S, Ballard C, Barber R, Kalaria RN, Perry RH. Ischemic basis for deep white matter hyperintensities in major 

depression: a neuropathological study. Arch Gen Psychiatry. 2002, 59:785-92. 

Neuropathology of Dementia 

1. Perry EK, Kilford L, Lees AJ, Burn DJ, Perry RH. Increased Alzheimer pathology in Parkinson's disease related to antimuscarinic drugs. Ann 

Neurol. 2003, 54:235-8. 

2. Singleton AB, Hall R, Ballard CG, Perry RH, Xuereb JH, Rubinsztein DC, Tysoe C, Matthews P, Cordell B, Kumar-Singh S, De Jonghe C, 

Cruts M, van Broeckhoven C, Morris CM. Pathology of early-onset Alzheimer's disease cases bearing the Thr113-114ins presenilin-1 mutation. 

Brain. 2000, 123: 2467-74 

Neurochemistry of Neurodegenerative Disease 

1. Court JA, Piggott MA, Lloyd S, Cookson N, Ballard CG, McKeith IG, Perry RH, Perry EK. Nicotine binding in human striatum: elevation in 

schizophrenia and reductions in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease and in relation to neuroleptic 

medication. Neuroscience. 2000, 98:79-87. 

2. Piggott MA, Marshall EF, Thomas N, Lloyd S, Court JA, Jaros E, Burn D, Johnson M, Perry RH, McKeith IG, Ballard C, Perry EK. Striatal 

dopaminergic markers in dementia with Lewy bodies, Alzheimer's and Parkinson's diseases: rostrocaudal distribution. Brain. 1999, 122:1449- 

68. 

Molecular Analysis of Disease 

1. O'Brien KK, Saxby BK, Ballard CG, Grace J, Harrington F, Ford GA, O'Brien JT, Swan AG, Fairbairn AF, Wesnes K, del Ser T, Edwardson 

JA, Morris CM, McKeith IG. Regulation of attention and response to therapy in dementia by butyrylcholinesterase. Pharmacogenetics. 2003, 

13:231-9. 

2. Melton LM, Keith AB, Davis S, Oakley AE, Edwardson JA, Morris CM. Chronic glial activation, neurodegeneration, and APP immunoreactive 

deposits following acute administration of double-stranded RNA. Glia. 2003, 44:1-12.


Partner 32: Eindhoven (K. Nicolay) 

Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The 

Netherlands 

The Department of Biomedical Engineering is a joint initiative of Eindhoven University of Technology and Maastricht 

University. Each year circa 80-90 new students enrol in a teaching program at the intersection between the technological 

and medical sciences. One of the major priority research themes in the department is molecular imaging of 

cardiovascular disease, which involves a large number of collaborating groups from the two partner universities. The 

Cardiovascular Research Institute of the University of Maastricht (CARIM) has longstanding experience in 

cardiovascular research. CARIM has extensive facilities for molecular biology, animal model research as well as 

biomolecular imaging, including Magnetic Resonance Imaging, ultrasound and fluorescence microscopy, both for 

studies in human patients and laboratory animals. Eindhoven University of Technology has built up an advanced MR 

research facility for studies on laboratory animals (6.3 Tesla) and humans (1.5 Tesla). Its chemistry division focuses on 

the design and synthesis of polymers for molecular imaging agents for MRI and other modalities. In addition, the 

department has set up an advanced infrastructure for the in-depth analysis and multi-modality matching of biomedical 

images. The joint research program on molecular imaging focuses on the measurement of key events in ischemic heart 

disease processes, including atherosclerosis, angiogenesis, apoptosis, myocardial infarction and its healing. The impact 

of molecular imaging on ischemic heart disease can be envisioned in several ways: (1) the identification of patients at 

risk before symptom development; (2) the generation of early surrogate markers of therapy success and design; (3) the 

increased understanding of disease processes and their dynamics; (4) a reduction in the development time of new 

diagnostic and therapeutic agents. Apart from the close collaborations within the local network, the Department of 

Biomedical Engineering has joint research programs with a wide range of groups at the international level. 


1. Prof. Dr. K. Nicolay: Head of the Department of Biomedical NMR, Eindhoven University of Technology and 

Maastricht University; MR imaging and spectroscopy of the cardiovascular and musculoskeletal system. 

Further members of the group: Dr. G.J. Strijkers (physics; development of sequences for MRI of the 

cardiovascular and musculoskeletal system); Dr. J.J. Prompers (chemistry; MR spectroscopy of rodent and 

human skeletal muscle and development of molecular imaging agents for MR) 

2. Prof. Dr. E.W. Meijer: Head of the Department of Molecular Bio-engineering, Eindhoven University of Technology; 

design and synthesis of dendrimer-based molecular imaging agents for MRI and fluorescence microscopy. 

Further member of the group: Dr. M.H.P. van Genderen (chemistry; development of targeted dendrimeric 

molecular imaging agents) 

3. Prof. Dr. B.M. ter Haar Romeny: Head of the Department of Biomedical Image Analysis, Eindhoven University of 

Technology; multi-scale image analysis and multimodality matching. 

Further member of the group: Dr. L.M.J. Florack (mathematics; multi-scale image analysis) 

4. Prof. Dr. J.M.A. van Engelshoven: Head of the Department of Radiology, Maastricht University Hospital; MRIbased 

molecular imaging of human atherosclerosis and tumor angiogenesis. 

Further members of the group: Dr. M.E. Kooi (physics; MRI of atherosclerosis); Dr. W.H. Backes (physics; 

MRI of angiogenesis) 

5. Prof. Dr. M.J.A.P. Daemen: Head of the Department of Pathology, Maastricht University; atherosclerosis, 

identification of early markers of endothelial dysfunction 

Further member of the group: Dr. K.B.J.M. Cleutjens (biology; molecular biology of vulnerable atherosclerotic 

plaques for novel target identification) 

6. Prof. Dr. J. Smits: Head of the Department of Pharmacology, Maastricht University; myocardial infarction, the 

development of markers of infarct healing 

Further member of the group: Dr. W.M. Blankesteijn (pharmacology; molecular markers for myofibroblasts in 

relation to heart failure) 

7. Dr. C.P.M. Reutelingsperger: Department of Biochemistry, Maastricht University; probe development for multimodality 

monitoring of apoptosis 

Further members of the group: Dr. L. Hofstra (cardiology; development of molecular imaging probes for 

monitoring apoptosis in human myocardium); Dr. M.A.M.J. van Zandvoort (physics; development of twophoton 

microscopy techniques for molecular imaging of cardiovascular disease)


References 

1. Veldhuis WB, Van der Stelt M, Wadman MW, Van Zadelhoff G, Maccarrone M, Fezza F, Veldink GA, Vliegenthart JFG, Bär PR, Nicolay K, Di 

Marzo V. The role of vanilloid receptors in neuroprotection by the endogenous cannabinoid anadamide and arvanil against in vivo excitotoxicity 

in the rat. J Neuroscience 2003; 23: 4127-4133 

2. Veldhuis WB, Van der Stelt M, Delmas F, Gillet B, Veldink GA, Vliegenthart JFG, Nicolay K, Bär PR. In vivo excitotoxicity induced by 

ouabain, a Na + /K + -ATPase inhibitor. J Cereb Blood Flow & Metabol 2003; 23: 62-74 

3. Schepers J, Garwood M, Van der Sanden BPJ, Nicolay K. Improved subtraction by adiabatic FAIR perfusion imaging. Magn Reson Med 2002; 

47: 330-336 

4. Geerts L, Bovendeerd P, Nicolay K, Arts T. Characterization of the normal cardiac myofiber field in goat measured with MR Diffusion Tensor 

Imaging. Am J Physiol Heart Circ Physiol 2002; 283: H139-H145 

5. Peeters-Scholte C, Koster J, Veldhuis WB, Van den Tweel E, Zhu C, Blomgren K, Bär PR, Van Buul-Offers S, Hagberg H, Nicolay K, Van Bel 

F, and Groenendaal F. Neuroprotection by selective nitric oxide synthase inhibition at 24 hours after perinatal hypoxia-ischemia. Stroke 2002; 33: 

2304-2310 

6. Kruiskamp MJ, De Graaf RA, Van der Grond J, Lamerichs R, Nicolay K: Magnetic coupling between water and creatine protons in human brain 

and skeletal muscle, as measured using inversion transfer 1 H-MRS. NMR Biomed 2001; 14: 1-4 

7. Biessels G-J, Braun KPJ, De Graaf RA, Van Eijsden P, Gispen W-H, Nicolay K: Cerebral energy metabolism in streptozotocin-diabetic rats: an 

in vivo magnetic resonance spectroscopy study. Diabetologia 2001; 44: 346-353 

8. Delmas F, Beloeil J-C, Van der Sanden BPJ, Nicolay K, Gillet B: Two-voxel localization sequence for in vivo two-dimensional homonuclear 

correlation spectroscopy. J Magn Reson 2001; 149:119-125 

9. Kruiskamp MJ, Nicolay K: On the importance of exchangeable NH protons in creatine for the magnetic coupling of creatine methyl protons in 

skeletal muscle. J Magn Reson 2001; 149: 8-12 

10. De Graaf RA, Braun KPJ, Nicolay K: Single-shot diffusion trace 1 H NMR spectroscopy. Magn Reson Med 2001; 45: 741-748 

11. Nicolay K, Braun KPJ, De Graaf RA, Dijkhuizen RM, Kruiskamp MJ. Diffusion NMR Spectroscopy. NMR Biomed 2001; 14: 94-111 

12. Van der Stelt M, Veldhuis WB, Bär PR, Veldink GA, Vliegenthart JFG, Nicolay K: Neuroprotection by 9 -tetrahydrocannabinol, the main active 

compound in marijuana, against ouabain-induced in vivo excitotoxicity. J Neuroscience 2001; 21: 6475-6479 

13. Van der Stelt M, Veldhuis WB, Van Haaften GW, Fezza F, Bisogno T, Bär PR, Veldink GA, Vliegenthart JFG, Di Marzo V, Nicolay K. 

Exogenous anandamide protects rat brain against acute neuronal injury in vivo. J Neuroscience 2001; 21: 8765-8771 

14. Hoehn M, Nicolay K, Franke C, Van der Sanden BPJ: Application of Magnetic Resonance to animal models of cerebral ischemia. J Magn Reson 

Imaging 2001; 14: 491-509 

15. Braun KPJ, Vandertop WP, Gooskens RHJM, Tulleken CAF, Nicolay K: NMR spectroscopic evaluation of cerebral metabolism in 

hydrocephalus: A review. Neurol Res 2000; 22: 51-64 

16. Kruiskamp MJ, Van Vliet G, Nicolay K: 1 H and 31 P NMR magnetization transfer studies of hindleg muscle in wild-type and creatine kinasedeficient 

mice. Magn Reson Med 2000; 43: 657-664 

17. De Graaf RA, Van Kranenburg A, Nicolay K: In vivo 31 P-NMR diffusion spectroscopy of ATP and phosphocreatine in rat skeletal muscle. 

Biophys J 2000; 78: 1657-1664 

18. Kay L, Nicolay K, Wieringa B, Saks VA, Wallimann T: Direct evidence for the control of mitochondrial respiration by mitochondrial creatine 

kinase in oxidative muscle cells in situ. J Biol Chem 2000; 275: 6937-6944 

19. De Graaf RA, Dijkhuizen RM, Biessels G-J, Braun KPJ, Nicolay K: In vivo glucose detection by homonuclear spectral editing. Magn Reson Med 

2000; 43: 621-626


Partner 33: Uppsala (A. Nordberg) 

Department of Geriatric Medicine, Neurotec, Karolinska institute and Uppsala PET centre/ Imanet, Uppsala, 

Sweden 

At the Department of Geriatric Medicine 800 new referrals are assessed for cognitive impairment. Especially patients 

with mild cognitive impairment (MCI) are investigated and longitudinally followed with clinical assessments, brain 

imaging, neuropsychology, CSF, neurochemistry. The staff includes 20 doctors, 3 neuropsychologists, research 

nurses, PhD students. The department has a longstanding experience of collaboration with Uppsala PET centre with 

respect to FDG studies, activation studies, and analysis of nicotinic receptors in Alzheimer patients undergoing 

treatment with different AD drugs. Recently a new PET ligand PIB for measurement of amyloid in brain has been 

studied in AD patients as collaborative effort between Uppsala PET centre, Imanet, KI and Pittsburgh university. 

The Uppsala PET Centre/ Imanet is a leading institute in the field of positron emission tomography (PET). It has a 

strong position in the development of new tracers, including synthesis and preclinical evaluation. The PET centre 

includes 30 employees that are MDs, chemists, physicists, pharmacologists, and computer specialists. 


1. Professor Agneta Nordberg, MD PhD; pharmacologist and geriatrician with long experience of brain receptor 

studies and clinical studies of Alzheimer patients and MCI patients with focus on early diagnosis and drug 

intervention as studied by PET. 

2. Assoc. Professor Elka Stefanova, MD PhD; neurologist with experience of clinical assessment and 

neuropsychological studies in patients with Parkinson´s disease and Alzheimer´s disease and PET studies. 

3. Assoc. Professor Ove Almkvist, PhD; neuropsychologist with extensive experience of neuropsychology 

assessments in MCI and Alzheimer´s disease patients. 

4. Professor Bengt Långström, PhD; organic chemist and head of Imanet. More than 25 years experience of tracer 

development and applications of short-lived radionuclides. Development of a wide range of synthetic strategies for 

specific labelling of bioactive compounds. 

5. Dr. Henry Engler, MD; neurologist with great experience of PET studies in patients with different neurological 

diseases including Alzheimer´s disease and MCI. 

6. Assoc. Professor Gunnar Blomqvist, PhD; long-term experience in PET studies with focus on modeling work. 

7. Dr Anders Wall, PhD; pharmacologist with substantial experience of PET evaluations in the field of Alzheimer´s 

disease. 

8. PhD students Anton Forsberg and Ahmadul Kadir. 

References 

1. Stefanova, E., Blennow, K., Almkvist, O., Hellström-Lindahl, E., Nordberg, A. Cerebral glucose metabolism, cerebrospinal fluid-ß-amyloid 1- 

42 (CSF-Aß42), tau and apolipoprotein E genotype in long-term rivastigmine and tacrine treated Alzheimer disease (AD) patients. Neurosci 

Lett 2003; 338: 159-163. 

2. Arnaiz, E., Jelic,V., Almkvist, O., Wahlund, L.O., Winblad, B., Valind, B., Nordberg, A. Impaired cerebral glucose metabolisms and cognitive 

function predict detoriation in mild cognitive impairment. NeuroReport 2001; 12: 851-855. 

3. Bäckman L, Andersson JLR, Nyberg L, Winblad B, Nordberg A, Almkvist O. Brain regions associated with episodic retrieval in normal aging 

and Alzheimer´s disease. Neurology 1999: 52: 1861-1870.Sihver, W., Långström, B., Nordberg, A. Ligands for in vivo imaging of nicotinic 

subtypes of Alzheimer brain. Acta Neurol Scand 2000; 176: 27-33. 

4. Wahlund, L.O., Basun, H., Almkvist, O., Julin, P., Viitanen, M., Axelman, K., Shigeta, M., Jelic, V., Nordberg, A., Lannfelt, L. A follow up of 

a family with the Swedish Alzheimer mutation. Dementia and Geriatric Cognitive Disorders 1999; 10: 526-533. 

5. Herholz K, Nordberg A, Salmn E, Perani D, Kessler J, Mielke R, Halber M, Jelic O, Almkvist O, Collelle F, Alheroni M, Kennedy A, 

Hasselbach S, Fazio F, Heiss W D. Impairment of neocortical metabolism predicts progress in Alzheimer´s disease. Dementia and Geriatric 

Cognitive Disorders 1999; 10: 494-504. 

6. Eriksdotter-Jönhagen, M., Nordberg, A., Amberla, K., Bäckman, L., Ebendahl, T., Meyersson, B., Olson, L., Seiger, Å., Shigeta, M., 

Theodorsson, E., Viitanen, M., Winblad, B., Wahlund, L.O. Intraventricular infusion of nerve growth factors in three patients with Alzheimer´s 

disease. Dementia and Geriatric Cognitive Disorders 1998; 9: 246-257. 

7. Nordberg, A., Amberla, K., Shigeta, M., Lundqvist, H., Viitanen, M., Hellström-Lindahl, E., Johansson, M., Andersson, J., Hartvig, P., Lilja, 

A., Långström, B., Winblad, B Long-term tacrine treatment in three mild Alzheimer patients: effects on nicotinic receptors, cerebral blood 

flow, glucose metabolism, EEG and cognitive abilities, Alzheimer´s Disease Assoc Disorders 1998; 12: 228-237. 

8. Corder E H, Jelic V, Basun H, Lannfelt L, Valind S, Winblad B, Nordberg A. No difference in cerebral glucose metabolism in patients with 

Alzheimer´s disease and differing apolipoprotein E genotypes. Arch Neurol 1997: 54: 273-277. 

9. Nordberg, A., Lundqvist, H., Hartvig, P., Lilja, A., Långström, B. Kinetic analysis of regional (S)(-) 11C-nicotine binding in normal and 

Alzheimer brains-in vivo assessment using positron emission tomography. Alzheimer’s Disease and Associated Disorders 1995; 9: 21-27.


Partner 34a: Naples (S. Pappata) 

I.B.B., CNR Naples and Department of Clinical and Experimental Medicine, University of Naples “Federico 

II”, Italy 

The Bioimaging and Biostructure Institute (IBB) of CNR (National Research Council) has been created by merging 

the Biocrystallography Centre, Nuclear Medicine Centre from Naples, Italy, and part of the Institute for the study of 

natural substances of alimentary and chemo-pharmaceutical interest from Catania, in order to create a 

multidisciplinary approach in the research areas of biochemical, biostructural and bioimaging techniques. 

The Bioimaging Section is located in the Department of Diagnostic Imaging and Radiotherapy of the University 

“Federico II” of Naples and has particularly grown in the last years in terms of human and technical recourses, with 

over 30 researchers, including physicists, engineers, physicians, biologists and chemists which are involved in basic 

and clinical research in oncology and in clinical and methodological research in cardiology and neurology. Available 

equipment includes: a two-heads and a brain dedicated SPECT cameras, a recently installed CT-PET camera (GE- 

DISCOVERY) with a radiochemistry laboratory and a Cyclotron (GE-10Mev) Unit, a new 1.5T MRI (Philips Intera 

with echo-planar capabilities), and two Spiral multi-slices CT scanner. A basic research laboratory is also available for 

cell and molecular biology, biochemistry and in vitro tissue analysis. The neuroscience group comprises MD 

(neuroradiologists and nuclear medicine physicians) physicists and engineers. The research focuses on the 

development and/or application of SPECT/PET/MRI tools for imaging of neurodegenerative diseases and dementia. 

To achieve this aim close interactions with the department of Clinical and Experimental Medicine of the University 

"Federico II" and with a network of international collaborations have been developed, which have enabled the 

neuroimaging research group to coordinate the European project "Enhancement of Clinical Value of Functional 

Imaging through Automated Removal of Partial Volume Effect" (PVEOut) , V Framework Programme, QoL 9.4 and 

to participate in other European projects (NCI-MCI). The ambition of this group is also to develop, in the next future, 

research with potential new molecular tracers for PET and microPET. The IBB is the coordinator of a recently 

established “Centre of Competence in pharmacological and molecular diagnostics” (supported by the government of 

Regione Campania, involving two research areas focussing on Diagnostic imaging and Pharmacological research) and 

is part of the Centre of Excellence in Biotechnology and Biomedicine for the study of animal models of human 

diseases of the University "Federico II" (supported by the Italian Ministry of Education, University and Research) that 

includes a small animal imaging facility equipped with a microPET scanner. 

The Department of Clinical and Experimental Medicine of the University of Naples “Federico II” is devoted to the 

study and prevention of chronic and degenerative diseases such as cardiovascular (atherosclerosis, thrombosis, stroke) 

and dementia. The Department is located in the University Hospital of the University of Naples “Federico II”, hosts a 

ward with 30 in-patients, several out-patient sections including the Alzheimer Evaluation Unit and the Memory 

Clinic. The research laboratory utilizes many biochemical facilities aiming at the study of cellular and molecular 

biology of age-related degenerative diseases, endothelial and neuronal cultures, biological markers and genetic 

polymorphisms of many proteins involved in degenerative diseases related to neurogeriatrics and atherosclerosis, such 

as apolipoprotein E, plasminogen activator inhibitor, fibrinogen, angiotensin converting enzyme and others. The 

neuroscience group comprises MD, neuropsychologists and laboratory technicians. It has a strict collaboration with 

the Neuroscience group of I.B.B and both participate to neuroimaging studies of dementias. Both are involved in the 

European Project NCI-MCI and the Department of Clinical and Experimental Medicine is the main responsible 

partner of the work package aimed to test the interest of 123-Iomazenil/SPECT as an early marker of AD. The group 

is also interested in the research of neuropsychological, biological and genetic markers that could be of interest, in 

conjunction with the neuroimaging, for the early and differential diagnosis of dementias. Other interests are: the study 

of the pathophysiological mechanisms involved in cerebral ischemia, testing compounds able to exert neuroprotection, 

the identification of subjects predisposed to stroke. 


1. S. Pappatà: Researcher of CNR, neuroradiologist; neurodegenerative and cerebrovascular disorders imaging by 

PET/SPECT and MRI, validation of new PET tracers and/or methodology and application to the study of basic 

and clinical research. 

2. A. Varrone: Researcher of CNR, Nuclear Medicine specialist; neurodegenerative disorders (dementia and 

parkinsonism) imaging by SPECT (CBF and receptors), validation of methods for neuroreceptor quantification by 

SPECT. 

3. Dr. R. Panico and Dr A. Speranza: chemistry, radiochemistry and cyclotron. 

4. B. Alfano: Research Director of CNR, Physicist; Coordinator of the EC project PVEOut, instrumentation and 

development of brain segmentation and correction of partial volume effects methods. 

5. A. Prinster: Engineer; optimization of MRI sequences and methods for brain volumetry, functional MRI and 

diffusion. 

6. M Larobina: Physicist; instrumentation, integration of project-specific modules into general image processing 

software packages.


7. M. Quarantelli: Researcher of CNR, Radiologist and Nuclear Medicine specialist; development, validation and 

clinical application of MRI segmentation methods for brain volume quantification, SPECT/PET imaging, partial 

volume effect correction. 

8. A. Brunetti: Full Professor, Radiology and Nuclear Medicine specialist; head of the Bioimaging Section; 

dementia and Multiple Sclerosis Imaging by MRI, SPECT/PET imaging. 

9. M. Salvatore: Full Professor, Radiology, Nuclear Medicine and Radiotherapy Specialist; head of the Department 

of Diagnostic Imaging and Radiotherapy of the University “Federico II”; SPECT/PET/MRI imaging in oncology, 

cardiology and neurology. 

10. A. Postiglione: Associate Professor of Geriatrics; head of Alzheimer Evaluation Unit of the University Hospital 

“Federico II”; Naples, clinical, neuropsychological and genetic laboratories in dementia and stroke. 

11. G. Di Minno: Full Professor, Internal Medicine; head of haemorrhagic and thrombotic diseases of the University 

Hospital “Federico II”, Naples; clinical, biochemical and genetic laboratories in thrombotic and vascular diseases. 

12. G. Gallotta: Researcher of Geriatrics; head of the Memory Clinic of the Dept. of Clinical and Experimental 

Medicine in the University Hospital “Federico II”; neuropsychology, clinical studies in dementia. 

13. R. Paternò: Researcher of Geriatrics; experimental stroke, neuronal cultures, molecular and cellular biology in 

stroke and dementia. 

14. F. Cirillo: Biologist; head of the laboratory of the Dept. of Clinical and Experimental Medicine of the University 

of Naples “Federico II”. 

References 

PET-SPECT imaging: methodology and clinical application (neurodegenerative, cerebrovascular and psychiatric 

disorders) 

1. Kim KM, Varrone A, Watabe H, Shidahara M, Fujita M, Innis RB, Iida. Contribution of scatter and attenuation compensation to SPECT 

images of nonuniformly distributed brain activities. J Nucl Med 2003; 44: 512-519. 

2. Pappata S, Dehaene S, Poline JB, Gregoire MC, Jobert A, Delforge J, Frouin V, Bottlaender M, Dolle F, Di Giamberardino L, Syrota A. In 

vivo detection of striatal dopamine release during reward: a PET study with [(11)C]raclopride and a single dynamic scan approach. 

Neuroimage 2002; 16: 1015-1027. 

3. Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF Reduced prefrontal activity 

predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 2002; 5: 267-271. 

4. Blomqvist G, Tavitian B, Pappata S, Crouzel C, Jobert A, Doignon I, Di Giamberardino L. Quantitative measurement of cerebral 

acetylcholinesterase using 11C-Physostigmine and PET. J Cereb Blood Flow Metab 2001; 21: 114-131. 

MRI imaging : methodology, clinical applications, automated brain volume segmentation 

1. Quarantelli M, Ciarmiello A, Morra VB, Orefice G, Larobina M, Lanzillo R, Schiavone V, Salvatore E, Alfano B, Brunetti A. Brain tissue 

volume changes in relapsing-remitting multiple sclerosis: correlation with lesion load. Neuroimage 2003; 18: 360-366. 

2. Le Provost JB, Bartres-Faz D, Paillere-Martinot ML, Artiges E, Pappata S, Recasens C, Perez-Gomez M, Bernardo M, Baeza I, Bayle F, 

Martinot JL. Paracingulate sulcus morphology in men with early-onset schizophrenia. Br J Psychiatry 2003; 182: 228-232. 

3. Quarantelli M, Larobina M, Volpe U, Amati G, Tedeschi E, Ciarmiello A, Brunetti A, Galderisi S, Alfano B. Stereotaxy-based regional brain 

volumetry applied to segmented MRI: validation and results in deficit and nondeficit schizophrenia. Neuroimage 2002; 17: 373-384. 

4. Ciarmiello A, Brunetti A, Larobina M, Quarantelli M, Ziviello M, Alfano B, Salvatore M. Assessment of scanner performance and 

normalization of estimated relaxation rate values. MRI 2001; 19: 123-128. 

MRI imaging: other appliations in cerebrovascular disorders 

1. Molko N, Pappata S, Mangin JF, Poupon F, LeBihan D, Bousser MG, Chabriat H. Monitoring disease progression in CADASIL with diffusion 

magnetic resonance imaging: a study with whole brain histogram analysis. Stroke 2002; 33: 2902-2908. 

2. Molko N, Pappata S, Mangin JF, Poupon C, Vahedi K, Jobert A, LeBihan D, Bousser MG, Chabriat H. Diffusion tensor imaging study of 

subcortical gray matter in cadasil., Stroke 2001; 32: 2049-2054. 

3. Chabriat H, Pappata S, Ostergaard L, Clark CA, Pachot-Clouard M, Vahedi K, Jobert A, Le Bihan D, Bousser MG. Cerebral hemodynamics in 

CADASIL before and after acetazolamide challenge assessed with MRI bolus tracking. Stroke 2000; 31:1904-1912. 

Genetics in dementia and cerebrovascular disease 

1. D'Andrea G, Di Perna P, Brancaccio V, Faioni EM, Castaman G, Cibelli G, Di Minno G, Margaglione M. A novel G-to-A mutation in the 

intron-N of the protein S gene leading to abnormal RNA splicing in a patient with protein S deficiency. Haematologica 2003; 88: 459-464. 

2. Davi G, Di Minno G, Coppola A, Andria G, Cerbone AM, Madonna P, Tufano A, Falco A, Marchesani P, Ciabattoni G, Patrono C. Oxidative 

stress and platelet activation in homozygous homocystinuria. Circulation 2001; 104, 1124-1128. 

3. Postiglione, G. Milan, A. Ruocco, G. Gallotta, G. Guiotto, G. Di Minno, Plasma folate, Vitamin B12 and total homocysteine and homozygosity 

for the C677T mutation of the 5,10 methylene tetrahydrofolate reductase gene in patients with Alzheimer’s dementia. A Case-Control Study. 

Gerontology 2001; 47: 324-329. 

Cellular biology and neuroprotection 

1. Paternò R., Ruocco A., Postiglione A., Hubsch A., Andresen I., Lang M.G.: Reconstituted high-density lipoprotein exhibits neuroprotection in 

two rat models of stroke. Cerebrovascular Diseases 2003 (in press) 

2. Ruocco, A. Postiglione, M.R. Santillo, R. Seru, E.V. Avvedimento, G. Cuda, R. Paternò, New possible role of statins in age-related diseases. 

Journal of the American Geriatric Society 2002; 50: 2099-2100. 

3. Paternò R., Cuda G., Ceravolo R., Candigliota M., Perrotti N., Perticone F., Faniello M.C., Schepis F., Ruocco A., Mele E., Cassano S., Bifulco 

M., Santillo M., Avvedimento E.V.: Protection of human endothelial cells from oxidative stress. Role of Ras-ERK1/2 signaling. Circulation 

2002; 105: 968-974. 

4. S.G. Hasselbalch, G.M. Knudsen, B. Capaldo, A. Postiglione, O.B. Paulson, Blood-brain barrier transport and brain metabolism of glucose 

during acute hyperglycemia in humans. Journal of Clinical Endocrinology and Metabolism 2001; 86: 1986-1990. 

5. Santillo M., Mondola P., Serù R., Annella T., Cassano S., Ciullo I., Tecce M.F., Iacomino G., Damiano S., Cuda G., Paternò R., Martignetti V., 

Mele E., Feliciello A., Avvedimento E.V. Opposing functions of Ki- and Ha-Ras genes in the regulation of redox signals. Current Biology 11: 

616-619, 2001.


Partner 34b: Naples (A. Auricchio) 

Telethon Institute of Genetics and Medicine (TIGEM) and The Biostructure and Bioimaging Institute of the 

National Research Center (CNR), Naples, Italy. 

The Telethon Institute of Genetics and Medicine (TIGEM) is a large Italian research institution (entirely funded by 

Telethon, a private non-profit foundation) with a main focus on the isolation and characterization of disease genes, 

creation of animal models of inherited diseases, and, more recently, developing pre-clinical gene-based therapies. 

Since last September the Institute has recruited principal investigators with experience in adeno-associated viral 

(AAV) vector mediated gene transfer to retina, muscle, liver and lung of animal models of inherited disease. In 

addition, one of the TIGEM PIs, Alberto Auricchio, has successfully developed methods to monitor in vivo gene 

transfer using either Nuclear Magnetic Resonance (NMR) Spectroscopy or Single Photon Emission Computerized 

Tomography (SPECT). TIGEM offers all the infrastructures for vector development, production and administration to 

animal models of retinal, peripheral nerve, inner ear and metabolic disorders. To image in vivo gene transfer, TIGEM 

has teamed up with the Department of Radiology of the University of Pennsylvania, as part of an ongoing fruitful 

collaboration between Drs. Auricchio and Acton. Dr. Acton is in charge at PENN of a facility for imaging of small 

animals including a micro SPECT (Philips Medical Systems, Cleveland, OH) with either conventional fanbeam 

collimators, giving a spatial resolution of approx 7 mm, or custom-made pinhole collimators (Nuclear Fields, Des 

Plaines, IL) with a spatial resolution of approx 2mm. Recently, the facility has acquired a micro-TAC apparatus to 

match the functional SPECT imaging with anatomical information. Rodents transduced at TIGEM are imaged at 

PENN’s Dept. Of Radiology. Molecular and histological characterization of the animals is performed at TIGEM. 


1. Dr. Alberto Auricchio, MD: TIGEM Research Scientist, AAV vector development and their application to gene 

therapy of animal models of retinal diseases, type I diabetes, hemophilia, regulated gene expression and imaging of 

gene transfer. 

2. Dr. Paul Acton, PhD: Assistant Professor, Dept. of Radiology, University of Pennsylvania, Philadelphia, PA; 

SPECT imaging of the central nervous system dopamine and serotonin transporters and type 2 dopamine receptor 

in preclinical and clinical settings. 

Further members of the group: Libera Lo Presti (PhD student, development of AAV vectors required for the 

studies, support for the animal studies from vector administration to analysis of mice phenotype). Monica 

Doria (technician, production of AAV vectors) 

References 

Gene transfer with AAV vectors 

1. Reich SJ, Auricchio A, Hildinger M, Glover E, Maguire AM, Wilson JM, Bennett J: Efficient trans-splicing in the retina expands the utility of 

adeno-associated virus as a vector for gene therapy. Hum. Gene Ther. 2003; 14:37-44. 

2. Auricchio A, Acton P, Hildinger M, Louboutin JP, Ploessl K, O’Connor E, Kung H and Wilson JM: In vivo non-invasive imaging of gene 

transfer with single-photon emission computerized tomography. Hum. Gene Ther. 2003; 14 (3):255-262. 

3. Auricchio A, Gao GP, Yu QC, Raper S, Rivera V , Wilson JM: Constitutive and regulated expression of processed insulin following in vivo 

hepatic gene transfer. Gene Therapy 2002; (9): 962-970. 

4. Auricchio A, O’Connor E, Weiner D, Gao GP, Hildinger M, Wang L, Calcedo R, Wilson JM: Non-invasive gene transfer to lung for systemic 

delivery of therapeutic proteins. J. Clin. Invest. 2002; 110(4):499-504. 

5. Dejneka N*, Auricchio A*, Maguire A, Ye X, Gao GP, Wilson JM, Bennett J: Pharmacologically-regulated gene expression in the retina 

following transduction with viral vectors. Gene Therapy 2001; 8: 442-446. *these two authors contributed equally to the work. 

Imaging Neurotransporters/Receptors 

1. Acton PD, Hou C, Kung MP, Plossl K, Keeney CL, Kung HF. Occupancy of dopamine D2 receptors in the mouse brain measured using ultrahigh-resolution 

single-photon emission tomography and [123]IBF. Eur J Nucl Med Mol Imaging. 2002 Nov;29(11):1507-15. 

2. Acton PD, Choi SR, Plossl K, Kung HF. Quantification of dopamine transporters in the mouse brain using ultra-high resolution single-photon 

emission tomography. Eur J Nucl Med Mol Imaging. 2002 May;29(5):691-8. Epub 2002 Mar 07. 

3. Acton PD, Choi SR, Hou C, Plossl K, Kung HF.Quantification of serotonin transporters in nonhuman primates using [(123)I]ADAM and 

SPECT. J Nucl Med. 2001 Oct;42(10):1556-62. 

Monitoring/Imaging Gene transfer 

1. Auricchio A, Acton P, Hildinger M, Louboutin JP, Ploessl K, O’Connor E, Kung H, Wilson JM. In vivo non-invasive imaging of gene transfer 

with single-photon emission computerized tomography. Hum. Gene Ther. 2003; 14 (3):255-262. 

2. Auricchio A, Zhou R, Wilson JM, Glickson J. In vivo detection of gene expression in liver by (31)P-nuclear magnetic resonance spectroscopy 

employing creatine kinase as a marker gene. Proc. Natl. Acad. Sci. U S A. 2001; 24; 98(9):5205-10.


Partner 35: Durham (D. Parker) 

Department of Chemistry, University of Durham, UK 

There are three academic groups (Parker/Williams and Beeby) in Durham (Chemistry is 5*A rated) that each have 

over 10 years experience in devising new chemistry for de novo imaging probes. At present the work is restricted to 

studies in cells, and in vitro probes have been devised for a range of bioactive species, mostly based upon the 

modulation of lanthanide luminescence. Within the University a new Interdisciplinary Centre for Bioactive Chemistry 

has been formed (5 million euros invested in 2004 for space/equipment) with Optical Imaging Probes a key element in 

this initiative. This work has secured national and regional funds supporting collaborative projects with colleagues in 

Biological and Biomedical Sciences in the University. Durham is also serving as a coordinating centre in part of the 

approved NoE ‘EMIL’, and through other established European contacts (e.g. CIS-Bio/France Amersham 

Health/Biosciences, UK). The groups will develop the synthesis, and evaluation of new luminescent imaging agents 

for subsequent applications, focusing initially on selected assays that may aid the early detection of inflammation. 


1. Prof. D. Parker, Chairman of Department of Chemistry: chemistry of responsive lanthanide probes for use in 

imaging and MRI; metal-complex conjugates in analysis, diagnosis and therapy. 

2. Dr. A. Beeby, photochemist: imaging systems based on CCD technology; mechanisms of photochemical processes; 

time-resolved spectroscopy. 

3. Dr. J. A. G. Williams, synthetic inorganic and coordination chemist: development of new redox probes; longlived 

metal complex probes. 

References 

1. Dickins, R.S.; Aime, S.; Batsanov, A.S.; Beeby, A.; Botta, M.; Bruce, J.; Howard, J.A.K.; Love, C.S.; Parker, D.; Peacock, R.D.; Puschmann, 

H. Structural, luminescence, and NMR studies of the reversible binding of acetate, lactate, citrate, and selected amino acids to chiral diaqua 

ytterbium, gadolinium, and europium complexes. J Am Chem Soc 2002, 124: 12697-12705. 

2. Bretonniere, Y.; Cann, M.J.; Parker, D.; Slater, R. Ratiometric probes for hydrogencarbonate analysis in intracellular or extracellular 

environments using europium luminescence. Chem Commun 2002, 1930-1931. 

3. Bruce, J.I.; Parker, D.; Lopinski, S.; Peacock, R.D. Survey of factors determining the circularly polarised luminescence of macrocyclic 

lanthanide complexes in solution. Chirality 2002, 14: 562-567. 

4. Parker, D.; Dickins, R.S.; Puschmann, H.; Crossland, C.; Howard, J.A.K. Being excited by lanthanide coordination complexes: Aqua species, 

chirality, excited-state chemistry, and exchange dynamics. Chem Rev 2002, 102: 1977-2010. 

5. Blair, S.; Kataky, R.; Parker, D. Sol gel-immobilised terbium complexes for luminescent sensing of dissolved oxygen by analysis of emission 

decay New J Chem 2002, 26: 530.


Partner 36: Milan (D. Perani) 

Vita-Salute San Raffaele University, Milan and Scientific Institute Hospital San Raffaele, Milan Italy, Institute 

of Bioimaging and Molecular Physiology-CNR, Milan, Italy 

The Milan center has an infrastructure that comprises the Vita-Salute San Raffaele University with the Faculty of 

Medicine and the Faculty of Psychology; the Cyclotron and PET equipments in the Department of Nuclear Medicine, 

the MRI and fMRI facilities in the Radiology and Neuroradiology Departments, the Neurology and Psychiatry 

Departments at the Scientific Institute Hospital San Raffaele. The Institute of Bioimaging and Molecular Physiology- 

CNR at the Laboratorio Interdisciplinare Tecnologie Avanzate is located nearby. All these components can be 

considered part of the same infrastructure because of the spatial contiguity, because they are connected electronically, 

because the scientific staff gaining access to the research facilities and resources has strict interrelationships. The 

infrastructure owns a large number of facilities devoted to the study of brain function in normal subjects and 

dysfunction in neurological and psychiatric disorders and is well established in carrying out multidisciplinary 

molecular imaging research: 1. Radiochemistry laboratories for the development of novel radioligands for positron 

emission tomography studies of molecular biology and neurochemical processes. 2. Laboratory for testing of the new 

radio-tracers in animals (rats and monkeys). 3. Psychology laboratory for the development and testing of cognitive 

paradigms for functional imaging experiments. 4. Neurophysiology laboratories equipped with ERPs and EEG 

Mapping techniques, 5. Two cyclotrons and three 3D positron emission tomography (PET) scanners (GE-Advance 

PET). The cyclotrons allow the routine production of PET ligands for studies of brain metabolism (using 18F-FDG), 

brain activation (using 15O-H2O as rCBF tracer) and neurotransmission (18F and 11C labelled tracers). 4. Networks 

of computers connected with the other infrastructures and with the Internet (SPARC SUN Workstations dedicated for 

data analysis and PC platforms for computing). 5. Primatology Center with a colony of 30 monkeys (macaca 

nemestrina) for behavioural and functional imaging studies. regular access to two 1.5 Tesla MRI scanners (GE-Signa 

1.5T, Picker 1.5T, equipped with EPI hardware) and a 3 Tesla MRI scanner (Phillips). The scientific personnel of the 

Milan Infrastructure includes a multidisciplinary group of experts in radiochemistry, neuropharmacology, computing 

sciences, PET and fMRI physics and engineering, psychology, neuropsychology, neurology, psychiatry, primatology. 

This infrastructure can offer the opportunity of an articulated research plan starting from behavioural observations in 

humans and primates, to in vivo measurements of brain activation and brain molecular biology and neurochemical 

processes. All this can be at one research site with access to patient population of the Departments of Neurology and 

Psychiatry of the San Raffaele Hospital. Close interactions exist with the Departments of Neurology, Neurosurgery 

and Psychiatry and the Neuropsychology Laboratory for patient selection and evaluation, the Departments of 

Radiology and Neuroradiology for MRI and fMRI acquisition, co-registering molecular PET imaging data with 

anatomical and spectroscopic information obtained by MRI and MRS as well as diffusion/tensor imaging for fiber tract 

studies; the Department of Genetics for correlation of PET and MRI data with genetic findings; the Molecular Biology 

Laboratory of the IBFM-CNR for development of mouse models of human diseases and potential application of 

molecular imaging methods. The Milan Center plays an essential role in neuroscience research at the Vita-Salute San 

Raffaele University, focussing on diagnosis and treatment strategies in neurodegenerative disease, stroke, staging and 

therapy follow-up in neurooncology. The scientific production of the Milan Center is well known for 

neuropsychological, neurological and psychiatric studies using metabolic measurements of brain activity and 

molecular imaging data in various disorders and syndromes. The laboratory is now also well known for activation PET 

and fMRI studies in normal subjects and patient populations. The Milan Center has close collaborations with 

international research groups (EU-Groups involved in NEST-DD; Cognitive Neuroscience MIT, Boston; Institute for 

Language UCSD, San Diego; Institute of Neuroscience-INSERM Lyon; INSERM-CEA-SHFJ, Orsay, France). 


1. Prof. Dr. Ferruccio Fazio: Director of the IBFM-CNR and the Department of Nuclear Medicine; experimental and 

imaging by PET and SPECT in neurology, oncology and cardiology. 

2. Prof. Dr. Daniela Perani: Neurologist, Neuropsychologist and Functional Imaging; PET and fMRI studies of 

cognitive functions; image analysis; early diagnosis of Alzheimer’s disease and differential diagnosis from other 

forms of dementia by neuropsychology and molecular PET and SPECT imaging. 

Further members of the group: Dr. J Abutalebi (MD, Neurologist, patient selection and evaluation, data 

analysis); Dr. D. Anchisi (MD, statistical analysis, image analysis); Dr. M. Tettamanti (biologist, PET, 

SPECT, MRI and fMRI image analysis); Dr. V. Garibotto (MD, patient selection and evaluation, PET, 

SPECT data analysis); Dr. P. Vitali (psychologist; neuropsychological patient evaluation, cognitive paradigm 

preparation and validation, effective connectivity analysis in PET and fMRI); Dr. S. Brambati (psychologist; 

MRI structural and PET fMRI functional imaging analysis, correlation of rehabilitation therapeutic efficiency 

in patients). 

3. Prof Dr. Stefano Cappa: Neurologist and Neuropsychologist, Head of the Department of Neurology and the 

Neuropsychology Laboratory, H San Raffaele Ville Turro; patient recruitment and assessment; development and


validation of neuropsychological testing; correlation of clinical and neuropsychological findings with imaging 

results. 

Further members of the group: Dr. A. Marcone (MD, neurologist, patient recruitment and assessment); Dr M. 

Zamboni (MD, neurologist, patient recruitment and assessment); Dr P. Ortelli (MS, psychologist, 

development and administration of neuropsychological testing). 

4. Prof. Dr. MC Gilardi: Physicist; instrumentation, hard- and software development. 

Further members of the group: V Bettinardi and I Castiglioni (physics; optimization of PET data images); P 

Scifo and G Rizzo (engineers, informatics; software development for image coregistration; integration of 

project-specific modules into image processing package. 

5. Dr. Mario Matarrese: Organic Chemist, Radiochemist; design and radiosinthesis of radioligands labelled with 18 F 

and 11 C; development of new radioligands analogues of PK11195 for visualization of periperal benzodiazepine 

receptors. 

Further members of the group: Dr. Sergio Todde (chemist, radiochemist, development of radioligands 

labelled with 18 F and 11 C); Dr. Maria Grazia Minotti (radiochemist); Dr. Francesco Perugini (radiochemist); 

Dr. Assunta Carpinelli (radiochemist, [ 11 C]- and [ 18 F]probes); Dr. Elia Anna Turolla and Dr. Azzurra 

Filannino (organic chemistry and radiochemistry, development of new molecular imaging probes which pass 

blood brain barrier). 

6. Dr. R.M Moresco: Pharmachologist; preclinical and clinical tracer development, molecular imaging in brain 

neurochemistry of normal behavior and neuropsychiatry disease including sporadic and inherited forms of 

Parkinon’s disease, and major depression. 

Further members of the group: Dr. A Panzacchi, M.D. (SPECT, PET studies and image analysis) Dr. S. 

Belloli (biotechnologist, PET, SPECT tracer development, animal model of pathologies); Dr. Pietra L 

(pharmacist, tracer pharmachokinetics, PET, SPECT images analysis). 

References 


1. Bettinardi V, Pagani E, Gilardi MC, Alenius S, Thielemans K, Teras M, Fazio F Implementation and evaluation of a 3D one-step late 

reconstruction algorithm for 3D positron emission tomography brain studies using median root prior. Eur J Nucl Med Mol Imaging. 2002; 

29(1):7-18. 

2. Todd-Pokropeck A and Gilardi MC Technologies and methods in nuclear medicine. Q J Nucl Med. 2002;46(1):1-2. 

3. Jacobson M, Levkovitz R, Ben-Tal A, Thielemans K, Spinks T, Belluzzo D, Pagani E, Bettinardi V, Gilardi MC, Zverovich A, Mitra 

G.Enhanced 3D PET OSEM reconstruction using inter-update Metz filtering. Phys Med Biol. 2000;45(8):2417-39. 

4. Picchio M, Savi A, Lecchi M, Landoni C, Gianolli L, Brioschi M, Rossetti C, Gilardi MC, Fazio F. Evaluation of the clinical performances of a 

large NaI(Tl) crystal 3D PET scanner. Q J Nucl Med. 2000;47(2):90-100. 

Neuropsychology/Neurology 

1. Volontè MA, Perani D, Lanzi R, Poggi A, Anchisi D, Balini A, Comi G, Fazio F. Regression of ventral striatum hypometabolism after 

calcium/calcitriol therapy in paroxysmal kinesigenic choreoathetosis due to idiopathic primary hypoparathyroidism. J Neurol Neurosurg 

Psychiatry. 2001;71(5):691-5. 

2. Perani D, Brunelli GA, Tettamanti M, Scifo P, Fazio F. Remodelling of sensorimotor map in paraplegia. Neuroscience Letters, 2001, 303: 62- 

66. 

3. Meola G, Sansone V, Perani D, Colleluori A, Cappa SF, Cotelli M, Fazio F, Thornton CA, Moxley RT. Cognitive, brain MRI and PET studies 

in proximal myotonic myopathy and myotonic dystrophy. Neurology 1999, 22;53:1042-50 

4. Cappa SF, Binetti G, Pezzini A, Padovani A, Rozzini L, Trabucchi M Object and action naming in Alzheimer's disease and fronto-temporal 

dementia, Neurology 1998, 50: 351-355. 

5. Binetti G, Cappa SF, Magni E, Padovani A, Bianchetti A, Trabucchi M, Visual and spatial perception in the early phase of Alzheimer's 

disease, Neuropsychology 1998, 12: 29-33. 





2. Perani D. The role of emission tomography in dementia. Ital J Neurol Sci. 2000; 20(8):S254-S257. 


1. Lucignani G, Gobbo C, Moresco RM, Antonini A, Panzacchi A, Bonaldi L, Carpinelli A, Caraceni T, Fazio F. The feasibility of statistical 

parametric mapping for the analysis of positron emission tomography studies using 11C-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)-tropane 

in patients with movement disorders. Nucl Med Commun. 2002 ;23(11):1047-55 

2. Moresco RM, Volonte MA, Messa C, Gobbo C, Galli L, Carpinelli A, Rizzo G, Panzacchi A, Franceschi M, Fazio F. New perspectives on 

neurochemical effects of amantadine in the brain of parkinsonian patients: a PET - [(11)C]raclopride study. J Neural Transm. 

2002;109(10):1265-74. 


1. Montagna, F. Provini, P. Plazzi, R. Vetrugno, R. Galassi, G. Pietrangeli M. Ragno, P. Cortelli, D. Perani Bilateral paramedian thalamic 

syndrome: abnormal circadian wake-sleep and autonomic functions. Journal of Neurology, Neurosurgery and Psychiatry 2002, 73, 772-774. 

2. Perani,D, S.F. Cappa, M. Tettamanti, M. Rosa, P. Scifo, A. Miozzo, A. Basso, F. Fazio A fMRI study of word retrieval in aphasia Brain 

Lang. 2003; 85(3):357-68. 

Imaging Cognitive Functions 

1. Wartenburger, H.R. Heekeren, J. Abutalebi, S.F.Cappa, A.Villringer and D. Perani. Early Setting of Grammatical Processing in the Bilingual 

Brain. Neuron. 2003, 37, 159-170. 

2. Tettamanti M, Alkadhi H, Moro M, Perani D, Kollias S, Weniger D Neural correlates for the acquisition of natural language syntax.


NeuroImage, 2002, 17: 700-709. 

3. Perani D, Fazio F, Borghese NA, Tettamanti M, Ferrari S, Decety J, Gilardi MC. Different brain correlates for watching real and virtual hand 

actions. NeuroImage, 2001, 14:749-758. 

4. Moro A, Tettamanti M, Perani D, Donati C, Cappa SF,Fazio F. Syntax and the brain: disentangling grammar by selective anomalies. 

NeuroImage, 2001, 13: 110-118. 

5. Paulesu E, McCrory E, Fazio F, Menoncello L, Brunswick N, Cappa SF, Cotelli M, Cossu G, Corte F, Lorusso M, Pesenti S, Gallagher A, 

Perani D, Price C, Frith CD, Frith U. A cultural effect on brain function. Nature Neuroscience; 2000; 3 (1): 91-95 

Imaging of brain neurochemistry/neurotransmission 

1. Messa C, Colombo C, Moresco RM, Gobbo C, Galli L, Lucignani G, Gilardi MC, Rizzo G, Smeraldi E, Zanardi R, Artigas F, Fazio F. 5- 

HT(2A) receptor binding is reduced in drug-naive and unchanged in SSRI-responder depressed patients compared to healthy controls: a PET 

study. Psychopharmacology (Berl). 2003 Apr;167(1):72-8. 

2. Moresco FM, Dieci M, Vita A, Messa C, Gobbo C, Galli L, Rizzo G, Panzacchi A, De Peri L, Invernizzi G, Fazio F. In vivo serotonin 

5HT(2A) receptor binding and personality traits in healthy subjects: a positron emission tomography study. Neuroimage. 2002 

Nov;17(3):1470-8. 

3. Zanardi R, Artigas F, Moresco R, Colombo C, Messa C, Gobbo C, Smeraldi E, Fazio F. Increased 5-hydroxytryptamine-2 receptor binding in 

the frontal cortex of depressed patients responding to paroxetine treatment: a positron emission tomography scan study. J Clin 

Psychopharmacol. 2001 Feb;21(1):53-8. 

4. Fazio F, Perani D. Importance of partial-volume correction in brain PET studies. J Nucl Med. 2000 Nov;41(11):1849-50. 

5. Moresco RM, Colombo C, Fazio F, Bonfanti A, Lucignani G, Messa C, Gobbo C, Galli L, Del Sole A, Lucca A, Smeraldi E. Effects of 

fluvoxamine treatment on the in vivo binding of [F-18]FESP in drug naive depressed patients: a PET study. Neuroimage. 2000 Oct;12(4):452- 

65. 


1. Belloli S, Moresco RM, Matarrese M, Biella G, Sancito F, Simonelli P, Belloli S, Turolla E, Olivieri S, Popoli P, Cappelli A, Vomero S, Galli- 

Kienle M, and Fazio F. Evaluation of three quinoline-carboxamide derivatives as potential radioligands for the in vivo PET imaging of 

neurodegeneration. Neurochemistry International 2003 (in press). 

2. Matarrese M, Moresco RM, Romeo G, Turolla EA, Simonelli P, Todde S, Belloli S, Carpinelli A, Magni F, Russo F, Galli Kienle M, Fazio F. 

[ 11 C]RN5: a new agent for the in vivo imaging of myocardial receptors. Eur. J. Pharm. 2002, 453(2-3):231-238. 

3. Soloviev D, Matarrese M, Moresco RM, Todde S, Bonasera TA, Sudati F, Simonelli P, Magni F, Colombo D, Carpinelli A, Galli Kienle M, 

Fazio F. Asymmetric synthesis and preliminary evaluation of (R)- and (S)-[ 11 C]bisoprolol, a putative 1 -selective adrenoceptor radioligand. 

Neurochem Int, 2001; 38(2): 169-180. 

4. Matarrese M, Moresco RM, Cappelli A, Anzini M, Vomero S, Simonelli P, Verza E, Magni F, Sudati F, Soloviev V, Todde S, Carpinelli A, 

Galli Kienle M, Fazio F. Labelling and evaluation of N-[ 11 C]methylated quinoline 2-carboxamides as potential radioligands for visualization of 

peripheral benzodiazepine receptors. J Med Chem, 2001; 44(4): 579-585. 

1. Todde S, Moresco RM, Simonelli P, Baraldi, PG, Cacciari B, Spalluto G, Varani, K, Monopoli A, Matarrese M, Carpinelli A, Magni F, Galli 

Kienle M, Fazio F. Design, radiosynthesis, and biodistribution of a new potent and selective ligand for in vivo imaging of the Adenosine A 2A 

receptor system using Positron Emission Tomography. J Med Chem, 2000; 43: 4359-4362


Partner 37: Leiden (R. Poelmann) 

High field magnetic resonance microscopy of small animal models of human cardiovascular disease at Leiden, 

Netherlands 

The University of Leiden (UL), TNO-Gaubius and the Leiden University Medical Center (LUMC) are collaborating 

intensively in e.g. the research cluster Leiden Vascular Medicine, that has established the Expert Center Vascular 

Medicine. Imaging facilities are located in various departments and are available for these collaborations, including 

patients and small laboratory animals, more particularly (transgenic) mice. The animal models are part of larger 

studies involving the cardiovascular system. Three main points of interest can be defined, depending on specific organ 

systems. These comprise the heart muscle including the coronary arteries, the peripheral vascular system, and finally 

the cerebral circulation. As the adult system has to be organized from the embryonic state onwards, we have also 

incorporated the developmental biology of the cardiovascular system, realizing that embryonic genes and mechanisms 

are often re-expressed in adult disease, although in a warped way. The collaborations of the Leiden group require and 

provide imaging facilities for various reasons and scopes. An important overall fact is the necessity of having 

available material from living animals that can be studied longitudinally. The latter aspect saves expensive animal 

lives. Several projects are imminent being neurological, cardiological and vascular in origin. These usually require 

different approaches, but have common demands when using magnetic resonance imaging. Among these are high 

contrast and high signal in high magnifications. The magnification and contrast are given by the ultra high-field 

magnets that are available, the largest reaching 17.6 Tesla (Bruker). This specific machine results from an earlier 

European-funded project (Prof. Dr. H.de Groot, Leiden). 

Heart: The ischemic and failing heart is a major issue in western societies. We have developed a stemcell-based 

approach, using modified mesenchymal, adult and embryonic precursor cells to improve the quality of the failing 

heart. Imaging of the anatomical, cellular and molecular biological, as well as the functional consequences of the (so 

far preclinical) experimental set-up is of utmost importance. Magnetic resonance microscopy is a major tool for 

imaging cardiac anatomy and performance. 

Brain: Migraine is a complex neurovascular disease. Recently two genes have been identified and recently the first 

knock-in transgenic mouse model has been developed in Leiden for one of them. As blood perfusion of the brain plays 

a major role in the pathophysiology of migraine attacks and can be changed experimentally by specific challenges, we 

need to develop magnetic resonance tools to image the changes in perfusion. 

Peripheral circulation: Atherosclerosis is an invalidating and oftentimes lethal disease. A number of projects 

investigate the role of blood-borne substances (lipids, cholesterol, glucose) and the changes in e.g. the vascular wall. 

Imaging tools rely heavily on the contrast media to be developed to pinpoint the constituents of vulnerable areas in the 

vascular system. 

Development of the cardiovascular system: During embryonic life the dimensions of heart and vessels are of a 

different magnitude but nevertheless function as a coordinated and integrated system. Although this small dimension is 

a challenge in itself, we can study differentiation and remodelling under experimental conditions by growth factors, 

changes in the transcriptional apparatus and by altering flow and shear stress. 

Contrast agents: An important technical point concerns the innovation of specific markers for both (stem) cells and for 

gene expression studies. Therefore, we need to pay much attention to further development of i.e. USPIO’s and 

Gadolinium-based agents. 


1. Prof. Dr. R. E. Poelmann, Department of Anatomy and Embryology, Leiden University Medical Center (LUMC), 

developmental cardiovascular biology, hemodynamics and magnetic resonance microscopy (MRM). 

Further members of the group: Dr. B.Hogers, biomedical sciences, contrast agents, MRM; Dr. V. van 

Ginneken, MRM; Prof. Dr. A. C. Gittenberger-de Groot, Embryology of cardiovascular anomalies, 

embryonic stem cells; Dr. H. Lie-Venema, transcription factors in coronary development. 

2. Prof. Dr. H. de Groot, Leiden Institute of Chemistry, Leiden University: solid state NMR. 

Further members of the group: Dr C. Erkelens, Head of the NMR facility; Dr. J.v.d. Maarel, spectroscopy 

physics. 

3. Prof Dr. A. de Roos: Department of Radiology (LUMC): cardiovascular imaging. 

Further members of the group: Prof. Dr.J.H.C.Reiber and Dr. R. J. van der Geest, image processing; Dr. 

J.Doornbos, cardiovascular imaging. 

4. Prof. Dr. E. E. van der Wall, Department of Cardiology (LUMC) 

Further members of the group: Prof. Dr. A. van der Laarse, Prof. Dr. M. Schalij, Dr. D. E. Atsma, Dr. W. 

Jukema, Dr. P. Steendijk): cardiac imaging, electrophysiology, pressure-volume loops, biochemistry of 

cardiac differentiation, stem cells in heart failure. 

5. Prof. Dr. L. M. Havekes, Department of Internal Medicine (LUMC) and TNO-Gaubius, cholesterol and


carbohydrate metabolism. 

Further members of the group: Prof. Dr. J.A.Romijn, diabetes; Dr. P.H.Quax (TNO-Gaubius), 

atherosclerosis. 

6. Prof. Dr. R. R. Frants, Department of Human Genetics (LUMC): genetics of human disease. 

Further members of the group: Prof. Dr. M. Ferrari: Department of Neurology (LUMC): migraine; Dr. 

A.M.J.M. van den Maagdenberg: (functional) genetics of migraine; Prof. Dr. M. Van Buchem (LUMC): 

radiology and MRI. 

References 

Cardiac developmental biology 

1. Stekelenburg-de Vos S, Ursem NTC, Hop WCJ, Wladimiroff JW, Gittenberger-de Groot AC, Poelmann RE. Acutely altered hemodynamics 

following venous obstruction in the early chick embryo. J Exp Biol 2003; 206:1051-1057. 

2. Hogers B, Gross D, Lehmann V, de Groot HJ, de Roos A, Gittenberger-de Groot AC, Poelmann RE. Magnetic resonance microscopy at 17.6- 

Tesla on chicken embryos in vitro. J Magn Reson Imaging. 2001;14(1):83-6. 

3. Hogers B, Gross D, Lehmann V, Zick K, De Groot HJ, Gittenberger-De Groot AC, Poelmann RE. Magnetic resonance microscopy of mouse 

embryos in utero. Anat Rec. 2000; 260(4):373-7. 

4. Carmeliet P, Lampugnani MG, Moons L, Breviario F, Compernolle V, Bono F, Balconi G, Spagnuolo R, Oosthuyse B, Dewerchin M, Zanetti 

A, Angellilo A, Mattot V, Nuyens D, Lutgens E, Clotman F, de Ruiter MC, Gittenberger-de Groot A, Poelmann R, Lupu F, Herbert JM, Collen 

D, Dejana E. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and 

angiogenesis. Cell. 1999; 98(2):147-57. 

Cardiac imaging 

1. Bavelaar-Croon CD, Kayser HW, van der Wall EE, de Roos A, Dibbets-Schneider P, Pauwels EK, Germano G, Atsma DE. Left ventricular 

function: correlation of quantitative gated SPECT and MR imaging over a wide range of values. Radiology 2000; 217: 572-575. 

2. Van der Geest RJ, Lelieveldt BP, Reiber JH. Quantification of global and regional ventricular function in cardiac magnetic resonance imaging. 

Top Magn Reson Imaging 2000; 11:348-358. 

3. Westenberg JJ, Van der Geest RJ, Wasser MN, Doornbos J, Pattynama PM, de Roos A, Vanderschoot J, Reiber JH. Stenosis quantification 

from post-stenotic signal loss in phase-contrast MRA datasets of flow-phantoms and renal arteries. Int J Card Imaging 1999; 483-493. 

4. Van der Geest RJ, Reiber JH. Quantification in cardiac MRI. J Magn Reson Imaging 1999; 10:602-608. 

Peripheral circulation 

1. Tacken PJ, Delsing DJ, Gijbels MJ, Quax PH, Havekes LM, Hofker MH, Van Dijk KW. VLDL receptor deficiency enhances intimal 

thickening after vascular injury but does not affect atherosclerotic lesion area. Atherosclerosis 2002; 162: 103-110. 

2. Van de Poll SW, Delsing DJ, Jukema JW, Princen LM, Havekes LM, Puppels GJ, van der Laarse A. Raman spectroscopic investigation of 

atorvastatin, amlodipine, and both on atherosclerotic plaque development in APOE-3 Leiden transgenic mice. Atherosclerosis 2002; 164:65- 

71. 

3. Lardenoye JH, Delsing DJ, de Vries MR, Deckers MM, Princen HM, Havekes LM, van Hinsbergh VW, van Bockel JH, Quax PH. Accelerated 

atherosclerosis by placement of a perivascular cuff and a cholesterol-rich diet in APOE-3 Leiden transgenic mice. Circ Res 2000; 87: 248-253. 

Neurobiology 

1. van Molkot KJR, Kors EE, Hottenga JJ, Terwindt GM, Haan J, Hoefnagels WAJ, Black DF, Sandkuijl LA, Frants RR, Ferrari MD, van den 

Maagdenberg AMJM. Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign 

familial infantile convulsions. Annals Neurol 2003, published online. 

2. Spilt A, Box FM, Van der Geest RJ, Reiber JH, Kunz P, Kamper AM, Blauw GJ, Van Buchem MA Reproducibility of total blood flow 

measurements using phase contrast magnetic imaging. J Magn Res Imaging 2002; 16:1-5. 

3. Goadsby PJ, Lipton RB, Ferrari MD. Migraine-current understanding and treatment. N.Engl J Med 2002; 346:257-270. 

4. Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, 

Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR. Familial hemiplegic migraine and episodic ataxia type-2 are caused 

by mutations in the Ca2+ channel gene CACNL1A. Cell 1996; 87:543-552.


Partner 38: Grenoble (P. Rizo) 

CEA/LETI: Département Systèmes pour l’Information et la Santé, Grenoble, France 

CEA-LETI, the Laboratory for Electronics & Information Technology is operated by Direction de la Recherche 

Technologique at CEA – the French Atomic Energy Commission. It mainly aims at helping companies to increase 

their competitiveness through technological innovation and transfer of its technical know-how to industry. 

LETI is currently employing some 800 people among whom 619 CEA employees and co-workers of various status 

including 100 people from industrial partners, working in the LETI premises within the framework of bilateral 

collaborations. 

CEA-LETI: «Département Systèmes pour l’Information et la Santé (DSIS)» develops instrumentation for biology 

since 1994. It is involved in fluorescence optical reader design and optimisation. It produced: 

• Reading devices based on epifluorescence microscopes. These systems have demonstrated a measurement 

repeatability better than 1%. 

• A scanner dedicated for Affymetrix DNA chips. This system relies on a CD ROM reader optical actuator, devices 

measuring fluorescence polarisation on 48 capillaries simultaneously. These systems were used to control 

hybridisation in capillaries. 

• Optical devices performing immuno-photodetection on competition tests. These systems can reach a sensitivity 

close to 1pM. 

In parallel, CEA/LETI/DSIS has been involved in the development of reconstruction algorithm since 1980. It 

developed a competence in 3D tomographic imaging, dynamic reconstruction and on algebraic and analytic 

reconstruction algorithms. 

These skills in optical instrumentation for fluorescence and in image reconstruction are being applied to setup reading 

systems dedicated to fluorescence molecular imaging. The fields addressed by our researches are 3D tomographic 

imaging, deep structure imaging in small animal as well as dynamic surface imaging for human clinical use. 

To perform its developments, CEA/LETI/DSIS relies on six optical clean rooms, fluorescence microscopes, 

spectrometers and one confocal microscope. 


List of the persons in the laboratory involved in in vivo fluorescence imaging: 

1. Jean-Pierre Moy PhD: Specialist in physics and optics, in charge of the development of in vivo fluorescence 

imaging. 

2. Philippe Peltié: Specialist in optics, in charge of the development of fluorescence imaging of humans for clinical 

use 

3. Anne Planat-Chrétien PhD: Specialist in image processing and modelling, in charge of the development of 

modelling of light propagation in tissues 

4. Anabela Da Silva PhD: Specialist in physics and signal processing, in charge of the development of 

reconstruction algorithms 

5. Pascale Parrein PhD: Specialist in optics, in charge of the experimental aspects of the optical tomography 

6. Aurélie Laidevant: PhD student, working on the 2D deep structure imaging in small animals 

7. Michel Berger: Technician, working on the experimental aspects of the fluorescence imaging of humans for 

clinical use 

(Of these persons only Jean-Pierre Moy will directly participate to the DIMI network) 

References 

LETI is aiming at developing instrumentation for industrial partner. Therefore the work is more oriented toward patents more than publications 

Perraut F, Lagrange A, Pouteau P, Peyssonneaux O, Puget P, McGall G, Menou L, Gonzalez R, Labeye P, Ginot F. A new generation of scanners 

for DNA chips. Biosensors and Bioelectronics 2002; 17 803-813


Partner 39: Liege (E. Salmon) 

Cyclotron Research Centre, University of Liege, Belgium 

The Cyclotron Research Centre is multidisciplinary and combines expertise in neuroimaging, radiochemistry, 

neurology and neuropsychology. Researchers have links with University faculties of Medicine, Science and 

Psychology and with the University Hospital, all located on the same campus. CRC harbors a 3T-MRI (Siemens), a 

CTI 951 R 16/31 PET (Siemens), a fully equipped laboratory for synthesis of radiolabelled elements for PET, 

according to XMP manufactural production criteria and a small animal laboratory to test distribution of radioligands. 

We plan to acquire a high resolution head only PET camera. We have research projects on synthesis of different 

serotoninergic compounds, on brain activation using drugs or cognitive paradigms, on brain activation, cognition and 

behaviour in patients with degenerative diseases. The CRC has collaborations with international research groups (EC 

NEST-DD project, EC EADC project) and national research groups (IUAP). 


1. Prof. A. Luxen: Director of the CRC, Head of the Radiochemistry Unit 

Senior Researchers in radiochemistry: A. Plenevaux (Post-doctoral Researcher National Fund for Scientific 

Research/FNRS), G. Delfiore, F. Mievis and C. Lemaire (asymmetric synthesis of radiolabelled aminoacids; 

solid supported radiochemistry) 

Junior Researchers in chemistry: L. Brichard, F. Giaccomelli, C. Defraiteur, C. Kech, L. Wauters 

Senior Researchers in physics: C. Degueldre, C. Philips (FNRS), E. Balteau (FNRS) 

Senior Researchers in pharmacy: J. Aerts, C. Cantarinni, C. Mella 

2. Prof. Dr. E. Salmon: Medical director of the CRC, Head of the Memory Centre –University Hospital (functional 

imaging of normal and pathological cognition and behaviour) 

Senior Researchers in neuropsychology: F. Lekeu, P. Peigneux 

Junior Researcher in neurology: G. Garraux (FNRS) 

3. Prof. Dr. Psy. F. Collette: Post-doctoral Researcher National fund for Scientific Research, Head of the Cognitive 

Aging Unit, Department of Neuropsychology (cognitive, neuropsychological and functional imaging studies of 

executive functions) 

Junior Researcher in neuropsychology: M. Hogge (FNRS) 

4. Dr. Psy. S. Majerus: Post-doctoral Researcher National fund for Scientific Research, Department of Cognitive 

Sciences 

References 


1. Lekeu, F., Van der Linden, M., Degueldre, C., Lemaire, C., Luxen, A., Franck, G., Moonen, G., & Salmon, E. Effects of Alzheimer's disease on 

the recognition of novel versus familiar words: neuropsychological and clinico-metabolic data. Neuropsychology 2003; 17: 143-154. 

2. Lekeu, F., Van der Linden, M., Chicherio, C., Collette, F., Degueldre, C., Franck, G., Moonen, G., & Salmon, E. Brain correlates of performance 

in a free/cued recall task with semantic encoding in Azheimer's disease. Alzheimer's Disease and Associated Disorders 2003; 17: 35-45. 

3. Salmon E. Functional brain imaging applications to differential diagnosis in the dementias. Curr Opin Neurol 2002; 15: 439-444. 




5. Daniel H.S. Silverman, Gary W. Small, Carol Y. Chang, Carolyn S. Lu., Michelle A. Kung de Aburto, Wei Chen, Johannes Czernin, Stanley I. 

Rapoport, Pietro Pietrini, Gene E. Alexander, Mark B. Schapiro, William J. Jagust, John M. Hoffman, Kathleen A. Welsh-Bohmer, Abass Alavi, 

Christopher M. Clark, Eric Salmon, Mony J. de Leon, Ruediger Mielke, Jeffrey L. Cummings, Arthur P. Kowell, Sanjiv S. Gambhir, Carl K. 

Hoh, Michael E. Phelps. Neuroimaging in Evaluation of Dementia: Regional Brain Metabolism and Long-Term Outcome. JAMA 2001, 286: 

2120-2127. 

Imaging cognitive functions 

1. Alexandre Schaefer, Fabienne Collette, Pierre Philippot, Martial Van der Linden, Steven Laureys, Guy Delfiore, Christian Degueldre, Pierre 

Maquet, Andre Luxen, Eric Salmon.Neural correlates of “hot” and “cold” emotional processing: a multilevel approach to the functional anatomy 

of emotion. Neuroimage 2003; 18: 938-949. 

2. Lekeu F, Marczewski P, Van der Linden M, Collette F, Degueldre C, Del Fiore G, Moonen G, Salmon E. Effect of incidental and intentional fea 

binding on recognition: behavioural and PET activation study. Neuropsychologia 2002; 40(2):131-144. 

3. Majerus S, Collette F, Vanderlinden M, Peigneux P, Laureys S, Delfiore G, Degueldre C, Luxen A, Salmon E. A PET investigation of lexicality 

phonotactic frequency in oral language processing. Cogn Neuropsychol 2002; 19: 343-360. 

4. Cornette L, Dupont P, Salmon E, Orban G. The neural substrate of orientation working memory. J Cogn Neurosci 2001; 13(6): 813-828. 

5. F. Collette, Van der Linden M, Delfiore G, Degueldre, C, Luxen A, Salmon E. The functional anatomy of inhibition processes investigated with 

Hayling task. Neuroimage 2001; 14: 258-267. 

Imaging serotoninergic pathways 

1. Zimmer L, Latifa R, Giacommelli F, Le Bars D, Renaud B. A reduced extracellular serotonin level increases the 5-HT1A PET ligand 18F-MPPF 

binding in the rat hippocampus. J Nucl Med, 2003; 44: 1495-1501. 

2. Lemaire C, Damhaut P, Lauricella B, Mosdzianowsky C, Morelle JL, Monclus M, van Naemen, J, Mulleneers E, Aerts J, Plenevaux A, Brihaye


C, Luxen A. Fast [18F]FDG synthesis by alkaline hydrolysis on a low polarity solid phase support. J Label Comp Radiopharm, 2002; 45: 435- 

447. 

3. Zimmer, L, Pain F, Mauger G, Plenevaux, A, Le Bars, D, Mastrippolito R, Pujol JF, and Renaud B. The potential of the B-Microprobe,an 

intracerebral radiosensitive probe, to monitor the[18F]MPPF binding in the rat dorsal raphe nucleus. Eur J Nucl Med, 2002; 29: 1237-1247. 

4. Zimmer, L, Luxen A, Giacommelli F, Pujol J. Short and long-term effects of p-ethylnylphenylalanine on brain serotonin levels. Neurochemical 

research, 2002; 27: 269-275. 

5. Plenevaux A, Lemaire C, Aerts J, Lacan G, Rubins D, Melega WP, Brihaye C, Degueldre C, Fuchs S, Salmon E, Maquet P, Laureys S, Damhaut 

P, Weissmann D, Le Bars D, Pujol J, Luxen A. (18F)-p-MPPF: a radiolabeled antagonist for the study of 5-HT1A receptors with PET. Nucl Med 

Biol 2000; 27: 467-471.


Partner 40a: Muenster (M. Schaefers) 

Interdisciplinary Molecular Imaging Network for Cardiovascular Diseases (IMINCAD) Münster, Departments 

of Nuclear Medicine, Cardiology and Angiology, Anaesthesiology and Intensive Care, Institute of Anatomy and 

Institute for Arteriosclerosis Research, University of Münster, Germany 

Münster has formed a local network for molecular imaging of cardiovascular diseases. In this network, scientists from 

several institutions and clinical departments work together to identify and image molecular targets in cardiovascular 

diseases. Such targets are identified within the interdisciplinary group based on clinical questions/challenges and basic 

research findings (Dept. of Cardiology and Dept. of Anaesthesiology). Appropriate binding ligands for the selected 

targets are identified, structurally modified and radiolabelled (Dept. of Nuclear Medicine). The developed compounds 

are evaluated in vitro, ex vivo and in vivo and finally pre-clinically tested in suitable target-expressing animal models 

of human cardiovascular diseases. Radioligands that successfully complete this procedure are then used for basic 

research in animal models as well as transferred to clinical application in clinical studies (Dept. of Nuclear Medicine, 

Dept. of Cardiology, Institute of Anatomy). Major aims of the Interdisciplinary Molecular Imaging Network for 

Cardiovascular Diseases (IMINCAD) are the established imaging of the cardiac nervous system, cardiac perfusion 

and metabolism as well as the recently developed novel imaging approaches of the molecular activity of 

atherosclerotic plaques (vulnerable vs. stable). 

Within the nuclear medicine group, a cyclotron with state-of-the-art PET radiochemistry ( 18 F-/ 11 C-synthesis modules, 

124 I-labelling facility) and laboratories for organic synthetic chemistry exist. Imaging devices comprise a dedicated 

BGO-PET scanner (CTI ECAT Exact 47), a state-of-the-art PET/CT scanner (Siemens Biograph with LSO-PET and 

16-slice CT, Installation October 2003), and the recently (11/2002) installed high-resolution small animal PET 

(quadHIDAC, Oxford Positrons) as one of the three installations Europe-wide. In addition, a three-headed SPECT 

camera (Siemens MultiSPECT 3), a double-headed SPECT camera with transmission sources for attenuation 

(Siemens E.CAM), a SPECT/CT device (GE Hawkeye) and 3 planar gamma cameras are available. The Dept. of 

Cardiology together with the Molecular Cardiology Department in the Institute for Arteriosclerosis Research is 

equipped with all instrumentation for basic cell and animal work as well as animal breeding and housing facilities. 

Access to modern Gene Chip, Proteomics and Bioinformatics facilities is available through the Interdisciplinary 

Clinical Research Center (IZKF) Münster. In the basic research departments, several transgenic and knockout animal 

models for atherosclerosis, myocardial infarction and heart failure are established and serve as in vivo-testing models 

for new radioligands. The Institute of Anatomy is equipped with a confocal microscope, and a NIRF imager is 

available through cooperation with the Institute of Clinical Radiology. 

The Interdisciplinary Molecular Imaging Network for Cardiovascular Diseases (IMINCAD) Münster provides the 

ideal infrastructure for future development and clinical application of new cardiac molecular imaging techniques. It is 

a significant player within the cardiovascular focus of the medical faculty at the University of Münster and is currently 

preparing an application for a collaborative research centre (SFB) “Cellular and Molecular Cardiac Imaging” of The 

Deutsche Forschungsgemeinschaft (DFG). Furthermore, the network has close collaborations with European research 

groups such as MRC Cyclotron Centre, London, Great Britain; Free University Amsterdam PET centre, The 

Netherlands; University Zurich, PET centre, Switzerland; University Aarhus, PET centre, Denmark. 


1. Prof. Dr. M. Schäfers: Head of Experimental Nuclear Medicine, Dept. of Nuclear Medicine; cardiovascular PET 

imaging, development of new radioligands, clinical studies. 

2. Prof. Dr. Dr. O. Schober: Nuclear Medicine Specialist, physicist, Head of the Dept. of Nuclear Medicine; nuclear 

medicine imaging, medical physics. 

3. PD Dr. B. Levkau: Molecular Cardiologist, Group leader “Cardiovascular Apoptosis Research Laboratory”, 

Department of Molecular Cardiology, Institute of Arteriosclerosis Research, Münster; target identification, basic 

research, animal models. 

4. PD Dr. G. Theilmeier: Basic Scientist, Anaesthesiologist; vascular inflammation, ischemia-reperfusion, animal 

models. 

5. Dr. K. Schäfers, medical physics, informatics; compartmental modelling, human and small animal PET, hard- and 

software development. 

6. Dr. K. Kopka, Dr. S. Wagner: Radiochemistry; organic synthesis and radiolabelling, PET radiochemistry. 

7. Dr. M. Law: Radiobiologist; in vitro/ex vivo evaluation of new radioligands, biodistribution. 

References 


1. Schäfers KP. Imaging small animals with positron emission tomography. Nuklearmedizin. 2003;42:86-89 

2. Schäfers KP, Spinks TJ, Camici PG, Bloomfield PM, Rhodes CG, Law MP, Baker CS, Rimoldi O. Absolute quantification of myocardial 

blood flow with H(2)(15)O and 3-dimensional PET: an experimental validation. J Nucl Med 2002;43:1031-1040 

3. Stegger L, Biedenstein S, Schäfers KP, Schober O, Schäfers MA. Elastic surface contour detection for the measurement of ejection fraction in 

gated myocardial perfusion SPET. Eur J Nucl Med 2001;28:48-55 

4. Biedenstein S, Schäfers M, Stegger L, Kuwert T, Schober O: Three-dimensional contour of left ventricular myocardium using elastic surfaces.


Eur J Nucl Med 1999;26:201-207 

Radiochemistry/New Radioligands 

1. Kopka K, Breyholz HJ, Wagner S, Law MP, Riemann B, Schröer S, Trub M, Guilbert M, Levkau B, Schober O, Schäfers M. Synthesis and 

preliminary biological evaluation of new radioiodinated MMP inhibitors for imaging MMP activity in vivo. Nucl Med Biol 2003; in press 

2. Riemann B, Schäfers M, Law MP, Wichter T, Schober O. Radioligands for imaging myocardial alpha- and beta-adrenoceptors. 

Nuklearmedizin 2003;42:4-9 

3. Kopka K, Wagner S, Riemann B, Law MP, Puke C, Luthra SK, Pike VW, Wichter T, Schmitz W, Schober O, Schäfers M. Design of new 

beta(1)-selective adrenoceptor ligands as potential radioligands for in vivo imaging. Bioorg Med Chem 2003;11:3513-3527 

4. Schäfers M, Riemann B, Levkau B, Wichter T, Schafers K, Kopka K, Breithardt G, Schober O. Current status and future applications of 

cardiac receptor imaging with positron emission tomography. Nucl Med Commun 2002;23:113-115 

5. Knickmeier M, Matheja P, Wichter T, Schäfers KP, Kies P, Breithardt G, Schober O, Schäfers M. Clinical evaluation of routinely produced 

n.c.a. meta-[ 123 I]iodobenzylguanidine for myocardial scintigraphy. Eur J Nucl Med 2000;27:302-307 

Imaging 

1. Wichter T, Matheja P, Eckardt L, Kies P, Schäfers KP, Schulze-Bahr E, Haverkamp W, Borggrefe M, Schober O, Breithardt G, Schäfers M. 

Cardiac autonomic dysfunction in Brugada syndrome. Circulation 2002;105:702-706 

2. Wichter T, Schäfers M, Borggrefe M, Rhodes CG, Lerch H, Lammertsma AA, Hermansen F, Schober O, Breithardt G, Camici PG. 

Abnormalities of the cardiac sympathetic innervation in arrhythmogenic right ventricular cardiomyopathy. Quantitative assessment of 

presynaptic norepinephrine re-uptake and postsynaptic beta-adrenoceptor density using positron emission scintigraphy. Circulation 2000; 

101:1552-1558 

3. Kuhn H, Gietzen FH, Schäfers M,, Freick M, Gockel B, Strunk-Müller C., Jachmann E, Schober O. Changes of left ventricular outflow tract 

after transcoronary ablation of septum hypertrophy (TASH) for hypertrophic obstructive cardiomyopathy as assessed by transoesophageal 

echocardiography and by measuring myocardial glucose utilization and perfusion. Eur Heart J 1999;20:1808-1817 

4. Schäfers M, Dutka D, Rhodes CG, Lammertsma AA, Hermansen F, Schober O, Camici PG: Myocardial pre- and postsynaptic autonomic 

dysfunction in hypertrophic cardiomyopathy. Circ Res 1998;82:57-62 

5. Schäfers M, Lerch H, Wichter T, Rhodes CG, Lammertsma AA, Borggrefe M, Hermansen F, Breithardt G, Schober O, Camici PG: Cardiac 

sympathetic innervation in patients with idiopathic right ventricular outflow tract tachycardia. J Am Coll Cardiol 1998;32:181-186 

Target Identification and Basic Science Research 

1. Theilmeier G, Michiels C, Spaepen E, Vreys I, Collen D, Vermylen J, Hoylaerts MF. Endothelial von Willebrand factor recruits platelets to 

atherosclerosis-prone sites in response to hypercholesterolemia. Blood 2002;99:4486-4493 

2. Theilmeier G, Verhamme P, Dymarkowski S, Beck H, Bernar H, Lox M, Janssens S, Herregods M-C, Verbeken E, Collen D, Plate K, Flameng 

W, Holvoet P, Hypercholesterolemia in Minipigs Impairs Left Ventricular Response to Stress - Association with Decreased Coronary Flow 

Reserve and Reduced Capillary Density. Circulation 2002;106:1140-1146. 

3. Conway EM, Van de Wouwer M., Pollefeyt S, Jurk K, Van Aken HK, deVriese A, Weitz JI, Weiler H, Hellings P, Schaeffer P, Herbert JM, 

Collen D, Theilmeier G. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing 

adhesion molecule expression via NFkB and MAP kinase pathways. J Exp Med 2002;196: 565-577. 

4. Levkau B, Garton KJ, Ferri N, Kloke K, Nofer JR, Baba HA, Raines EW, Breithardt G. xIAP induces cell cycle arrest and activates NF-κB: 

new survival pathways disabled by caspase-mediated cleavage during apoptosis of human endothelial cells. Circ Res. 2001, 88: 282-290 

5. Levkau B, Scatena M, Giachelli CM, Ross R, Raines EW. Apoptosis overrides survival signals through a caspase-generated dominant-negative 

NF-B loop. Nat Cell Biol. 1999, 1: 227-233


Partner 40b: Muenster (C. Bremer) 

Department of Clinical Radiology, University of Muenster, Germany 

The University of Muenster has a local network of different laboratories working in the field of Molecular imaging. 

We are closely collaborating with the local Departments of Nuclear Medicine (Prof. Schäfers), Oncology (Prof. 

Mester) and Experimental Anaesthesiology (PD Dr. Theilmeier). The group is embedded in an interdisciplinary 

network of excellence (IZKF) covering basic research efforts in oncology, cardiovascular and inflammatory diseases. 

The work is mainly focused on imaging tumor- as well as cardiovascular biology by means of MRI and optical 

imaging. Besides two 1.5T clinical scanners, we are equipped with a 3.0T MR scanner and a prototype Near infrared 

reflectance imager. Three group members have been working in a postdoctoral fellowship at the Center for Molecular 

Imaging Research (Harvard Medical School, Boston, USA) to which the group is still closely linked. 


1. PD Dr. Christoph Bremer, radiologist; tumor-related animal models for optical imaging, imaging of gene 

expression, imaging of angiogenesis and anti-angiogenic therapy; evaluation of novel imaging modalities by 

conventional imaging methods such as magnetic resonance imaging. 

2. Dr. rer. nat. Angelika von Wallbrunn, molecular biologist; protein-analysis, DNA and RNA analysis, genetic 

engineering of tumor cells. 

3. Dr. rer. nat. Carsten Höltke, radiochemist; design of ‚targeted’ optical probes. 

4. Dr. L. Matuszewski, radiologist; extensive experience in animal models for molecular imaging projects, covering 

MRI and optical imaging, MRI techniques for cell tagging. 

5. Dr. Alexander Wall, radiologist; extensive experience in animal models for molecular imaging projects covering 

MRI and optical imaging. 

6. Dr. Thorsten Persigehl, radiologist; imaging of tumor neovasculature by MRI and optical techniques. 

7. Mrs. Ingrid Otto-Valck, lab technician. 

8. Mrs. R. Kuhlpeter, MD-student; cell tagging techniques for optical and MR imaging. 

References 

1. C. Bremer, M. Mustafa, A. Bogdanov Jr., V. Ntziachristos, A. Petrovsky and R. Weissleder, "Steady-state blood volume measurements in 

experimental tumors with different angiogenic burdens a study in mice", Radiology 2003, 226: 214-220. 

2. V. Ntziachristos, CH. Tung, C. Bremer, Weissleder R, “Fluorescence molecular tomography resolves protease activity in vivo”, Nat Med. 

2002, 8: 757-60. 

3. C. Bremer, C. Tung, A. Bogdanov Jr. and R. Weissleder, "Imaging of differential protease expression in breast cancers for detection of 

aggressive tumor phenotypes", Radiology 2002, 222: 814-818. 

4. C. Bremer, C. Tung and R. Weissleder, "Imaging of metalloproteinase2 inhibition in vivo", Nature Med 2001, 7: 743-748. 

5. C. Bremer and R. Weissleder, "In vivo imaging of gene expression: MR and optical technologies", Acad Radiol 2001, 8: 15-23.


Partner 41: Leuven (K. Van Laere, A. Verbruggen) 

K.U.Leuven Division of Nuclear Medicine, Medical Imaging, Laboratory of Radiopharmaceutical Chemistry , 

Neurology and Colloid Biochemistry; University of Leuven, Belgium 

K.U.Leuven has a local network of different laboratories which is well established in carrying out multidisciplinary 

molecular imaging research. The K.U.Leuven Molecular Imaging Research Center (LMIRC) incorporates knowledge 

and expertise of the Nuclear Medicine Division, Laboratory of Radiopharmaceutical Chemistry and the Medical 

Imaging group. Within its Neuroscience Group, it works together on instrumentation physics, image reconstruction 

and registration, radiochemistry, neurodegenerative diseases (dementia and movement disorders), epilepsy, 

neurooncology, as well as gene-based therapies. The LMIRC has one dedicated high-resolution PET-scanner (Siemens 

HR+), one PET/CT (Siemens Biograph), a microPET (Concorde FOCUS, PETNET CTI), microSPECT (Siemens 

ECAM pinhole), a bioluminescence imaging camera, as well as direct access to a 1.5- and 3T-MRI (Siemens), located 

at the next-door Radiology Department. The K.U.Leuven Laboratory of Radiopharmaceutical Chemistry has an IBA 

10/5 cyclotron (to be replaced by an 18/9 cyclotron in a near future), fully equipped organic synthesis and 

radiochemistry laboratories, LC-MS for radiotracer structure confirmation (Micromass LCT), digital autoradiography 

equipment (Cyclone, Packard). 

The K.U.Leuven-group has therefore all infrastructure necessary to carry out innovative research integrating the 

various imaging modalities (PET, SPECT, MRI, bioluminescence imaging). The LMIRC plays an essential role in 

neuroscience research at the University of Leuven, focussing on the development of potential clinically applicable new 

treatment strategies including phenotyping of neurodegenerative disease, epilepsy surgery, stereotactic deep brain 

stimulation for movement disorders and psychiatric disorders, gene therapy, staging and therapy follow-up in 

neurooncology. The LMIRC has close interactions with the Departments of Neurology (with large expertise in a.o. 

dementia and movement disorders), Neurosurgery, the Department of Radiology for co-registering molecular PET 

imaging data with anatomical MRI and the Department of Neuropathology for correlation of PET data with 

histological findings. Furthermore, the LMIRC has close collaborations with national and international research groups 

as well as (pre)clinical trials on multiple aspects of human and animal imaging (see website 

http://www.kuleuven.ac.be/nucmed/research.html). 

Associated with formal joint research projects, is the group of Biocolloids at the Interdisciplinary Research Center, 

located at the K.U.Leuven campus in Kortrijk (KULAK) (Prof. M. De Cuyper) Using an interdisciplinary approach, 

this group has developed over the last decades so-called magnetoliposomes, i.e. nano-sized magnetizable grains which 

are enveloped by a bilayer, consisting of various types of phospholipids. Purification and concentration is done in a 

high-gradient magnetic field (Bruker BE-15 electromagnet). Upon grafting the magnetoliposome’s surface by 

activatable polymer chains, the resulting biocolloids can be excellently applied for targeting and imaging purposes. 


1. Nuclear Medicine: Prof. Dr. L. Mortelmans: Head of the LMIRC - Division of Nuclear Medicine; Nuclear 

Medicine Physician, Engineer; overall coordination; Prof. Dr. K. Van Laere : Nuclear Medicine Physician, 

Physicist; movement disorders, dementia, epilepsy, neuro-oncology, data analysis. 

Further members of the group: Dr. J. Van den Eynden: physician (early diagnosis and differentiation of 

movement disorders in humans, phenotyping in humans and in animal models with SPECT and PET). 

2. Medical Physics: Prof. Dr. J. Nuyts: Engineer – image reconstruction, instrumentation, software development; 

Prof. Dr. P. Dupont : Physicist – image coregistration, instrumentation, data analysis, quality control; 

Further members of the group: Dirk Bequé - microSPECT reconstruction; Kristof Baete - AMAP 

reconstruction, epilepsy SISCOM; Stefaan Vleugels: performance optimisation of PET, software 

development. 

3. Radiopharmacy: Prof. Dr. A. Verbruggen: Co-head of the LMIRC and head of the Department of Radiopharmacy; 

Prof. Dr. G. Bormans : Radiopharmacist: PET radiopharmacy, probe development; 

Further members of the group: Dr. B. Vanbilloen – SPECT ligand development; Dr. T. de Groot: PET 

ligand development; Dr. D. Rattat, radiolabelling techniques, J. Cleynhens, organic synthesis of ligands 

and precursors. 

4. Neurology: Prof. Dr. R. Vandenberghe: Neurologist, head memory clinic; Prof. Dr. R. Dom: Neurologist, head 

movement disorders clinic; 

Further members: Dr. M. Vandenbulcke: acetylcholinesterase PET imaging, neuropsychology, psychiatry. 

5. Colloid Biochemistry: Prof. Dr. M. De Cuyper: development of activatable Stealth-magnetoliposomes; proteinimmobilisation; 

(bio)synthesis and biophysics of (phospho)lipids. 

Further members of the group: Wim Noppe: chromatographic separation techniques.


Selected publications 

Nuclear Neuro-Imaging 

1. Van Paesschen W, Dupont P, Van Driel G, Van Billoen H, Maes A. SPECT perfusion changes during complex partial seizures in patients 

with hippocampal sclerosis. Brain 2003; 126(5):1103-1111. 

2. Nuttin BJ, Gabriels LA, Cosyns PR, Meyerson BA, Andreewitch S, Sunaert SG, Maes AF, Dupont PJ, Gybels JM, Gielen F, Demeulemeester 

HG. Long-term electrical capsular stimulation in patients with obsessive-compulsive disorder. Neurosurgery 2003; 52(6):1263-1272. 

3. Maes A, Vanbilloen H, Cleynhens B, Mortelmans L, Bormans G, Verbruggen A. 99mTc-TRODAT-M is not superior to 99mTc-TRODAT-1 

for the diagnosis of Parkinson's disease. Eur J Nucl Med Mol Imaging. 2003 May;30(5):796-797. 

4. Bosman T, Van Laere K, Santens P. Anatomically standardised 99mTc-ECD brain perfusion SPECT allows accurate differentiation between 

healthy volunteers, multiple systematrophy and idiopathic Parkinson's disease. Eur J Nucl Med Mol Imaging 2003; 30(1):16-24. 

5. Van Laere K et al. Brain perfusion SPECT correlated to voxel-based morphometry in healthy adults: effects of age and gender. Radiology 

2002; 221: 810-817 

6. Cornette L, Dupont P, Bormans G, Mortelmans L, Orban G. Separate Neural Correlates for the Mnemonic Components of Successive 

Discrimination and Working Memory Tasks Cereb Cortex 2001;11: 59-72. 

Medical Physics 

1. Nuyts J, Fessler JA. A penalized-likelihood image reconstruction method for emission tomography, compared to postsmoothed maximumlikelihood 

with matched spatial resolution. IEEE Trans Med Imaging. 2003 Sep;22(9):1042-1052. 

2. Beque D, Nuyts J, Bormans G, Suetens P, Dupont P. Characterization of pinhole SPECT acquisition geometry. IEEE Trans Med Imaging. 

2003 May;22(5):599-612. 

3. Nuyts J, Bequé D, Dupont P, Mortelmans L. A concave prior penalizing relative differences for maximum-a-posteriori reconstruction in 

emission tomography. IEEE Trans Nucl Sci. 2002 Feb;49(1):56-60. 

4. Nuyts J, Michel C, Dupont P. Maximum-likelihood expectation-maximization reconstruction of sinograms with arbitrary noise distribution 

using NEC-transformations. IEEE Trans Med Imaging 2001; 20(5):365-375. 

Radiopharmacy 

1. Bormans GM, Van Oosterwyck G, De Groot TJ, Veyhl M, Mortelmans L, Verbruggen AM, Koepsell H. Synthesis and biologic evaluation of 

11C-methyl-D-glucoside, a tracer of the sodium-dependent glucose transporters. J Nucl Med. 2003 Jul;44(7):1075-1081. 

2. Vanbilloen HP, Cleynhens BJ, de Groot TJ, Maes A, Bormans GM, Verbruggen AM. RP-HPLC separation of the diastereomers of 

technetium-99m labelled tropanes and identity confirmation using radio-LC-MS. J Pharm Biomed Anal 2003; 32(4-5):663-668. 

3. Gilissen C, de Groot TJ, Bronfman F, van Leuven F, Verbruggen AM, Bormans GM. Evaluation of 18F-FA-4 and 11C-pipzA-4 as 

radioligands for the in vivo evaluation of the high-affinity choline uptake system. J Nucl Med 2003; 44(2):269-275. 

4. Dezutter NA, Landman WJ, Jager PL, de Groot TJ, Dupont PJ, Tooten PC, Zekarias B, Gruys E, Verbruggen AM. Evaluation of 99mTc- 

MAMA-chrysamine G as an in vivo probe for amyloidosis. Amyloid 2001; 8(3):202-214.Biocolloid Chemistry 

1. Zollner, TCA, Zollner RL, De Cuyper M. , Santana MHA Adsorption of isotype “E” antibodies on affinity magnetoliposomes J. Dispersion 

Sci Technol 2003; 24: 615-622. 

2. De Cuyper M, Bulte JMW Magnetoliposomes as contrast agents. Methods in Enzymology 2003, 373 

3. De Cuyper M, Müller P, Lueken H, Hodenius M J Synthesis of magnetic Fe 3 O 4 particles covered with a modifiable phospholipid coat. Phys 

Condens Matter 2003; 15 : S1425-S1436 

4. De Cuyper M, Hodenius M, Lacava ZGM, Azevedo RB, Da Silva MF, Morais PC, Santana MHA Attachment of water-soluble proteins at the 

surface of (magnetizable) phospholipid colloids via NeutrAvidin derivatized phospholipids. Colloid Interface Sci 2002; 245 : 274-280. 

5. Hodenius M, De Cuyper M, Desender L, Muller-Schulte D, Steigel A, Leuken H. Biotinylated Stealth magnetoliposomes. Chem Phys Lipids 

2002; 120 : 75-85.


Partner 42: Caen (D. Vivien) 

Cerebral Imaging Centre For Research On Neuroscience 

Cyceron is a 4,500 m 2 facility made of a Cyclotron and laboratories for chemistry, cell biology and molecular biology, 

of animal facility, of PET laboratories. 

Radiochemistry: The original Cyclotron has been replaced in 2002 by an IBA Cyclone 18/9 allowing the production 

of carbon-11, fluorine-18, fluoride-18, nitrogen-13 and oxygen-15. A Zymark remote control synthesis robot is also 

available for fluorine-18 labelling. A new clean room has been installed with 3 hot cells for production and 

sterilization of radio-pharmaceuticals following the GMP (Good Manufacturing Practice). Analysis equipment 

includes 6 HPLC, 5 semi-preparative HPLC, 2 Gas Chromatography, and a Thin layer Chromatography recorder 

(Instantimager, Packard). 

Molecular and cellular biology: Molecular and cellular biology laboratories (500 m 2 ) are at this time located outside 

of the Cyceron campus. Implemented techniques include cerebral cell cultures such as neurons, astrocytes and 

microglia from rodents and humans, calcium imaging, confocal microscopy, real time PCR, reporter genes, cell 

transfection, mutagenesis, immunocytochemistry, and immunoblotting. 

Animal facility: The animal holding facilities within the GIP Cyceron are of the standard (low-risk) category, 

including facilities for baboons (Papio anubis), marmoset (Callithrix jacchus) and rodents. Animal facilities are 

associated to laboratories for animal experimentation. 

PET cameras: The original CEA-LETI time-of flight PET camera has been replaced in 1995 by a SIEMENS ECAT- 

HR+ high-resolution 3D PET machine that is in current use. A second PET camera (SIEMENS ART machine, 

Advanced Rotating Tomograph) was acquired in 2002 and is mostly used for the FDG studies in oncology. 

MRI: There is no MR machine installed on site yet. Thanks to the financial help of the Regional Council, Cyceron has 

access to the 1.5T MR machines, one of which is equipped with the fast gradients and imaging sequences required to 

perform FMRI. At present, fMRI studies can be performed once a week. 


1. Prof. Denis Vivien: Professor in Molecular Biology, University of Caen, UMR CNRS 6551, Head of the 

department of cell biology and molecular biology. 

2. Dr Eric T MacKenzie: Head of the UMR CNRS 6551. Adjunct director of the centre Cyceron, Head of the 

department of neuropathology 

3. Pr B. Mazoyer: Director of the centre Cyceron, head of the UMR CNRS 6095, Professor in neuroradiology at the 

Medical University of Caen. 

4. Dr L. Barré: Head of the UMR CEA, Head of the department of radio-chemistry. 

5. Prof. F. Eustache: Head of the EMI INSERM 0218, head of the department of brain imaging, professor in 

neurospychology at the “Ecole des hautes études” Paris 

References 

1. Gabriel C, Ali C, Lesne S, Fernandez-Monreal M, Docagne F, Plawinski L, MacKenzie ET, Buisson A, Vivien D Transforming growth factor 

alpha-induced expression of type 1 plasminogen activator inhibitor in astrocytes rescues neurons from excitotoxicity. FASEB J 2003; 17: 277- 

279. 

2. Houdé O and Mazoyer BM The roots of cognitive science: American yes, but European too. TICS 2003; 7:283-284. 

3. Houdé O, and Tzourio-Mazoyer N Neural foundations of logical and mathematical cognition. Nat Rev Neurosci 2003; 4:507-514. 

4. Lesne S, Docagne F, Gabriel C, Liot G, Lahiri DK, Buee L, Plawinski L, Delacourte A, MacKenzie ET, Buisson A, Vivien D Transforming 

Growth Factor-beta 1 Potentiates Amyloid-beta Generation in Astrocytes and in Transgenic Mice. J Biol Chem 2003; 278: 18408-18418. 

5. Valable S, Bellail A, Lesne S, Liot G, MacKenzie ET, Vivien D, Bernaudin M, Petit E Angiopoietin-1-induced PI3-kinase activation prevents 

neuronal apoptosis. FASEB J 2003; 17: 443-445. 

6. Vivien D, Fernandez-Monreal M, Nicole O, Buisson A Reply to "Tissue plasminogen activator and NMDA receptor cleavage". Nat Med 2003; 

9: 372-373. 

7. Chuquet J, Benchenane K, Liot G, Fernandez-Monreal M, Toutain J, Blanchet S, Eveno E, Auffray C, Pietu G, Buisson A, Touzani O, 

MacKenzie ET, Vivien D Matching gene expression with hypometabolism after cerebral ischemia in the nonhuman primate. J Cereb Blood 

Flow Metab 2002; 22: 1165-1169. 

8. Crivello F, Schormann T, Tzourio-Mazoyer N, Roland PE, Zilles K, Mazoyer BM A comparison of spatial normalization procedures and their 

impact on functional maps. Human Brain Mapping 2002; 16: 228-250. 

9. Desgranges B, Baron JC, Giffard B, Chételat G, Lalevée C, Viader F, de la Sayette V, Eustache F. The neural basis of intrusions in free recall 

and cued recall: a PET study in Alzheimer's disease. Neuroimage 2002; 17: 1658-1664. 

10. Docagne F, Nicole O, Gabriel C, Fernandez-Monreal M, Lesne S, Ali C, Plawinski L, Carmeliet P, MacKenzie ET, Buisson A, Vivien D 

Smad3-dependent induction of plasminogen activator inhibitor-1 in astrocytes mediates neuroprotective activity of transforming growth factorbeta 

1 against NMDA-induced necrosis. Mol Cell Neurosci 2002; 21: 634-644. 

11. Giffard B, Desgranges B, Nore-Mary F, Lalevée C, Beaunieux H, de la Sayette V, Pasquier F, Eustache F. The dynamic time course of 

semantic memory impairment in Alzheimer's disease: clues from hyperpriming and hypopriming effects. Brain 2002; 125: 2044-2057. 

12. Lasne MC, Perrio C, Rouden J, Barre L, Roeda D, Dolle F, Crouzel C Chemistry of b+-emitting compounds based on fluorine-18. Top Curr 

Chem 2002; 222: 201-258. 

13. Lesne S, Blanchet S, Docagne F, Liot G, Plawinski L, MacKenzie ET, Auffray C, Buisson A, Pietu G, Vivien D Transforming growth factor-


beta1-modulated cerebral gene expression. J Cereb Blood Flow Metab 2002; 22: 1114-1123. 

14. Mazard A, Mazoyer BM, Etard O, Tzourio-Mazoyer N, Kosslyn SM, Mellet E Impact of fMRI acoustic noise on the functional anatomy of 

visual mental imagery. Journal of Cognitive Neuroscience 2002; 14: 172-186. 

15. Touzani O, Boutin H, LeFeuvre R, Parker L, Miller A, Luheshi G, Rothwell N. Interleukin-1 influences ischemic brain damage in the mouse 

independently of the interleukin-1 type I receptor. J Neurosci 2002; 22: 38-43. 

16. Tzourio-Mazoyer N, de Schonen S, Crivello F, Reutter B, Aujard Y, Mazoyer BM Neural correlates of woman face processing by 2-month-old 

infants. Neuroimage 2002; 15: 454-461. 

17. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M Automated anatomical labelling of 

activations in spm using a macroscopic anatomical parcellation of the MNI MRI single subject brain. Neuroimage 2002; 15: 273-289. 

18. Ali C, Docagne F, Nicole O, Lesne S, Toutain J, Young A, Chazalviel L, Divoux D, Caly M, Cabal P, Derlon JM, MacKenzie ET, Buisson A, 

Vivien D. Increased expression of transforming growth factor-beta after cerebral ischemia in the baboon: an endogenous marker of neuronal 

stress? J Cereb Blood Flow Metab 2001; 21: 820-827. 

19. Baron JC, Chételat G, Desgranges B, Perchey G, Landeau B, de la Sayette V, Eustache F. In vivo mapping of gray matter loss with voxel-based 

morphometry in mild Alzheimer's disease. Neuroimage 2001 ; 14: 298-309. 

20. Docagne F, Colloc'h N, Bougueret V, Page M, Paput J, Tripier M, Dutartre P, MacKenzie ET, Buisson A, Komesli S, Vivien D. A soluble 

transforming growth factor-beta (TGF-beta ) type I receptor mimics TGF-beta responses. J Biol Chem 2001; 276: 46243-46250. 

21. Giffard B, Desgranges B, Nore-Mary F, Lalevée C, de la Sayette V, Pasquier F, Eustache F. The nature of semantic memory deficits in 

Alzheimer's disease: new insights from hyperpriming effects. Brain 2001; 124: 1522-1532. 

22. Nicole O, Ali C, Docagne F, Plawinski L, MacKenzie ET, Vivien D, Buisson A. Neuroprotection mediated by glial cell line-derived 

neurotrophic factor: involvement of a reduction of NMDA-induced calcium influx by the mitogen-activated protein kinase pathway. J Neurosci 

2001; 21: 3024-3033. 

23. Nicole O, Docagne F, Ali C, Margaill I, Carmeliet P, MacKenzie ET, Vivien D, Buisson A. The proteolytic activity of tissue-plasminogen 

activator enhances NMDA receptor-mediated signaling. Nat Med 2001; 7: 59-64. 

24. Pesenti M, Zago L, Crivello F, Mellet E, Samson D, Duroux B, Seron X, Mazoyer BM, Tzourio-Mazoyer N. Mental Calculation in a Prodigy is 

Sustained by Right Prefrontal and Medial Temporal Areas. Nature Neurosci 2001; 4: 103-107.


Partner 43: Oslo (MiceTech, SME) 

MiceTech (SME) / Institute for Nutrition Research, Faculty of Medicine, University of Oslo, Norway 

MiceTech is an SME company located at The Oslo Research Park. The company has the commercial rights to the NFκB 

luciferase transgenic reporter mice (Carlsen et al). The mice are freely available to collaborating scientists and are 

sold to commercial enterprises through a world-wide distributor located in California, USA. MiceTech aims at 

developing further transgenic reporter mice related to NF-κB and disease. These models includes mice with tissue 

specific expression pattern of luciferase (based on the Cre-LoxP system), as well as double and triple transgenic mice 

comprising luciferase as one of the transgenes. MiceTech are also aiming at developing luciferase based mouse models 

that report activities of specific protein kinases, as well as caspases. This specific project was in 2002 awarded the first 

prize in an Idea contest organized by the University of Oslo and the Oslo Research Park. Such mice will be available 

to the collaborating academic institutions within the DiMI-network as well as licensed to commercial entities. 

MiceTech is closely collaborating with Professor Blomhoff’s group at the University of Oslo. 

Scientic Staff 

Expertise 

1. H. Carlsen, Principal investigator at MiceTech: transgenic animal models, molecular imaging of transgenic reporter 

mice. 

2. J.O. Moskaug, Senior Research Scientist, University of Oslo: molecular biology, signal transduction, molecular 

imaging in mouse models. 

References 

Imaging gene regulation 

1. Carlsen H, Moskaug J.O., Fromm S.H., and Blomhoff R. In vivo imaging of NF-B activity in transgenic mice using luminescence. Journal 

of Immunology 2002, 168(3):1441-6.


Partner 45: Navarre (J. Masdeu) 

Neuroscience Centre, University of Navarre, Pamplona (Spain) 

The University of Navarre has experience in the performance of PET imaging in populations of well-characterized 

dementia patients. The Memory Disorders Unit, at the University Hospital, follows a cohort of patients with mild 

cognitive impairment, Alzheimer’s disease or vascular dementia. Prospectively, patients and controls are studied with 

neuropsychological batteries, FDG PET, MRI and MRs, as well as with a number of biological markers. The PET 

facility currently operates a high resolution PET scanner, (ECAT EXACT HR+); a PET/CT (Biograph LSO) will also 

be operative in November 2003. Additionally, a MicroPET, with a resolution of 1,5 mm, will be installed in 2004. The 

PET Radiochemistry Laboratory produces radioisotope using an IBA 18/9 MeV cyclotron. Compounds which are 

routinely produced are [F-18]FDG, [F-18]FDOPA, [C-11]Methionine, N-methyl[11C]Choline, [O-15]H 2 O, [N- 

13]Amonia, and [F-18]fluorohydroxybuthyl-guanine (FHBG). As 11C-Raclopride and 11C-FLB457 have also been 

produced it would be easy to produce [ 11 C] flumazenil. 

The biomedical center houses a primate facility for the study of Parkinson and Alzheimer diseases. The transgenic 

animal laboratory has developed mice (Tg VLWxTg2576) containing human APP and tau mutations, as an “in vivo” 

model of Alzheimer’s disease. The neuropathology in these mice, with plaques and tangles, resembles more closely 

the human disease than any previous models. A previously developed mouse model (Tg2576) allowed us to prove that 

the infusion of IG-F1 decreased amyloid deposition in the brain and preserved the memory of the animals. The 

neuroscience group also has an excellent neuropharmacology group. The Alzheimer research group has a close 

collaborative relationship with the Alzheimer Research Centre at the MGH, Boston. 


1. Dr. Jose Masdeu: Director of the Neuroscience Centre and of the Department of Neurology and Neurosurgery; 

imaging for diagnosis of neurological disorders. Heads the Neuroimaging Research Group of the World Federation 

of Neurology and the Scientific Panel on Neuroimaging of the European Federation of Neurological Societies. 

2. Dr. Teresa Gomez-Isla; Director of the Memory Disorders Unit and of the Alzheimer’s Disease Neurobiology 

Laboratory; neuropathology of mild cognitive impairment, early markers of AD (including neuroimaging), 

transgenic models of AD. 

3. Dr. Javier Arbizu: Director of the Brain Imaging Section, Department of Nuclear Medicine; PET and SPECT 

imaging of cerebral disorders; image analysis. 

4. Dr. Pablo Martínez Lage, staff neurologist, Memory Disorders Unit; correlation of clinical and neuropathological 

findings in vascular dementia and frontotemporal dementia. 

5. Dr. Jose L. Zubieta: Director of the Brain Imaging Section of the Department of Radiology; MRI for the study of 

neurological disorders. 

6. Dr. Ivan Peñuelas: Radiopharmacist, PET Radiopharmacy Unit. Director, MicroPET Research Unit. Radiopharmaceutical 

probe development and small animal imaging. 

References 

Imaging of Alzheimer’s Disease and Vascular Dementia 

1. Killiany RJ, Hyman BT, Gomez-Isla T, Moss MB, Kikinis R, Jolesz F, Tanzi R, Jones K, Albert MS. MRI measures of entorhinal cortex vs 

hippocampus in preclinical AD. Neurology. 2002; 58(8):1188-96. 

2. Killiany RJ, Gomez-Isla T, Moss M, Kikinis R, Sandor T, Jolesz F, Tanzi R, Jones K, Hyman BT, Albert MS. Use of structural magnetic 

resonance imaging to predict who will get Alzheimer's disease. Ann Neurol. 2000; 47(4):430-9. 

3. Masdeu, J.C., L. Wolfson, G. Lantos, J.N. Tobin, E. Grober, R. Whipple, and P. Amerman, Brain white-matter changes in the elderly prone to 

falling. Arch Neurol, 1989; 46: 1292-6. 

4. Masdeu JC, Grober E: The Hippocampal Index: A CT marker of cognitive impairment in the elderly. Neurology 1989; 39:237, 

5. Masdeu J, Aronson M: CT findings in early dementia. The Gerontologist 1985;25:82, 

Imaging of Other Neurological Disorders 

1. Pastor MA, Artieda J, Arbizu J, Marti-Climent JM, Penuelas I, Masdeu JC Activation of human cerebral and cerebellar cortex by auditory 

stimulation at 40 Hz. J Neurosci. 2002; 22:10501-6 

2. Ortuno, F., N. Ojeda, J. Arbizu, P. Lopez, J.M. Marti-Climent, I. Penuelas, and S. Cervera, Sustained attention in a counting task: normal 

performance and functional neuroanatomy. Neuroimage, 2002. 17: 411-20. 

3. Ojeda, N., F. Ortuno, J. Arbizu, P. Lopez, J.M. Marti-Climent, I. Penuelas, and S. Cervera-Enguix, Functional neuroanatomy of sustained 

attention in schizophrenia: contribution of parietal cortices. Hum Brain Mapp, 2002. 17: 116-30. 

4. Sanchez-Carpintero, R., J. Narbona, R. Lopez de Mesa, J. Arbizu, and L. Sierrasesumaga, Transient posterior encephalopathy induced by 

chemotherapy in children. Pediatr Neurol, 2001. 24: 145-8. 

5. Masdeu, J.C., Neuroimaging and gait. Adv Neurol, 2001. 87: 83-9. 

6. Masdeu, J.C., C. Quinto, C. Olivera, M. Tenner, D. Leslie, and P. Visintainer, Open-ring imaging sign: highly specific for atypical brain 

demyelination. Neurology, 2000. 54: 1427-33. 

7. Kertesz, A., P. Martinez-Lage, W. Davidson, and D.G. Munoz, The corticobasal degeneration syndrome overlaps progressive aphasia and 

frontotemporal dementia. Neurology, 2000. 55: 1368-75. 

8. Masdeu, J.C., B.P. Drayer, R.E. Anderson, B. Braffman, P.C. Davis, M.D. Deck, A.N. Hasso, B.A. Johnson, T. Masaryk, S.J. Pomeranz, D. 

Seidenwurm, and L. Tanenbaum, Multiple sclerosis--when and how to image. American College of Radiology. ACR Appropriateness Criteria. 

Radiology, 2000. 215: 547-62.


9. Braffman, B., B.P. Drayer, R.E. Anderson, P.C. Davis, M.D. Deck, A.N. Hasso, B.A. Johnson, T. Masaryk, S.J. Pomeranz, D. Seidenwurm, L. 

Tanenbaum, and J.C. Masdeu, Neurodegenerative disorders. American College of Radiology. ACR Appropriateness Criteria. Radiology, 2000. 

215: 597-605. 

10. Braffman, B., B.P. Drayer, R.E. Anderson, P.C. Davis, M.D. Deck, A.N. Hasso, B.A. Johnson, T. Masaryk, S.J. Pomeranz, D. Seidenwurm, L. 

Tanenbaum, and J.C. Masdeu, Dementia. American College of Radiology. ACR Appropriateness Criteria. Radiology, 2000. 215: 525-33. 

Neurobiology and Pharmacology of Alzheimer’s Disease 

1. Steidl, JV, T. Gomez-Isla, A. Mariash, K.H. Ashe, and L.M. Boland, Altered short-term hippocampal synaptic plasticity in mutant alphasynuclein 

transgenic mice. Neuroreport, 2003. 14: 219-23. 

2. Diez-Ariza, M., C. Redondo, M. Garcia-Alloza, B. Lasheras, J. Del Rio, and M.J. Ramirez, Flumazenil and tacrine increase the effectiveness of 

ondansetron on scopolamine-induced impairment of spatial learning in rats. Psychopharmacology (Berl), 2003. 169: 35-41. 

3. Martinez-Turrillas, R., D. Frechilla, and J. Del Rio, Chronic antidepressant treatment increases the membrane expression of AMPA receptors in 

rat hippocampus. Neuropharmacology, 2002. 43: 1230-7. 

4. Diez-Ariza, M., M. Garcia-Alloza, B. Lasheras, J. Del Rio, and M.J. Ramirez, GABA(A) receptor antagonists enhance cortical acetylcholine 

release induced by 5-HT(3) receptor blockade in freely moving rats. Brain Res, 2002. 956: 81-5. 

5. Carro, E., J.L. Trejo, T. Gomez-Isla, D. LeRoith, and I. Torres-Aleman, Serum insulin-like growth factor I regulates brain amyloid-beta levels. 

Nat Med, 2002. 8: 1390-7. 

6. Frechilla, D., A. Garcia-Osta, S. Palacios, E. Cenarruzabeitia, and J. Del Rio, BDNF mediates the neuroprotective effect of PACAP-38 on rat 

cortical neurons. Neuroreport, 2001. 12: 919-23. 

7. Greeve, I., I. Hermans-Borgmeyer, C. Brellinger, D. Kasper, T. Gomez-Isla, C. Behl, B. Levkau, and R.M. Nitsch, The human 

DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress. J 

Neurosci, 2000. 20: 7345-52. 

8. Frechilla, D., R. Insausti, P. Ruiz-Golvano, A. Garcia-Osta, M.P. Rubio, J.M. Almendral, and J. Del Rio, Implanted BDNF-producing 

fibroblasts prevent neurotoxin-induced serotonergic denervation in the rat striatum. Brain Res Mol Brain Res, 2000. 76: 306-14. 

9. Cataldo, A.M., C.M. Peterhoff, J.C. Troncoso, T. Gomez-Isla, B.T. Hyman, and R.A. Nixon, Endocytic pathway abnormalities precede 

amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. 

Am J Pathol, 2000. 157: 277-86. 

10. Buldyrev, S.V., L. Cruz, T. Gomez-Isla, E. Gomez-Tortosa, S. Havlin, R. Le, H.E. Stanley, B. Urbanc, and B.T. Hyman, Description of 

microcolumnar ensembles in association cortex and their disruption in Alzheimer and Lewy body dementias. Proc Natl Acad Sci U S A, 2000. 

97: 5039-43.


Partner 46: Tours (S. Benderbous) 

Laboratoire Biophysique Médicale et pharmaceutique, Université de Tours ; France 

Original aspect of the group of Tours is to be based on SPECT and PET molecular imaging with the aim of 

understanding, diagnosis and treating CNS disorders, beginning with the development of new radiopharmaceutical 

products (conception, synthesis, radiosynthesis), to animal studies (evaluation of new tracers, and study of 

mechanisms guiding the choice of new molecular targets for exploration), and finally resulting in clinical applications 

(neurodevelopmental and neurodegenerative disorders). The feasibility of our scientific project is based on a 

multidisciplinary team combining complementary competence, i.e. clinical (neurologists, neuropediatric doctors), 

experimental neurobiology, imaging (nuclear physicians, radiopharmacists, chemists) and technological expertise. 

This approach uses radiopharmaceutical products (γ or β emitters) specific to the molecular targets being explored. 

The development of these tracers requires multidisciplinary competence from chemistry to medicine, and requires 

several key-steps: 1) conception, synthesis and radiolabelling of new compounds, 2) pharmacological validation 

(affinity, specificity for the molecular target) in vitro and ex vivo in animals, 3) in vivo validation in small animals, in 

normal conditions and in animal models of human disorders. Our research activity on radiopharmaceutical 

development is mainly conducted in research-dedicated premises organized in: 

- an organic synthesis unit (chemistry laboratory specially equipped with preparatory HPLC and access to NMR and 

mass spectrometry), 

- a radiosynthesis unit (“hot” laboratory authorized for 3 H, 125 I, 123 I, 99m Tc, 18 F), 

- a biology unit (equipment for micro-surgery in rodents, cryocuting, image analyzer, “phosphorimaging” system, 

HPLC with electrochemical detection, γ and β counters). 

- a in vivo imaging unit: Cameras dedicated to in vivo imaging of small animals of “ToHR” type (High Resolution 

Tomographic system) is planned for 2003. The development of a micro-imaging platform for rodents (SPECT/ 

MicroPET /MRI) is planned in these premises. Scintigraphic protocols in monkeys are performed in researchdedicated 

premises including: an animal room for non-human primates, a CERASPECT brain γ camera, an MRI 

system for animal experiments. Scintigraphic protocols in humans are undertaken in the Hospital (Nuclear 

Medicine Unit): SPECT and PET camera available. 

Tours has close collaborations with international research groups (EU-Groups involved in COST B12: Radiotracer for 

assessment of biological function. European program EUREKA Dopimag “Development of a tracer for exploration 

by scintigraphy of the dopamine transporters”. International program with University of Sydney (Australia) and 

University of California (US) “Development of ligand for Alzheimer’s disease” 

MRI probes: Our team is specialized in MRI probes validation and characterization both in vitro on cellular model 

and in vivo in animal models. These studies are conducted in a complementary way to the neurotransmission 

exploration by SPECT as described above. 


Expertise 

1. Prof .Dr. L. Pourcelot: Specialist of Nuclear Medicine, Professor of Biophysics, Head of Dept of Nuclear 

Medicine and Ultrasound, University-Hospital, Tours. and of the INSERM Unit 316 "Nervous system from fœtus 

to Childhood" (1988-2003); Biomedical Engineering Clinical application of functional imaging in neurology, 

cardiovascular, obstetrics, abdomen, 

Further members of the group: Prof. Dr JL Baulieu, Pr JC Besnard (Specialists of Nuclear Medicine, 

quantification and clinical applications) Dr C Prunier (Neurologist and Specialist of Nuclear Medicine, 

Imaging Parkinson’s and Alzheimer’s Diseases) 

2. Prof. Dr. D. Guilloteau : Professor of Pharmaceutical Biophysic, Radiopharmacist,Head of the team for 

radiopharmaceutical development (INSERM U316) and of the laboratory associated to CEA: Neurotransmission: 

molecular imaging and clinical aspects (LRC 21V). From 2004, will be head of the INSERM Unit” Dynamics 

and pathology of cerebral development”; development of tracers for neurotransmission exploration study of 

neurotransmission in animal models an human during normal and abnormal brain development 

Further members of the group: Pr. Y Frangin, Dr P Emond, Dr S. Mavel : chemistry, radiochemistry; 

development of new molecular imaging probes for both PET and SPET for specific for neurotransmission 

targets. 

3. Dr S. Chalon, Biologist ; Study of monoaminergic neurotransmission by molecular imaging of dopamine and 

serotonin receptors and transporters, in animal models of neurodevelopmental and neurodegenerative 

disorders.Further members of the group:J Vergote, L Garreau , biologists; In Vitro Characterization of the new 

ligands 

4. Pr Dr E. Saliba Neonatologist, Head of neonatology department of University hospital, Tours; Neurotransmission 

related to maternal/foetal infection and hypoxia/ischaemia. Further members of the group Dr P. Castelnau, 

neurologist pediatrician 

5. Pr S Benderbous , Physicist , In charge of the MRI team and probes development. Dr L Barantin, Physicist


specialist of MR sequences. 

References 

Radiopharmaceutical development 

1. Chalon S, Tarkiainen J, Garreau L, Hall H, Emond P, Vercouillie J, Farde L, Dasse P, Varnas K, Besnard JC, Halldin C, Guilloteau D. 

Pharmacological characterization of N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine as a ligand of the serotonin transporter with 

high affinity and selectivity. J Pharmacol Exp Ther. 2003 Jan;304(1):81-7. 

2. Emond P, Vercouillie J, Innis R, Chalon S, Mavel S, Frangin Y, Halldin C, Besnard JC, Guilloteau D. Substituted diphenyl sulfides as selective 

serotonin transporter ligands: synthesis and in vitro evaluation. J Med Chem. 2002 Mar 14;45(6):1253-8. 

3. Emond P, Helfenbein J, Chalon S, Garreau L, Vercouillie J, Frangin Y, Besnard JC, Guilloteau D. Synthesis of tropane and nortropane 

analogues with phenyl substitutions as serotonin transporter ligands. Bioorg Med Chem. 2001 Jul;9(7):1849-55. 

4. Chalon S, Garreau L, Emond P, Zimmer L, Vilar MP, Besnard JC, Guilloteau D.Pharmacological characterization of (E)-N-(3-iodoprop-2- 

enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)n ortropane as a selective and potent inhibitor of the neuronal dopamine transporter. J 

Pharmacol Exp Ther. 1999 Nov;291(2):648-54. 

5. Hall H, Halldin C, Guilloteau D, Chalon S, Emond P, Besnard J, Farde L, Sedvall G. Visualization of the dopamine transporter in the human 

brain postmortem with the new selective ligand [125I]PE2I. Neuroimage. 1999 Jan;9(1):108-16. 

6. Helfenbein J, Sandell J, Halldin C, Chalon S, Emond P, Okubo Y, Chou YH, Frangin Y, Douziech L, Gareau L, Swahn CG, Besnard JC, Farde 

L, Guilloteau D. PET examination of three potent cocaine derivatives as specific radioligands for the serotonin transporter. Nucl Med Biol. 

1999 Jul;26(5):491-9. 


1. Prunier C., Bezard E., Montharu J., Mantzarides M., Besnard Jc., Baulieu Jl., Gros C., Guilloteau D., Chalon S.Presymptomatic diagnosis of 

experimental parkinsonism with 123I-PE2I SPECT. Neuroimage 2003,19:106-110. 

2. Prunier C, Payoux P, Guilloteau D, Chalon S, Giraudeau B, Majorel C, TafaniM, Bezard E, Esquerre JP, Baulieu JL. Quantification of 

dopamine transporter by 123I-PE2I SPECT and the non-invasive Logan graphical method in Parkinson's disease.J Nucl Med. 2003;44(5):663- 

70. 

3. Prunier C, Tranquart F, Cottier JP, Giraudeau B, Chalon S, Guilloteau D, De Toffol B, Chossat F, Autret A, Besnard JC, Baulieu JL. 

Quantitative analysis of striatal dopamine D2 receptors with 123 I-iodolisuride SPECT in degenerative extrapyramidal diseases. Nucl Med 

Commun. 2001 Nov;22(11):1207-14. 

Neurodegenerative models 

1. Fernagut PO, Chalon S, Diguet E, Guilloteau D, Tison F, Jaber M. Motor behaviour deficits and their histopathological and functional 

correlates in the nigrostriatal system of dopamine transporter knockout mice. Neuroscience. 2003;116(4):1123-30. 

2. Gouhier C, Chalon S, Aubert-Pouessel A, Venier-Julienne MC, Jollivet C, Benoit JP, Guilloteau D. Protection of dopaminergic nigrostriatal 

afferents by GDNF delivered by microspheres in a rodent model of Parkinson's disease. Synapse. 2002 Jun 1;44(3):124-31. 

3. Barc S, Page G, Barrier L, Garreau L, Guilloteau D, Fauconneau B, Chalon S. Relevance of different striatal markers in assessment of the 

MPP+-induced dopaminergic nigrostriatal injury in rat. J Neurochem. 2002 Feb;80(3):365-74. 

4. Gouhier C, Chalon S, Venier-Julienne MC, Bodard S, Benoit J, Besnard J,Guilloteau D. Neuroprotection of nerve growth factor-loaded 

microspheres on the D2 dopaminergic receptor positive-striatal neurones in quinolinic acid-lesioned rats: a quantitative autoradiographic 

assessment with iodobenzamide. Neurosci Lett. 2000 Jul 7;288(1):71-5. 

5. Chalon S, Emond P, Bodard S, Vilar MP, Thiercelin C, Besnard JC, GuilloteauD. Time course of changes in striatal dopamine transporters and 

D2 receptors with specific iodinated markers in a rat model of Parkinson's disease. Synapse. 1999 Feb; 31(2):134-9. 

MRI Probes 

1. Marchand B, Douek PC, Benderbous S, Corot C, Canet E. Pilot MR evaluation of pharmacokinetics and relaxivity of specific blood pool 

agents for MR angiography. Invest Radiol. 2000 Jan;35(1):41-9. 

2. Kroft LJ, Doornbos J, van der Geest RJ, Benderbous S, de Roos A. Infarcted myocardium in pigs: MR imaging enhanced with slow-interstitialdiffusion 

gadolinium compound P760. Radiology. 1999 Aug;212(2):467-73. 

3. Kroft LJ, Doornbos J, Benderbous S, de Roos A. Equilibrium phase MR angiography of the aortic arch and abdominal vasculature with the 

blood pool contrast agent CMD-A2-Gd-DOTA in pigs. J Magn Reson Imaging. 1999 Jun;9(6):777-85.


Partner 47: Saint Beauzine (CYCLOPHARMA, SME) 

CYCLOPHARMA Laboratoires 

Description 

Cyclopharma is a radiopharmaceutical company located in the suburbs of Clermont Ferrand. Though Cyclopharma 

sells directly or distributes equipment or molecules for single photon imaging, its main goal is in producing cyclotron 

products , and as such is fully licensed for producing and selling 18 FDG. Clermont Ferrand has a large medical and 

research background (University and Medical School) and Inserm and CNRS research laboratories with whom we 

have tight collaborations. One of our subsidiaries, ORPACHEM is highly skilled in building and labelling molecules. 

Units Scientific Staff 

Expertise 

1. Jean Bernard Deloye, Pharmacist, PhD, General Manager 

2. Prof. Serge Askienazy, MD, PhD, Medical Director , EANM president (01/1991-12/1993), 

3. Gilles Viot, Pharmacist , PhD 

References 

1) Nguyen C, Faraggi M, Giraudet AL, de Labriolle-Vaylet C, Aparicio T, Rouzet F, Mignon M, Askienazy S, Sobhani I 

Long-term efficacy of radionuclide therapy in patients with disseminated neuroendocrine tumors uncontrolled by conventional therapy. 

J Nucl Med. 2004 Oct;45(10):1660-8. 

2) Hindie E, Melliere D, Lange F, Hallaj I, de Labriolle-Vaylet C, Jeanguillaume C, Lange J, Perlemuter L, Askienazy S. 

Functioning pulmonary metastases of thyroid cancer: does radioiodine influence the prognosis? 

Eur J Nucl Med Mol Imaging. 2003 Jul;30(7):974-81. Epub 2003 May 07. 

3) Talbot JN, Rain JD, Meignan M, Askienazy S, Grall Y, Bok B, Misset JL. 

Impact of [18F]-FDG-PET on medical decision making in oncology: evaluation by the referring physicians during the opening year 

Bull Cancer. 2002 Mar;89(3):313-21. 

4) Hindie E, de LV, Melliere D, Jeanguillaume C, Urena P, Perlemuter L, Askienazy S. 

Parathyroid gland radionuclide scanning--methods and indications 

Joint Bone Spine. 2002 Jan;69(1):28-36. 

5) de Labriolle-Vaylet C, Cattan P, Sarfati E, Wioland M, Billotey C, Brocheriou C, Rouvier E, de Roquancourt A, Rostene W, Askienazy 

S, Barbet J, Milhaud G, Gruaz-Guyon A. 

Successful surgical removal of occult metastases of medullary thyroid carcinoma recurrences with the help of immunoscintigraphy and 

radioimmunoguided surgery. 

Clin Cancer Res. 2000 Feb;6(2):363-71. 

6) Mure A, Lebtahi R, de Labriolle-Vaylet C, Askienazy S. 

Imaging of somatostatin receptors in gastroenteropancreatic neuroendocrine tumors 

Gastroenterol Clin Biol. 1998 Oct;22(10):809-18. 

7) Askienazy S, Lebtahi R, Meder JF. 

SPECT HMPAO and balloon test occlusion: interest in predicting tolerance prior to permanent cerebral artery occlusion. 

J Nucl Med. 1993 Aug;34(8):1243-5. 

8) Spampinato U, Habert MO, Mas JL, Bourdel MC, Ziegler M, de Recondo J, Askienazy S, Rondot P. 

(99mTc)-HM-PAO SPECT and cognitive impairment in Parkinson's disease: a comparison with dementia of the Alzheimer type. 

J Neurol Neurosurg Psychiatry. 1991 Sep;54(9):787-92. 

9) Habert MO, Spampinato U, Mas JL, Piketty ML, Bourdel MC, de Recondo J, Rondot P, Askienazy S. 

A comparative technetium 99m hexamethylpropylene amine oxime SPET study in different types of dementia. 

Eur J Nucl Med. 1991;18(1):3-11.


Partner 48: medres – medical research GmbH 

medres – medical research GmbH, Cologne, Germany 

Introduction 

The ministry for education and research supported the project “medres” financially from may 2003 until may 2004 for 

the development of the cryodetector. This lead into the founding of medres in may 2004 as a spin-off from the Max- 

Planck-Institute for neurological research in cologne. 

Single cell imaging in vivo is something we are still working on. But increasing signal to noise (SNR) in a nuclear 

magnetic resonance (NMR) experiment by a factor two brings us an important step closer to the spatial resolution we 

need for single cell imaging. It is known for long that cooling RF-coils (cryodetector) increases the signal to noise 

(SNR) with in a NMR-experiment and there is no NMR conference today without someone presenting new 

cryodetector data. 

One major problem inhibits the routinely in vivo usage of cooled detectors. The thermal isolation between coil and 

tissue. We now present a setup of a nitrogen cooled RF-coil, using a two component thermal isolation of only 1,7 mm 

thickness. The patent for the detector is on its way („Gekühlte Detektoreinrichtung, insbesondere für 

Kernspinresonanzmessungen“, Deutsche Patentanmeldung 10160608.) With this sandwich isolation the temperature at 

the outer surface of the coil unit can be adjusted in a range between 0 and 40°C while the coil remains at liquid 

nitrogen temperature. In vivo experiments can be performed routinely for several hours without cooling the animal but 

with an SNR increase of 90%. 

Technology transfer 

The step into professional hardware development and therefor the founding of a company was necessary for the 

cologne research group because it turned out that detector development alone is not satisfying. Additional equipment 

like animal holder, the basic carrier system and electrophysiological amplifier are needed until research in the field of 

molecular imaging can be done properly. 

Staff 

Expertise 

1. Stefan Wecker: Physics, head of the company, responsible for NMR-hardware development 

2. Bernd Radermacher: Engineer, responsible for electrophysiological-hardware development 

References 

1. Patent: („Gekühlte Detektoreinrichtung, insbesondere für Kernspinresonanzmessungen“, german patent No.: 

10160608.)


Partner 49: Tartu 

VISGENYX LTD, spin off company of the University of Tartu, Tartu, Estonia 

Visgenyx Ltd. (www.visgenyx.com) has been founded by Prof. A. Karis and Prof. E. Vasar in 1999, as a spin-off 

company of the University of Tartu (agreement No SPIN0299, 19.10.1999) in response to an increasing demand for 

appropriate animal models to study the molecular background of human diseases. Research programs of Visgenyx 

focus on developing transgenic animals for the study of neurodegenerative and mental disorders, development of 

diagnostic and therapeutic methods, and more recently for gene polymorphism studies and biopharmaceutical 

production. Visgenyx Ltd locates at premises of University of Tartu using lab space and animal house. Visgenyx uses 

modern equipment to perform microinjections and well equipped laboratories. To generate mice models for human 

diseases Visgenyx Ltd applies transgenic technology in mice and analyses the phenotype of potential animal model. 

Visgenyx activity is mainly related to offer transgenic technology on service basis (cloning, targeting vector design 

and construction, embryonic stem cell cultures, blastocyst injection, pronuclear injections, breeding and genotyping of 

transgenic animals). In addition to generation of transgenic mice, Visgenyx has expertise to conduct animal 

experiments to analyze the phenotype of animal models of human disorders (biochemical, behavioral, molecular 

analysis of animals). In-house development projects are directed to creation of proprietary animal models of 

psychiatric and neurological disorders. Visgenyx Ltd has the international partners in Finland (University of Helsinki, 

University of Kuopio, and Cerebricon Ltd), in Germany (Lynkeus), in Belgium (KLU Leuven), and in Switzerland 

(Swiss Federal Institute of Technology, Lausanne). Several international projects are completed or in process 

(University of Tel-Aviv; Novartis Genomic Institue, San Diego; EGeen International, Redwood City). 


Expertise 

1. Prof. Eero Vasar, MD (1979), PhD (1983), Doctor of Medical Sciences (1992), University of Tartu, is currently a 

professor and head of the Department of Physiology in Tartu. His research focuses on the application of transgenic 

and gene technology for the study of emotional disorders.. 

2. Prof. Alar Karis, doctor in veterinary medicine (1981), PhD (1987), has been a visiting research fellow at the 

University of Hamburg, National Institute for Medical Research (London), Erasmus University (Rotterdam) and 

Northwestern University (Evanston, IL, USA). Since 1998 Dr. Karis is a professor in the Institute of Zoology and 

Hydrobiology at the University of Tartu. He is an expert in gene targeting and homologous recombination of 

embryonic stem cells. His main scientific interest is the development of central nervous system. 

3. Dr. Sulev Kõks, MD (1995), PhD (1999) from the Institute of Molecular and Cell Biology, University of Tartu. He 

is senior research fellow at the Department of Physiology and a project manager at the Visgenyx Ltd. His scientific 

activity is related to the gene expression analysis in different animal models using differential cDNA cloning. He is 

currently developing cDNA microarray technology to allow high-throughput gene expression profiling. 

4. Dr. Vootele Võikar. Currently he is working at the Neuroscience Centre of the University of Helsinki. From the 

beginning of 2005 he will become a senior research fellow at the Department of Physiology, University of Tartu. 

His scientific activity is focused on the extensive behavioral analysis of different mouse strains and different 

transgenic mice. 

References 

1. Tonissoo T, Meier R, Talts K, Plaas M, Karis A. Expression of ric-8 (synembryn) gene in the nervous system of developing and adult mouse. 

Gene Expr Patterns. 2003 5:591-4. 

2. Lindeboom F, Gillemans N, Karis A, Jaegle M, Meijer D, Grosveld F, Philipsen S. A tissue-specific knockout reveals that Gata1 is not essential 

for Sertoli cell function in the mouse. Nucleic Acids Research 2003; 18:5405-12. 

3. Raud S, Runkorg K, Veraksits A, Reimets A, Nelovkov A, Abramov U, Matsui T, Bourin M, Volke V, Kõks S, Vasar E. Targeted mutation of 

CCK2 receptor gene modifies the behavioural effects of diazepam in female mice.Psychopharmacoogy, 2003; 168:417-25. 

4. Võikar V., E. Vasar, H. Rauvala Behavioral alterations induced by repeated testing of C57BL/6J and 129S2/Sv mice: implications for 

phenotyping screens. Genes, Brain and Behavior, 2004; 3:27-38. 

5. Kõks S, Luuk H, A. Nelovkov, T. Areda, Vasar E. A screen for genes induced in the amygdaloid area during cat odor exposure. Genes, Brain 

and Behavior 2004, 3:80-89. 

6. A. Veraksitš, K. Rünkorg, K. Kurrikoff, S. Raud, U. Abramov, T. Matsui, M. Bourin, S. Kõks, E. Vasar Altered pain sensitivity and morphineinduced 

anti-nociception in mice lacking CCK 2 receptors. Psychopharmacology (2003) 166: 168-175 (DOI 10.1007/s00213-002-1333-6). 

7. S. Kõks, A. Planken, H. Luuk, E. Vasar Cat Odour Exposure Increases the Expression of Wolframin Gene in the Amygdaloid Area of Rat. 

Neuroscience Letters (2002) 322: 116-120. 

.


Partner 50: Prague (I. Lukes) 

Department of Inorganic Chemistry and Department of Organic Chemistry, Faculty of Science, 

Universita Karlova v Praze – Charles University in Prague 

The project is focused on synthesis and study of new ligands and their complexes with lanthanides with aim to 

participate on the international research and development of new contrast agents for Magnetic Resonance Imaging. 

Synthesis of new ligands derived from both linear and cyclic polyamines bearing acetate, methylphosphonate or 

phosphinate, eventually, other pendants and investigation of their complexing properties would be the main part of the 

project. 

Extensive synthetic work is required in applying methods that were used for synthesis of macrocycles (and, possibly, 

finding new ones) for introduction of the new types. The same is true for synthesis of organophosphorus compounds. 

Then, in an attempt to throw more light on the still elusive relation between the stability, structure and reactivity of the 

complexes mentioned above, it looks necessary to combine two further strategic approaches which are directed to the 

determination of the structure in solution and in the solid state as the basis for further considerations. Solution 

structure of the ligands and complexes will be studied by multinuclear NMR spectroscopy (as the most useful tool for 

this purpose), using equilibrium data obtained by potentiometry and spectrophotometry as the starting point as well as 

kinetic data giving an information on reaction mechanism. Single crystal X-ray diffraction (as the most definite tool) 

will be applied on representative solid compounds. 

In view of the fact that Prof. Lukes and his co-workers have been dealing with macrocycles and their co-ordination 

chemistry for many years, all facilities for synthesis and investigations both in solution and in the solid state are 

immediately available. Prof. Trnka and his co-workers have gained a lot of experiences in synthesis of sugar 

derivatives as well as glycopeptides and peptides. Their contribution would be oriented to the anchoring of the ligands 

to dendrimers and biomolecules through additional functional groups 

Department of Inorganic Chemistry of "Universita Karlova" is equipped with NMR techniques 400 spectrometer and 

a KappaCCD single crystal diffractometer. The UV-VIS and IR spectrometers for conventional absorption and 

reflectance measurements, as well as equipment for the potentiometric studies are available too. The NMR/NMRD 

relaxation studies on gadolinium(III) complexes studies are available in in Torino (Prof. S. Aime, Italy). 


Expertise 

1. Prof. Dr. I. Lukes: Head of Department of Inorganic Chemistry. Design of chelators, investigation of their 

complexing properties. 

2. Doz. Dr. P. Hermann: Design and synthesis of chelators. 

Further members of the group: Dr. J. Kotek (chemist, synthesis, x-ray structure determination); V. Kubicek 

(chemist, synthesis, NMR ); M. Polasek (chemist; synthesis, NMR and NMRD); J. Rudovsky (chemist; 

instrumation, NMR and NMRD); M. Foerstrova (chemist, synthesis, NMR); T. Vitha (chemist, synthesis, 

NMR). 

3. Prof. Dr. T. Trnka: (Organic synthesis, sugar chemistry, peptides) 

Further member of the group: J. Polakova (chemist; synthesis, anchoring of the ligand to biomolecules). 

References 

J. Rohovec, M. Kyvala, P. Vojtisek, P. Hermann, I. Lukes, "Synthesis, Crystal Structures and Solution Properties of Cyclen and Cyclam N- 

methylene(phenylphosphinic) Derivatives " Europ. J. Inorg. Chem., 2000, 195 

J. Rohovec, P. Vojtisek, P. Hermann, J. Mosinger, Z. Zák, I. Lukes, " Synthesis, Crystal Structures and NMR and Luminescent Spectra of 

Lanthanide Complexes of Cyclen derivated by N-methylene(phenyl)phosphinic Acid Pendant Arms. ” J. Chem. Soc., Dalton Trans. 1999, 3585 

J. Rohovec, I. Lukes, P. Hermann, "Lanthanide complexes of a cyclen derivative with phenylphosphinic pendant arms." New J. Chem., 23, (1999) 

1129 

J. Rohovec, P. Vojtisek, P. Hermann, J. Ludvik , I. Lukes, "Derivative of Cyclen with Three Methylene(phenyl)phosphinic Acid Pendant Arms. 

Synthesis and Crystal Structures of its Lanthanide Complexes" J. Chem. Soc., Dalton Trans. 2000, 141. 

J. Rohovec, R. Gyepes, I. Cisarova, J. Rudovsky, I. Lukes, "Nucleophilic Reactivity of Perhydro-3,6,9,12-tetraazacyclopenteno[1,3- 

f,g]acenaphthylene. A Unified Synthetic Aproach to N - Monosubstituted and N,N´´- Disubstituted Cyclene Derivatives." Tetrahedron Letters 41, 

(2000) 1249 

I. Lukes, J. Kotek, P. Vojtisek, P. Hermann, "Tetraazacycles with Methylphosphinic/phosphonic Acid Pendant Arms. A Comparison with their 

Acetic Acid Analogues." Coordination Chemistry Review, 216-217 (2001) 287 

J. Kotek, P. Lebduskova, P. Hermann, L. Vander Elst, R.N. Muller, C.F.G.C. Geraldes, T. Maschmeyer, I. Lukeš, J.A. Peters, 

„Lanthanide(III) Complexes of Novel Mixed Carboxylic-Phosphorus Acid Derivatives of Diethylenetriamine. A Step towards More Efficient MRI


Contrast Agents.“ Chem. Eur. J.; 2003, 9, 5899 - 5915 

P. Hermann, I. Lukes „Novel Chelating Agents and Conjugates thereof, their Synthesis and Use as Diagnostic and Therapeutic Agents.“ 

WO03008394 (2003) 

Kroutil J, Trnka T, Budesinsky M, et al. :Aziridine ring cleavage by nucleophiles in epimino derivatives of 1,6-anhydro-beta-D-hexopyranoses. 

Eur J Org.Chem 2002,15, 2449-2459, 

Kroutil, J., Karban, J., Trnka, T., Buděšínský, M., Černý, M.: Prepration of O- and N- benzyl derivatives of 1,6-anhydro--D-hexopyranoses via 

aziridine ring opening. Coll. Czech. Chem Commun. 2002, 67, 1805 - 1819


Partner 51: Otwock (R. Mikolajczak) 

POLATOM, Research and Development Department of Radioisotope Centre POLATOM, Poland 

The R&D group consists of 15 people of high education and experience in the field of radiochemistry and 

radiopharmacy in the following thematic groups: radiopharmaceuticals based on their affinity to tumour cell receptors, 

radiopharmaceuticals for infection imaging, production technologies for reactor produced beta-radionuclides of high 

specific activity, radiopharmaceuticals for diagnosis of the osseous system diseases and therapy of painful metastases 

in bones, labelled with 99m Tc, 188 Re, 153 Sm, 90 Y and 177 Lu, miniature radiation sources applied in radio-surgery and 

implantation brachytherapy, application of the liquid scintillator and gamma-spectrometry techniques for 

measurements of activity and radionuclidic purity of radionuclides used for production of the new type of 

radiopharmaceuticals. 

The first group of topics aims on research in molecular imaging with particular emphasis to “in vivo” characterisation 

of cancer, prediction of therapy response and therapy follow-up and involves radiopharmaceuticals based on 

biologically active substances, such as monoclonal antibodies, peptides, proteins or their sequences. This group 

comprises also preparations suitable for infection/inflammation imaging like antimicrobial peptides and cytokines. In 

these works, the advanced analytical techniques, such as HPLC, TLC, ICP, OES etc. are employed. The developed 

methods allow evaluation of radiolabelling yield and radiochemical purity of the obtained compounds, and assessment 

of their essential biological parameters, such as stability in the blood serum, capability of binding to blood cells 

(leukocytes, erythrocytes) and tumor cells in in vitro cell-lines as well as in suitable animal models. The development 

of radiopharmaceuticals labelled with cyclotron-produced isotopes such as iodine, 123 I (e.g. α-methylthyrosine- 123 I 

used for diagnosis of brain tumours) with the potential foe F-18 labelling and its use in PET imaging is also covered 

by this topic. 

The second group focuses the research on radiopharmaceuticals labelled with 99m Tc for diagnosis of the osseous 

system diseases as well as the radiopharmaceuticals applicable for therapy of bone tumours, labelled with the newly 

introduced to clinical practice β-emitters: 188 Re, 153 Sm, 90 Y and 177 Lu. Currently developed radionuclide generator 

188 W / 188 Re, makes an important step towards availability of the 188 Re /as perrhenate/ solution. This will be later used 

to develop therapeutic kits for treatment of different forms of cancer and palliative treatment of cancer metastases in 

bones. The 188 Re solutions find also their application in cardiology as they prevent restenosis of coronary vessels. 

The research works are accompanied by development of absolute methods of determination of isotope radioactivity in 

liquid scintillator-based systems for the nuclides: 89 Sr, 90 Sr/ 90 Y and 188 W / 188 Re to be used in the new types of 

pharmaceuticals. Similarly, the relative measurement methods useful for routine radioactivity measurements and 

analytical methods for chemical and radiochemical quality assessment of the newly developed products are 

developed. 

POLATOM has proper facilities to carry out the research works as well as the preparation of radiopharmaceuticals in 

GMP conditions, confirmed by GMP and ISO 9000 certification. The Centre developed very good communication 

network with the research institutions, clinical hospitals and industrial partners in Poland and in the surrounding 

countries accomplished by the application for the status of Centre of Excellence in Radiopharmacy and Nuclear 

Medicine in Poland. 


Expertise 

1. Dr. Renata Mikolajczak Deputy Director for Research and Development of the Radioisotope Centre POLATOM, 

development of new radiopharmaceuticals, labelling techniques, quality control methods, technological 

developments. 

2. Dr Ewa Byszewska-Szpocińska: biologist, development of methods for labelling hormones, monoclonal antibodies 

and molecules of biological origin with iodine ( 123 I, 125 I, 131 I) 

3. Ass. Prof. Dr. Joanna Michalik, biochemistry: molecular biology techniques, 

4. Prof. Dr. Joseph L. Parus; radiochemistry, development of technologies for radioisotope separation and 

radionuclide metrology, gamma spectrometry 

5. Dr. Urszula Karczmarczyk, biotechnology, biochemistry, radiochemistry, development of radiolabelling methods 

for human blood proteins and cytokines, animal studies 

6. MSc. Edyta Zakrzewska; radiochemistry, labelling techniques, radiopharmaceutical drug development, 

7. MSc. Barbara Janota, chemistry including peptide synthesis and modification, radiochemistry, in vitro studies of 

radiolabelled compounds, cell-line handling 

8. MSc. Dariusz Pawlak: chemistry, radiochemistry, drug development, instrumentation, hard and –software 

development 

9. MSc. Agnieszka Korsak: biologist, in vitro and in viovo evaluation of radiopharmaceuticals 

10. Ass. Prof. Dr. Edward Iller, radiochemistry, development of radiochemical technologies


11. Other team members: technologist with experience in handling radioisotopes and their QC 

References 

1. 1.Cz.Deptula, K.Chmielowski,T.Kempisty, Z.Kusnierz, M.Marciniak, R.Mikolajczak, S.Stefanczyk:”Method of 

preparation and application of strontium chloride- 89 SrCl 2 for palliative treatment of painful bone metastases. Part 

I. Production method of strontium - 89 Sr chloride.” Problemy Medycyny Nuklearnej, 1996 10(19) p.161 - 168 

2. R. Mikolajczak, A. Markiewicz, Cz. Deptula, W. Zulczyk, G. Birnbaum, E. Zakrzewska, I. Wozniak: 9m Tc 

Labelled Peptides For Imaging of Peripheral Receptors. Report IAEA TECDOC-1214 (2001) 98-101 

3. E. Mikiciuk-Olasik, E. Zurek, R. Mikolajczak, E. Zakrzewska, K.Blaszczak-Swiatkiewicz: New derivatives of 2- 

(N-arymethylideneamine)benzophenone oxime as potential radiopharmaceuticals for brain imaging. Nuclear 

Medicine Review, 2 (3) (2000) 149 - 152 

4. R.Mikolajczak, A.Markiewicz: Hynic-Tyr 3 - Octreotide labelling with technetium-99m and rhenium-188 using 

dry kit formulation. J.Labelled Cpd.Radiopharm. 44, Suppl.1 (2001) S570-S5726. 

5. P. Garnuszek , D. Pawlak, , I. Licińska: Development of the freeze-dried kit for preparation of EDTMP chelates 

with radio-lanthanides and Tc-99m; J. Labelled Cpd. Radiopharm, 44, suppl. 1(2001) S614-S616 

6. R.Mikolajczak, J.Staniszewska, S.Mikołajewski, E.Rurarz: ‘Rapid production of 18 Fluoride from 2-fluoroaniline 

via the 19 F(n,2n) 18 F reaction using 14 meV neutrons” Nukleonika, 47(1) (2002) pp.13-18 

7. R.Mikołajczak, A.Markiewicz, B. Gorska: Patent application „Pharmaceutical kit peptide based, its preparation 

and preparation of the radiopharmaceutical from the peptide based pharmaceutical kit” P 354567 

8. Mikolajczak R., Parus J.L., Pawlak D., Zakrzewska E., Michalak W., Sasinowska I.: Reactor produced 177 Lu of 

specific activity and purity suitable for medical applications. J. Radioanal. Nucl. Chem., 257 (1) (2003) 53-57 

9. M. Mirowski,R.Wiercioch,E. Balcerczak,G. Birnbaum,E.Byszewska-Szpocińska, D.Pawlak, R.Wierzbicki: 

Uptake of radiolabelled herceptin by experimental mouse mammary carcinomas. Eur.J.Nucl.Med. 28 (8) 

1193,2001. Congress of European Association of Nuclear Medicine 26-29 August 2001, Napoli,Italy. 

10. M. Mirowski,R. Wiercioch,D.Pawlak,G.Birnbaum,E.Byszewska-Szpocińska, A.Janecka. Uptake of radiolabelled 

morphiceptin and its analog by experimental mouse mammary carcinomas. Eur. J. Nucl. Med. 28(8) 1071,2001, 

Congress of European Association of Nuclear Medicine 26-29 August 2001, Napoli, Italy 

11. M. Mirowski, R.Wiercioch,E.Balcerczak,J.Świtalska,G.Birnbaum, E.Byszewska-Szpocińska,D.Pawlak, R. 

Wierzbicki. Uptake of radiolabelled herceptin by experimental mouse mammary tumors.Eur.J.Nucl.Med.28(8) 

1072,2001,Congress of European Association of Nuclear Medicine 26-29 August 2001, Napoli, Italy 

12. Płachcińska A, Mikołajczak R, Maecke HR, Młodkowska E, Kunert-Radek J, Michalski A, Rzeszutek K, Kozak 

J, Kuśmierek J: Clinical usefulness of 99m Tc-EDDA/HYNIC-TOC scintigraphy in oncological diagnostics – a 

preliminary communication. Eur J Nucl Med Mol Imaging. 30 (10) 2003 p. 1402 

13. Płachcińska A, Mikołajczak R, Maecke HR, Młodkowska E, Kunert-Radek J, Michalski A, Rzeszutek K, Kozak 

J, Kuśmierek J: Clinical usefulness of 99m Tc-EDDA/HYNIC-TOC scintigraphy in oncological diagnostics – a 

pilot study. Cancer Biotherapy and Radiopharmaceuticals. 2 (19) (2004) 261 - 270.. 

14. Parisella M.A., D’Alessandria C., Van de Bosche B., Chianelli M., Ronga G., Papini E., Mikolajczak R., Letizia 

C., De Toma G., Veneziani A., Scopinaro F., Signore A.: 99m Tc-EDDA/HYNIC-TOC in the management of 

Medullary Thyroid Carcinoma. Cancer Biotherapy and Radiopharmaceuticals. 2 (19) (2004) 211 - 217


Partner 52: Prague (E. Sykova) 

Institute of Experimental Medicine ASCR, Department of Neuroscience and Center for Cell Therapy and 

Tissue Repair, Charles University, Prague, Czech Republic 

The Institute of Experimental Medicine ASCR (IEM) consists of various laboratories actively conducting research into 

diffusion in the extracellular space of the nervous tissue, neurodegenerative diseases, animal models of human nervous 

system pathologies, the use of MRI to monitor stem cell migration, differentiation and fate in vivo, and stem cell-based 

therapies. For these studies the IEM utilizes a Leica two-photon confocal microscope, a Leica Image Analysis System, 

a Phillips electron microscope, and a Becton-Dickinson FACS Sorter. Together with the Institute for Clinical and 

Experimental Medicine (ICEM), the Czech Republic’s leading transplant center, the IEM has established a joint MR 

research unit where a Bruker 4.7T spectrometer and 1.5T whole-body Siemens system are used for MR studies of stem 

cells labeled by superparamagnetic nanoparticles. Thus, the IEM is able to provide the necessary equipment and 

infrastructure for performing innovative research integrating various imaging modalities (MRI, optical imaging, 

confocal microscopy). A priority is to develop techniques for the regeneration and repair of CNS injury. After their 

development, these techniques could also be applied to studies of cardiac dysfunction and other organ-specific 

pathologies in the ICEM. To develop novel cell therapies, the Department of Neuroscience focuses on the labeling and 

in vitro differentiation of bone marrow, embryonal and fetal stem cells and studies their differentiation and fate after 

implantation in animal models of neurodegenerative diseases, using superparamagnetic nanoparticles as contrast 

agents in magnetic resonance imaging to track migration and monitor cell fate. The Center for Cell Therapy and Tissue 

Repair explores the use of biocompatible polymer hydrogels to promote the regeneration of damaged tissue; animal 

studies have shown the potential for regenerating axonal ingrowth and the promise of the combined implantation of 

hydrogels and stem cells, even in extensive CNS lesions. Human clinical studies have recently been started using the 

autologous transplantation of bone marrow stem cells in patients with severe spinal cord injuries. The Center enjoys 

close collaboration with clinical departments at the medical faculties of Charles University as well as at the ICEM and 

is ready to employ new compounds for molecular imaging by MR. In additon, the IEM and the Center have close 

collaborations with leading international research groups throughout Europe, North America and Australia. 


Expertise 

1. Prof. Eva Sykova, M.D., DrSc. – Chairman, Dept. of Neuroscience, Charles University 2 nd Medical Faculty and 

Institute of Experimental Medicine ASCR, Prague; Director, Institute of Experimental Medicine ASCR, Prague; 

Head, Center for Cell Therapy and Tissue Repair, Charles University, Prague 

Further members of the group: Doc. Alexandr Chvatal, DrSc. (senior scientist; electrophysiology, the patchclamp 

technique and the membrane properties of glial cells; Vice-Director, Institute of Experimental Medicine 

ASCR); Pavla Jendelova, Ph.D. (senior scientist; stem cell cultures, labeling of cells with superparamagnetic 

nanoparticles, and the use of stem cells in cell therapy; Head, Dept. of Tissue Culture and Stem Cells, Institute 

of Experimental Medicine ASCR,); Miroslava Anderova, Ph.D. (senior scientist; electrophysiological studies, 

the patch-clamp technique, the membrane properties of glial cells and confocal microscopy); Lydia Vargova, 

M.D., Ph.D. (senior scientist; electrophysiological studies, measurements of extracellular space diffusion 

parameters, gliomas and their diffusion parameters and intrinsic optical imaging) 

2. Milan Hajek, DrSc. – Head, MR Unit, Institute for Clinical and Experimental Medicine, Prague; magnetic 

resonance imaging, magnetic resonance spectroscopy, functional magnetic resonance imaging, diffusion-weighted 

magnetic resonance imaging 

Further members of the group: Doc. Frantisek Saudek, M.D., DrSc. (Head of the Laboratory of Langerhans 

islets; responsible person for clinical studies using labeled cells at the ICEM); Jaroslav Tintera, Ph.D. 

(physicist responsible for cardiac MRI and fMRI); Vit Herynek, Ph.D. (biophysicist responsible for 

relaxometry and MRI studies of labeled cells at 4.7T); Monika Dezortova, Ph.D. (biophysicist responsible for 

relaxometry and MRI studies of labeled cells at 1.5T ) 

References 

Measurements of extracellular space diffusion parameters 

1. Vorisek, I. and Sykova, E. (1997) Evolution of anisotropic diffusion in the developing rat corpus callosum. J. Neurophysiol. 78: 912-919. 

2. Nicholson, C. and Sykova, E. (1998) Extracellular space structure revealed by diffusion analysis. Trends. Neurosci. 21: 207-215. 

3. Sykova, E., Mazel, T., and Simonova, Z. (1998) Diffusion constraints and neuron-glia interaction during aging. Exp. Gerontology 33:837-851. 

4. Piet R, Vargova L, Sykova E, Poulain DA, Oliet SH. (2004) Physiological contribution of the astrocytic environment of neurons to 

intersynaptic crosstalk. Proc Natl Acad Sci USA, 101:2151-5. 

5. Sykova, E. (2004) Diffusion Properties of the Brain in Health and Disease. Neurochem. Int. 45:453-466. 

Tissue grafts, biocompatible hydrogels 

1. Harvey, A. R., Kendall, C.L. and Sykova, E. (1997) The status and organization of astrocytes, oligodendroglia and microglia in grafts of fetal 

rat cerebral cortex. Neurosci. Lett. 228: 58-62. 

2. Woerly, S., Pinet, E., De Robertis, L., Bousmina, M., Laroche, G., Roitbak, T., Vargova, L. and Sykova, E. (1998) Heterogeneous PHPMA 

hydrogels for tissue repair and axonal regeneration in the injured spinal cord. J. Biomat. Sci. Polymer Edn. 9: 681-711. 

3. Sykova, E., Roitbak, T., Mazel, T., Simonova, Z. and Harvey, A.R. (1999) Astrocytes, oligodendroglia, extracellular space volume and


geometry in rat fetal brain grafts. Neuroscience 91:783-798. 

4. Woerly, S., Petrov, P., Sykova, E., Roitbak, T., Simonova, Z., Harvey, A.R. (1999) Neural tissue formation within porous hydrogels implanted 

in brain and spinal cord lesions: Ultrastructural, immunohistochemical, and diffusion studies. Tissue Eng. 5: 467-488. 

5. Lesny, P., De Croos, J., Pradny, M., Vacík, J., Michalek, J., Sykova, E. (2002) Polymer hydrogels usable for nervous tissue repair. J. Chem. 

Neuroanatom. 23: 243-247. 

Stem cells, use of nanoparticles in MRI 

1. Jendelova, P., Herynek, V., De Croos, J., Glogarova, K., Andersson, B., Hajek, M., Sykova, E. (2003) Imaging the fate of implanted bone 

marrow stromal cells labeled with superparamagnetic nanoparticles. Magn. Res. Med. 50: 767-776. 

2. Jendelova, P., Herynek, V., Urdzikova, L., Glogarova, K., Kroupova, J., Andersson, B., Burian, M., Hajek, M., Sykova, E. (2004) Magnetic 

resonance tracking of transplanted bone marrow and embryonic stem cells labeled by iron oxide nanoparticles in rat brain and spinal cord. J. 

Neurosci. Res, 76:232-243. 

3. Hudson, J.E., Chen, N., Song, S., Walczak, P., Jendelova, P., Sykova, E., Willing, A.E., Saporta, S., Bickford, P., Sanchez-Ramos, J., Zigova, 

T. (2004) Green fluorescent protein bone marrow cells express hematopoietic and neural antigens in culture and migrate within the neonatal rat 

brain. J. Neurosci. Res., 76:255-264 

Animal models of pathological states 

1. Roitbak, T. and Sykova, E. (1999) Diffusion barriers evoked in the rat cortex by reactive astrogliosis. Glia 28: 40-48. 

2. Sykova, E., Mazel, T., Vargova, L., Vorisek, I., Prokopova, S., (2000) Extracellular space diffusion and pathological states. Prog. Brain Res. 

125: 155-178. 

3. Sykova, E. (2001) Glial diffusion barriers during aging and pathological states. Prog. Brain Res. 132: 339-363 

4. Sykova, E., Fiala, J., Antonova, T., Vorisek, I. (2001) Extracellular space volume changes and diffusion barriers in rats with kaolin-induced 

and inherited hydrocephalus. Eur. J. Pediatr. Surg. 11: S34-S37. 

5. Sykova, E., Mazel, T., Hasenohrl, R.U., Harvey, A.R., Simonova, Z., Mulders, W.H.A.M., Huston J.P. (2002) Learning deficits in aged rats 

related to decrease in extracellular volume and loss of difussion anisotropy in hippocampus. Hippocampus. 12: 469-479. 

Intrinsic optical imaging 

1. Sykova, E., Vargova, L., Kubinova, S., Jendelova P., Chvatal, A. (2003) The relationship between changes in intrinsic optical signals and cell 

swelling in rat spinal cord slices. NeuroImage,18: 214-230. 

DW-MRI measurements 

1. Van der Toorn, A., Sykova, E., Dijkhuizen, R.M., Vorisek. I., Vargova, L., Skobisova, E., Van Lookeren Campagne, M., Reese, T. and 

Nicolay, K. (1996) Dynamic changes in water ADC, energy metabolism, extracellular space volume, and tortuosity in neonatal rat brain during 

global ischemia. Magn. Reson. Med., 36: 52-60. 

2. Pfeuffer, J., Dreher, W., Sykova, E. and Leibfritz, D. (1998) Water signal attenuation in diffusion-weighted 1 H NMR experiments during 

cerebral ischemia: Influence of intracellular restrictions, extracellular tortuosity, and exchange. Magn. Reson. Imaging 16:1023-1032 

3. Dezortova M, Hajek M, Tintera J, Hejcmanova L, Sykova E. (2001) MR in phenylketonuria-related brain lesions. Acta Radiol. 42: 459-466. 

4. Vorisek I., Hajek M., Tintera J., Nicolay K., Sykova E. (2002) Water ADC, extracellular space volume and tortuosity in the rat cortex after 

traumatic injury. Magn. Reson. Med. 48:994-1003. 

MRI Methodology 

1. Jirak D., Dezortova M., Taimr P., Hajek M. (2002) Texture analysis of human liver. J. Magn. Reson. Imaging 15: 68-74. 

2. Hajek M., Palyzova D., Koinek M., Kurkova D. (2002) Concentrations of free Mg2+, pH and 31P MR Metabolite Ratios in Calf Muscles of 

Healthy Controls and Patients with Primary Juvenile Hypertension. Physiol. Res. 51: 159-167. 

3. Jir F., Dezortova M., Burian M., Hajek M. (2003) The role of relaxation time corrections for the evaluation of long and short echo time 1H MR 

spectra of the hippocampus by NUMARIS and LCModel techniques. MAGMA 16: 135-142. 

4. Jirak D., Dezortova M., Hajek M. (2004) Phantoms for Texture Analysis of MR Images. Long-term and Multi-center Study. Medical Physics 

31: 616-622. 

5. Zizka J., Ceral J., Elias P., Tintera J., Klzo L., Solar M., Straka L. (2004) Vascular compression of rostral medulla oblongata: prospective MR 

imaging study in hypertensive and normotensive subjects. Radiology 230: 65-69.


Partner 53: Pessac (E. Dumont) 

Image Guided Therapy SA 

Image Guided Therapy SA is a small company whose object is the development of image based temperature control of 

non invasive energy deposition means based on focused ultrasounds. The company is working on the accurate 

temperature control of heating devices for thermal ablation, local drug delivery and localised gene expression. These 

last two applications require a very accurate temperature control over a volume of interest. This temperature control 

uses MRI based temperature maps and a flexible energy deposition device based on focused ultrasounds. 


Expertise 

1. Dr. E.A. Dumont: Physics, CEO Image Guided Therapy SA. 

2. Dr. B. Quesson: Physics, instrumentation, hard- and software development. 

References 

1. Temperature Imaging and heat deposition control 

Quesson, B., J. A. de Zwart, et al. (2000). "Magnetic resonance temperature imaging for guidance of 

thermotherapy." J Magn Reson Imaging 12(4): 525-33. 

Quesson, B., F. Vimeux, et al. (2002). "Automatic control of hyperthermic therapy based on real-time 

Fourier analysis of MR temperature maps." Magn Reson Med 47(6): 1065-72. 

Weidensteiner, C., B. Quesson, et al. (2003). "Real-time MR temperature mapping of rabbit liver in vivo 

during thermal ablation." Magn Reson Med 50(2): 322-30. 

Weidensteiner, C., N. Kerioui, et al. (2004). "Stability of real-time MR temperature mapping in healthy and 

diseased human liver." J Magn Reson Imaging 19(4): 438-46. 

2. Localised,temperature controled gene expression 

Guilhon, E., B. Quesson, et al. (2003). "Image-guided control of transgene expression based on local 

hyperthermia." Mol Imaging 2(1): 11-7. 

Guilhon, E., P. Voisin, et al. (2003). "Spatial and temporal control of transgene expression in vivo using a 

heat-sensitive promoter and MRI-guided focused ultrasound." J Gene Med 5(4): 333-42.


Proposal Number 512146 Proposal Acronym DIMI Participant number 1 

Participating organisation 

Organisation legal name Klinikum at the University of Cologne (Medizinische Einrichtungen Koeln) 

Organisation short name MEK 

Internet homepage 

http://www.medizin.uni-koeln.de 

List of RESEARCHERS to be integrated 

Last name First name(s) Professional 

Status 1 

Gender: 

male or 

female 

Connection with 

Joint Progr. of 

Activities 

Legal name 

researcher's 

Employer 4 

(JPA) 2 , 3 

Heiss Wolf-Dieter Director male I, M, S MEK + MPI 

Herholz Karl Professor male I, R MEK 

Jacobs Andreas MD, project male I, M, S, R MEK 

coordinator 

Winkeler Alexandra Post-Doc female I, M, S, R MEK 

Klein Markus Post-Doc male R MEK 

Galldiks Norbert MD male R Max-Planck-Institute 

Rueger Maria Adele MD female R MEK 

Wienhard Klaus Professor male R Max-Planck-Institute 

Knoess Christoph Post-Doc male R Max-Planck-Institute 

Wagner Rainer head of male R Max-Planck-Institute 

radiochemistry 

Bauer Bernd PhD, 

male R Max-Planck-Institute 

radiochemist 

Li Huongfeng PhD, 

radiochemist 

female R MEK 

Stoeckle Mathias PhD, 

radiochemist 

male R MEK 

Kracht Lutz MD male I, M, S, R Max-Planck-Institute 

Hilker Ruediger MD male R MEK 

Graf Rudolf Professor male R Max-Planck-Institute 

Vollmar Stefan PhD, physicist male R, M Max-Planck-Institute 

Klein Johannes MD male R Max-Planck-Institute 

1 e.g. Professor, Post-Doc, Research Director, Head of Reseach Unit xxx, 

2 If the researcher is intended to be directly involved in the JPA, indicate in which of the activities of the JPA the 

researcher will be involved in (can be more than one). Insert 

I for Integration Activities' 

R for Jointly Executed Research Activities, 

S for Spreading of Excellence Activities), and 

M for 'Management Activities' 

3 If the researcher, while intended to be integrated, will not be directly involved in the JPA, insert 

NDI for 'not directly involved' 

4 A 'researcher' must either be an employee of the contractor or be working under its direct management authority in 

the frame of a formal agreement between the contractor and the 'researcher's employer. Insert here the legal name 

researcher's employer if different from the contractor, otherwise insert


Last name First name(s) University 

degree 

List of DOCTORAL STUDENTS 

Gender: 

male or 

female 



Activities 

(JPA) 2,3 

Organiser of course 

doctoral Student is 

enrolled in 

Monfared Parisa PhD student female R Andreas Jacobs 

Ameli Mitra MD student female R Andreas Jacobs 

Scheffler Mathias MD student male R Andreas Jacobs 

Cizek Jiri PhD student male R Klaus Wienhard




Organisation legal name Wolfson Brain Imaging Centre, University of Cambridge 

Organisation short name WBIC 


http://www.wbic.cam.ac.uk 


Last name First name(s) Professional Status Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Pickard John Director, WBIC male R WBIC 

Clark John Director, PET male I, R, S, M WBIC 

Carpenter Adrian Director, MRI & male I, R, S WBIC 

Computing 

Fryer Tim PhD, PET physicist male I, R, S WBIC 

Barret Olivier PhD, PET physicist male R WBIC 

Shaw Nick PhD, MR physicist male R Physics 

Ansorge Richard PhD, physicist male R Physics 

Aigbirhio Franklin PhD, radiochemist male I, R WBIC 

Cleij Marcel PhD, radiochemist male R WBIC 

Johnstrom Peter PhD, radiochemist male R WBIC 

Beech John PhD, physiology male I, R Anaesthetics 

Richards Hugh PhD, physiology male I, R Neurosurgery 

Weissberg Peter Prof, Cardiovascular 

Medicine 

male R Cardiovascular 

Medicine 

Baron Jean-Claude Prof, Stroke male R Neurology 

Menon David Prof, Anaesthetics male R Anaesthetics 

Davenport Anthony PhD, pharmacology male R Pharmacology 

Harding Sally PhD, MR physicist female R WBIC 

Williams Guy PhD, computing male R WBIC 

Warburton Elizabeth MD, stroke female R Stroke Medicine 

Leeper Finian PhD, organic chemist male R Chemistry 


Last name First name(s) University degree Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Cockbill Andrew PhD student male R Tim Fryer 

Davies John PhD student male R Peter Weissberg 

Guadagno Joe PhD student male R Jean-Claude Baron 

Hughes Jess PhD student female R Jean-Claude Baron 

Manu-Marfo Mary PhD student female R Franklin Aigbirhio 

Price Chris PhD student male R Liz Warburton




Organisation legal name Università degli Studi di Torino) 

Organisation short name UniTo 


http://www.unito.it 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Aime Silvio Professor male I, M, S, R UniTo 

Gobetto Roberto Professor male R UniTo 

Silengo Lorenzo Professor male R UniTo 

Altruda Fiorella Professor female R UniTo 

Tarone Guido Professor male R UniTo 

Camussi Giovanni Professor male R UniTo 

Biancone Luigi Researcher male R UniTo 

Bussolati Benedetta Researcher female R UniTo 

Terreno Enzo Researcher male R UniTo 

Dastrù Walter Researcher male R UniTo 

Geninatti Crich Simonetta Researcher female R UniTo 

Barge Alessandro Researcher male R UniTo 

Gianolio Eliana Researcher female R UniTo 

Tei Lorenzo Researcher male R UniTo 

Viale Alessandra Researcher female R UniTo 

Reineri Francesca Researcher female R UniTo 

Delli Castelli Daniela Researcher female R UniTo 

Digilio Giuseppe Researcher male R UniTo 

Corpillo Davide Researcher male R UniTo 

Bracco Chiara Researcher female R UniTo 

Fedeli Franco Researcher male R UniTo 

Hamm Jorg Researcher male R UniTo 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Bruno Erik PhD student male R Silvio Aime 

Battistini Elisa PhD student female R Silvio Aime 

Esposito Giovanna PhD student female R Silvio Aime 

Belfiore Simona PhD student female R Silvio Aime 

Longo Dario PhD student male R Silvio Aime 

Bert Alberto PhD student male R Silvio Aime 

Lanzardo Stefania PhD student female R Silvio Aime 

Carrera Carla PhD student female R Enzo Terreno




Organisation legal name Laboratoire Biophysique Médicale et pharmaceutique, INSERM U 619 

Organisation short name INSERM U 619 



Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Guilloteau Denis Professor male R,M University, hospital 

Pourcelot Léandre Professor male R University, hospital 

Chalon Sylvie Biologist female R INSERM 

Besnard Jean Claude Professor male R University, hospital 

Saliba Elie Professor male R University, hospital 

Baulieu Jean Louis Professor male R University, hospital 

Prunier Caroline PhD, 

female R University, hospital 

Neurologist 

Emond Patrick PhD, Chemist male R University 

Vergotte Jackie PhD, Biologist female R University 

Mavel Sylvie PhD, Chemist female R University 

Frangin Yves PhD, Chemist male R University 

Benderbous Soraya Professor female R University 

Castelnau Pierre MD, 

male R University, hospital 

neurologist 

Barantin Laurent PhD male R University 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Galineau Laurent PhD Student male R S Chalon 

Giboureau Nicolas PhD Student male R D Guilloteau 

Quinlivan Mitch PhD Student male R D Guilloteau




Organisation legal name Institut d’Investigacions Biomèdiques de Barcelona 

Organisation short name IDIBAPS 


http://www.idibaps.ub.edu 



male or 

female 

Planas Anna M Research Scientist; 

Head Research Unit 

Experimental stroke 

Artigas Francesc Research Prof,Head 

Dep. Neurochem. 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

female I, R, , M, S IIBB-CSIC; IDIBAPS 

male R, S IIBB-CSIC; IDIBAPS 

Adell Albert Tenured Scientist male R IIBB-CSIC; IDIBAPS 

Celada Pau Scientist, PhD, 

electrophysiologist 

female R Ramon y Cajal (MEC)- 

IIBB-CSIC-IDIBAPS 

Sanfeliu Coral Tenured Scientist female R, S IIBB-CSIC; IDIBAPS 

Cristòfol Rosa Tenured Scientist female R IIBB-CSIC; IDIBAPS 

Serratosa Joan Research Sci, Head male R, S IIBB-CSIC; IDIBAPS 

Dep. Pharmacology 

Tusell Josep Tenured Scientist male R IIBB-CSIC; IDIBAPS 

Solà Carme Tenured Scientist female R IIBB-CSIC; IDIBAPS 

Saura Josep Scientist, PhD 

neurobiologist 

male R Ramon y Cajal (MEC)- 

IIBB-CSIC; IDIBAPS 

García de Frutos Pablo Tenured Scientist male R, S IIBB-CSIC; IDIBAPS 

Trullas Ramon Tenured Scientist male R, S IIBB-CSIC; IDIBAPS 

DeGregorio Nuria PhD, neurobiologist female R IIBB-CSIC; IDIBAPS 

Martínez Emili Tenured Scientist male R, S IIBB-CSIC, IDIBAPS 

Camón Luïsa Scientist female R IIBB-CSIC; IDIBAPS 

De Vera Núria Scientist female R IIBB-CSIC; IDIBAPS 

Petegnief Valérie PhD, neurobiologist male R Ramon y Cajal (MEC)- 

IIBB-CSIC; IDIBAPS 

Panés Julian MD, PhD male R Hospital Clínic- 

IDIBAPS 

Pavia Xavier PhD, Physicist male R Hospital Clínic- 

IDIBAPS 

Ros Domènec Associate Professor 

PhD, Physiscist 

male R,S Facultat Medicina: FM, 

Universitat Barcelona: 

UB; IDIBAPS 

Alberch Jordi Associate Professor male S, R FM, UB; IDIBAPS 

Pérez-Navarro Esther Assistant Professor female R FM, UB; IDIBAPS 

Canals Josep María Scientist, PhD, 

Neurobiologist 

male R Ramon y Cajal (MEC)- 

FM-UB; IDIBAPS 

Marín Concepció MD, PhD, Neurologist female R FIS-Fundació Clínic; 

IDIBAPS




male or 

female 



Activities 

(JPA) 



enrolled in 

Romanos Eduardo PhD Student male R Anna M. Planas 

Martín Abraham PhD Student male R Anna M. Planas 

Rojas Santiago PhD Student male R Anna M. Planas 

Gorina Roser PhD Student female R Anna M. Planas 

Bellido Dolores PhD student female R Pablo García de Frutos 

Luna Geroni PhD student female R Pablo García de Frutos 

Pérez Kamil PhD student female R Joan Serratosa/C Sola 

Ejarque Aroa PhD student female R Joan Serratosa/J Saura 

Díaz Llorens PhD student male R Francesc Artigas 

Kargieman Lucila PhD student female R Francesc Artigas 

Bosch Miquel PhD Student male R Jordi Alberch 

Pezzi Susana PhD Student female R Jordi Alberch 

Martín Raquel PhD Student female R Jordi Alberch 

Torres Jesus PhD Student male R Jordi Alberch 

Pertusa María PhD Student female R Coral Sanfeliu 

Gavaldà Núria PhD Student female R Jordi Alberch 

García José María PhD Student male R Jordi Alberch 

Saldaña Marisa PhD Student female R Concepció Marín 

Garcia Matas Silvia PhD Student female R Rosa Cristòfol 

Abad Fernández MªAlba PhD Student female R Ramon Trullas 

Enguita Martínez Marta PhD Student female R Ramon Trullas




Organisation legal name Università degli Studi di Milano 

Organisation short name UNIM 


www.unimi.it 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

M, I, S 

Legal name 

researcher's 

Employer 

Maggi Adriana Professor of female 

Pharmacology 

UNIMI 

Ciana Paolo Research male R UNIMI 

Associate 

Vegeto Elisabetta Assistant female R UNIMI 

Professor 

Scarlatti Fabrizio Post .Doc male R UNIMI 

Brena Andrea Post. Doc. male R UNIMI 

Grassi Anna Post. Doc female R UNIMI 

Ottobrini Luisa Post. Doc. female R UNIMI 

Rossi Daniela Post. Doc. female R UNIMI 

Belcredito Silvia Post. Doc. female R UNIMI 

Lucignani Giovanni Professor of male M, I, S UNIMI 

Radiology 

Volterra Andrea Professor of 

Pharmacology 

male M, I, S 

UNIMI 

Sparaciari Paolo M. Vet. male R UNIMI 

Oldoni Samanta Technician female R UNIMI 

Meda Clara Technician female R UNIMI 

Rebecchi Monica Technician female R UNIMI 

Lana Alessandra Post. Doc. female R UNIMI 

Zagari Francesca Post. Doc. female R UNIMI 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Biserni Andrea Ph.D. male R Prof. Lucignani 

Ghisletti Serena Ph.D. female R Prof. Crosignani 

Mussi Paola Ph.D. female R Prof. Crosignani 

Raviscioni Michele Ph.D male R Prof. Crosignani 

Etteri Sabrina Ph.D female R Prof. Crosignani




Organisation legal name Neurobiology Research Unit 

Organisation short name NRU 

Internet homepage http://www.nru.dk 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Knudsen Gitte M. Head of NRU Female I, R, S, M RH-CU 

Pinborg Lars Post-doc Male I, S RH-CU 

Waldemar Gunhild Professor, MD Female I RH-CU 

Aznar Susana Senior researcher Female I RH-CU 

Svarer Claus Chief engineer Male I, R, S RH-CU 

Paulson Olaf B. Head of DMRC Male I DMRC-CU & RH- 

CU 

Hanson Lars Chief physicist Male I DMRC-CU 

Gillings Nic Chief radiochemist Male I RH-CU 

Madsen Jacob Post doc Male I RH-CU 

Hasselbalch Steen G. Associate prof. Male I RH-CU 

Rowland Ian Senior researcher Male I, R DMRC-CU 

Sørensen Per S. Professor, MD Male I RH-CU 

Rostrup Egill Post doc Male I DMRC-CU 

Nielsen Finn A. Post doc Male I, S RH-CU 



male or 

female 



Activities 

(JPA) 



enrolled in 

Frøkjær Vibe MD Female NDI Gitte M. Knudsen 

Rahbek Birgitte human biologist Female NDI Gitte M. Knudsen 

Kostova Viktorija human biologist Female I Susana Aznar 

Høgh-Rasmussen Esben engineer Male S Claus Svarer 

de Nijs Robin physicist Male S Lars G. Hanson 

Lund Torben human biologist Male I Olaf B. Paulson 

Krakauer Martin MD Male I Per S. Sorensen 

Patta Pamela MD Female I Per S. Sorensen




Organisation legal name University of Antwerp 

Organisation short name UA 


http://www.ruca.ua.ac.be/biomag/ 



male or 

female 



Activities 

(JPA) 

Verhoye Marleen Postdoc Physics, Bio- female SE, R UA 

Imaging Lab 

Postnov Andrea Postdoc Physics, 

MicroCT lab 

female SE, R UA 

De Clerck Nora Professor, MicroCT lab female SE, R UA 

Van Dyck Dirk Professor, Image 

Processing, Visielab 

Scheunders Paul Professor, Image 


Raman Erik Professor, Medical 

Physics, Visielab 

Sijbers Jan Postdoc Physics, Image 


Van de Gert 

Postdoc Physics, Image 

Wouwer 


Weyn Barbara Postdoc Physics, Image 


De Backer Steve Postdoc Physics, Image 


Jaber Juntu Postdoc Physics, Image 


Van der Linden Annemie Professor, Biologist, Bio- 

Imaging Lab 

Timmermans Jean Pierre Professor, Cell and 

Tissue, dept Biomedical 

Sciences 

Adriaanssens Dirk Professor, Cell and 


Sciences 

Van Nassauw Luc Professor, Cell and 


Sciences 

Brouns Inge Postdoc, Cell and Tissue, 

dept Biomedical 

Sciences 

De Laet Ann Postdoc, Cell and Tissue, 

dept Biomedical 

Sciences 

male I UA 

male R UA 

male R UA 

male R, SE UA 

male R UA 

female R UA 

male R UA 

male R UA 

female M, SE, I UA 

male R UA 

male SE, R UA 

male R UA 

female R UA 

female R UA 

Legal name 

researcher's 

Employer




male or 

female 



Activities 

(JPA) 



enrolled in 

Vanhoutte Greet Biomedical Sciences, 

Bio-Imaging Lab 

female R Annemie Van der 

Linden 

Van Camp Nadja Biomedical Sciences, 



Linden 

Tisson Greg Physics, Visie Lab male R Dirk Van Dyck 

Leemans Alexander Physics, Visie Lab male R Dirk Van Dyck 

Bogo Edwin Physics, Visie Lab male R Dirk Van Dyck 

Van Meir Vincent Biology, Bio-Imaging 

lab 

Tindemans Ilse Biology, Bio-Imaging 

lab 

Boumans Tiny Biomedical Sciences, 


Pintelon Isabel Cell and Tissue, 

Biomedical Sciences 

Tombeur Christoph Cell and Tissue, 


De Proost Ian Cell and Tissue, 


Moelans Cathy Cell and Tissue, 


De Jonge Frederik Cell and Tissue, 


male R Annemie Van der 

Linden 


Linden 


Linden 

female R J.P. Timmermans 

male R J.P. Timmermans 

male R J.P. Timmermans 

female R J.P. Timmermans 

male R J.P. Timmermans




Organisation legal name 

Imagerie Moléculaire et Fonctionnelle: de la Physiologie à la Thérapi (CNRS/University of 

Bordeaux 2) 

Organisation short name IMF 


http://www.imf.u-bordeaux2.fr 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Moonen Chrit Director male I, M, S, R CNRS 

Allard Michèle Professor female R University Hospital 

Grenier Nicolas Professor male R, I, S University Hospital 

Loiseau Hugues Professor male R University Hospital 

Couillaud Franck PhD, biology male R, S CNRS 

Trillaud Hervé Professor male R University Hospital 

Ries Colette technician female R University 

De Sèze Marianne MD female R University Hospital 

Hauger Christoph MD male R University Hospital 

Hesling Isabelle MD female R University Hospital 

Palussiere Jean MD male R Bergonié Anticancer 

Inst 

Dilharreguy Bixente PhD, image female R University 

processing, postdoc 

Ries Mario PhD, physics male R CNRS 

postdoc 

Rome Claire PhD, biology female R University 

postdoc 

Salomir Rares PhD, physics male R INSERM 

postdoc 

Desbarats Pascal PhD, informatics male R, S University 



male or 

female 



Activities 

(JPA) 



enrolled in 

Lepetit-Coiffé Matthieu PhD student male R Chrit Moonen 

Mougenot Mitra PhD student male R Chrit Moonen 

Aguerre Cedric PhD student male R Achille Braquelaire 

Seror Olivier PhD student male R Hervé Trillaud 

Denis De Baudouin PhD student male R Christophe Schlick 

Senneville 

Modolo Carine PhD student female R Christophe Schlick 

Kabongo Luis PhD student male R Christophe Schlick




Organisation legal name Nuklearmedizinische Klinik der Technischen Universität München 

Organisation short name NUK_TUM 


http://www.nuk.med.tu-muenchen.de 



male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Schwaiger Markus Director male I, M, S NUK_TUM 

Bengel Frank MD, group 

male I, M, S, R NUK_TUM 

coordinator 

Drzezga Alexander MD male I, M, S, R NUK_TUM 

Wermke Marc MD male R NUK_TUM 

Botnar Rene PhD, physics male I, S, R, M NUK_TUM 

Nekolla Stephan PhD, physics male R, M NUK_TUM 

Ziegler Sibylle PhD, physics female I, S, M NUK_TUM 

Wester Hans-Juergen PhD, chemistry male I, S, M, R NUK_TUM 

Haubner Roland PhD, chemistry male R NUK_TUM 

Wagner Bettina DVM female R NUK_TUM 

Anton Martina PhD, biology female I, S, M, R Institut für exp. 

Onkologie der TU 

München 



male or 

female 



Activities 

(JPA) 



enrolled in 

Beyer Moritz MD student male R Frank Bengel 

Wittermann Constanze MD student female R Frank Bengel 

Keller Eva MD student female R Alexander Drzezga 

Schreiner Julia MD student female R Alexander Drzezga




Organisation legal name University of Oslo 

Organisation short name UiO 


http://www.uio.no 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Blomhoff Rune Professor male I, R, S, M UiO 

Alexander George Researchers male I, R, S UiO 

Hauglin Harald Postdoc male I, R, S UiO 

Bogen Bjarne Professor male I, R UiO 

Munthe Ludvig Postdoc male I, R UiO 

Corthay Alexander Researcher male I, R UiO 

Lundin Katrin Postdoc female I, R UiO 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 



enrolled in 

Austenaa Liv PhD student female R, S Rune Blomhoff 

Paur Knudsen Ingvild PhD student female R, S Rune Blomhoff 

Zangani Michael PhD student male R Bjarne Bogen




Organisation legal name Commissariat à l’Energie Atomique 

Organisation short name CEA 


www.cea.fr* 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

TAVITIAN Bertrand Researcher M I, M, R, S CEA-LIGE 

BOISGARD Raphaël Researcher M R,I,S CEA-LIGE 

DUCONGE Frederic Researcher M R,I,S CEA-LIGE 

JEGO Benoit Technician M R,I,S CEA-LIGE 

GOMBERT Karine Technician F CEA-LIGE 

KUHNAST Bertrand Researcher M R,I,S CEA-LIGE 

BOUTIN Hervé Post-doc M R,I,S CEA-LIGE 

MERGUI Simone Administrative F I,S,M CEA-LIGE 

MEHL Nadine Administrative F I,S,M CEA-LIGE 

RIZO Philippe Researcher M R,I,S CEA-LETI 

DOLLE Frederic Researcher M R,I,S CEA-SHFJ 

TREBOSSEN Régine Researcher F R,I,S CEA-SHFJ 

COMTAT Claude Researcher M R,I,S CEA-SHFJ 

MAROY Renaud Researcher M R,I,S CEA-SHFJ 

CECCARELLI Elena Engineer F I,S CEA - INSTN 

HAMMADI Akli Professor M I,S CEA - INSTN 



degree 

Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

PESTOURIE Carine PhD F R,I,S CEA-LIGE 

CHAUVEAU Fabien PhD M R,I,S CEA-LIGE 

GUILLERMET Stephanie PhD F R,I,S CEA-LIGE 

VIEL Thomas PhD M R,I,S CEA-LIGE 

RONCALI Emilie PhD F R,I,S CEA-LIGE




Organisation legal name BIOSPACE MESURES 

Organisation short name BIOSPACE 


http://www.biospace.fr 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

MEYNADIER Marie President and female M BIOSPACE 

CEO 

MAITREJEAN Serge Scientific male R BIOSPACE 

Director 

TEYSSEYRE Sébastien Engineer male R BIOSPACE 

DESAUTE Pascal Engineer male R BIOSPACE 

CUSCITO Philippe Engineer male R BIOSPACE 

ASSELIN Pascal Engineer male R BIOSPACE




Organisation legal name Katholieke Universiteit Leuven 

Organisation short name K.U.Leuven R&D 


www.kuleuven.ac.be 



male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Baekelandt Veerle Professor female I, M, S, R K.U.Leuven R&D 

Nuttin Bart Professor male I, S K.U.Leuven R&D and 

University Hospitals 

Leuven 

Van den Haute Chris Post-Doc, biologist male I, R, S K.U.Leuven R&D 

Lauwers Erwin Post-Doc, biochemist male R K.U.Leuven R&D 

Baker Alexis Post-Doc, pharmacology male R K.U.Leuven R&D 

Eggermont Kristel Supervision of 

female R K.U.Leuven R&D 

stereotactic neurosurgery 

Debyser Zeger Professor male I, M, S, R K.U.Leuven R&D 

Gijsbers Rik Post-Doc, vectorology male I, R, S K.U.Leuven R&D 

Nefkens Isabelle Post-Doc, bio-engineer female R K.U.Leuven R&D 

Michiels Martine Head of vectorology unit female R K.U.Leuven R&D 

Willems Sofie Vectorology female R K.U.Leuven R&D 

Duportail Christiane Supervision of vector 

construction 

Desender Linda Supervision of protein 

purification 



male or 

female 





Activities 

(JPA) 



enrolled in 

Vercammen Linda PhD student female R Veerle Baekelandt 

Reumers Veerle PhD student female R Veerle Baekelandt 

Geraerts Martine PhD student female R Zeger Debyser 

Bartholomeeusen Koen PhD student male R Zeger Debyser 

De Rijck Jan PhD student male R Zeger Debyser




Organisation legal name Lund University 

Organisation short name ULUND 


http://www.lu.se 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Kirik Deniz Group leader Male I, R, M ULUND 

Romero-Ramos Marina Post-Doc Female R ULUND 

Breysse Nathalie Post-Doc Female R ULUND 

Morris-Irvin Dwain Post-Doc Male R ULUND 

Carlsson Thomas Student Male R ULUND 

Stott Simon Student Male R ULUND 

Maingay Matt Student Male R ULUND 

Björklund Tomas Student Male R ULUND 

Nordin Eva Admin Female M ULUND 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Carlsson Thomas PhD student Male R Denis Kirik 

Stott Simon MD student Male R Deniz Kirik 

Maingay Matt MD student Male R Deniz Kirik




Organisation legal name Lund university 

Organisation short name ULUND-II 


http://www.inflam.lu.se 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Holmdahl Rikard Professor, MD male I, M, S, R ULUND-II 

Matsson Ragnar Professor male I, R ULUND-II 

Andersson Åsa MD female S, R ULUND-II 

Issazadeh Shohreh PhD female S, R ULUND-II 

Blom Thomas PhD male I, R ULUND-II 

Anna-Karin Lindqvist PhD female R ULUND-II 

Lu Shemin MD male R ULUND-II 

Balik Dzhambazov Post-Doc male R ULUND-II 

Nandakumar Kutty Selva PhD male R ULUND-II 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Bockermann Robert PhD student male R Rikard Holmdahl 

Teige Ingrid PhD student female R Shohreh Issazadeh 

Treschow Treschow PhD student female R Shohreh Issazadeh 

Carlsén Stefan PhD student male R Rikard Holmdahl 

Meirav Holmdahl PhD student female R Rikard Holmdahl 

Karlsson Jenny PhD student female R Åsa Andersson 

Hultqvist Malin PhD student female R Rikard Holmdahl


Proposal Number 512146 Proposal Acronym DIMI Participant number 17A 


Organisation legal name Imperial College London 

Organisation short name ICL 


http://www.med.ic.ac.uk 



male or 

female 

Connection 

with Joint 

Progr. of 

Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Brooks David Professor male I, M, R, S Imperial College 

Brignell Catherine MD female R Imperial College 

Edison Paul MD male R Imperial College 

Hammers Alexander MD male R Imperial College 

Gerhard Alexander MD, Research Fellow male R Imperial College 

Trender-Gerhard Iris MD female R Imperial College 

Hotton Gary MD male R Imperial College 

Pavese Nicola MD male R Imperial College 

Piccini Paola MD female R Imperial College 

Tai Yen Foung MD male R Imperial College 



male or 

female 

Connection 

with Joint 


Activities 

(JPA) 



enrolled in 

Vendrell Ignacio MSc Student male R Imperial College 

Es Melthem MSc Student female R Imperial College


Proposal Number 512146 Proposal Acronym DIMI Participant number 17B 


Organisation legal name Imperial College of Science Technology and Medicine 

Organisation short name Imperial College Lo# 


http://www.imperial.ac.uk 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Jones Hazel Ann Research Fellow female I, R, S, M Imperial College Lo# 

Boobis Alan Raymond Professor male R, S Imperial College Lo# 

Ind Philip Waterloo Senior Lecturer male NDI Imperial College Lo# 

Stagg Andrew John Research Fellow male R, S Imperial College Lo#




Organisation legal name Hospital de la Santa Creu i Sant Pau 

Organisation short name HSP 


http://www.santpau.es 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Carrió Ignasi Professor male I, M, R, S HSP 

Director 

Estorch Montserrat MD female I, R, S HSP 

Flotats Albert MD male I, R, S, HSP 

Camacho Valle MD female I, R, S HSP 

Mena Esther MD female R HSP 

Hernandez Angels PhD female R HSP 

Piera Carlos PhD male R CETIR-Cyclotron 

Ramirez Isabel PhD female R CETIR-Cyclotron 

Pavia Xavier PhD male R CETIR-Cyclotron 

Fuertes Jordi MD male R HSP 

Ato Francesc MD male R HSP 

Simó Marc MD male R CETIR-PET Unit 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Cristina Ferrer MD student female R Ignasi Carrió 

Imma Esteban MD student female R Ignasi Carrió




Organisation legal name lnstitut National de la Santé et de la Recherche Médicale 

Organisation short name INSERM 



Status 


Gender: 

Male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Charpak Serge Director, Professor male R, M Inserm 

Audinat Etienne Research Director male R CNRS 

Angulo Maria-Cécilia PhD, 

female R CNRS 

electrophysiologist 

Moreaux Laurent PhD, Optician male R, CNRS 

Ducros Mathieu PhD, Optician male R, M Inserm 

Galante Micaela Post-Doc female R Inserm 

Léobon Bertrand MD male R CHU-Toulouse 

Royer Sébastien Post-Doc male R MRC 



male or 

female 



Activities 

(JPA) 



enrolled in 

Chaigneau Emmanuelle PhD student female R Serge Charpak 

Lemeur Karim PhD student male R Etienne Audinat 

Christophe Elodie PhD student female R Serge Charpak 

Lecoq Jérôme PhD student male R Serge Charpak 

Pons Thomas PhD student male R Serge Charpak




Organisation legal name The University of Edinburgh 

Organisation short name UEDIN 


http://www.ed.ac.uk 

Last name 

First 

name(s) 


Professional Status 

Gender: 

male or 

female 



Activities 

(JPA) 

Legal name researcher's 

Employer 

Ebmeier Klaus Peter Professor male I, R, S UEDIN 

Wyper David Professor male I, R University of Glasgow 

Paterson Jim PhD, 

Head of Neuro-SPECT 

male R North Glasgow University 

Hospitals NHS Trust 

Pimlott Sally PhD, 

radiochemist 

female R North Glasgow University 


Dougall Nadine Research Fellow female I, R UEDIN 

Best Jonathan Professor Radiology male R UEDIN 

Cavanagh Jonathan MD, Senior Lecturer in male R University of Glasgow 

Psychiatry 

Hadley Donald Professor Neuroradiology 

male R University of Glasgow 

Brown Derek MD, Old Age 

Psychiatrist 

male R Greater Glasgow Primary 

Care NHS Trust 

Grossett David MD, Neurologist male R South Glasgow University 


Last name 

First 

name(s) 


University degree 

Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Lonie Jane PhD student female R Klaus Ebmeier 

Kronhaus Dina PhD student female NDI Klaus Ebmeier




Organisation legal name Klinikum of the University of Bonn (Universitätsklinikum Bonn) 

Organisation short name UKB 


http://www.meb.uni-bonn.de/fakultaet/ 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Fleischmann Bernd Director male I, M, S,R UKB 

Brandt Sebastian Post-Doc male I, R UKB 

Hashemi Toktam MD female R UKB 

Duan Yaqi MD female R MEK 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 



enrolled in 

Breitbach Martin PhD student male R Bernd Fleischmann 

Sasse Philipp MD student male R Bernd Fleischmann




Organisation legal name Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section 

Organisation short name KI 


http://www.ki.se 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Halldin Christer Professor, project male I, M, S, R KI 

coordinator 

Farde Lars Professor male I, M, S, R KI 

Gulyas Balazs Assoc. Professor male I, S, R KI 

Nordström Anna-Lena Assoc. Professor female R KI 

Andree Bengt MD male R KI 



male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 



enrolled in 

Schou Magnus PhD student male R Christer Halldin 

Seneca Nicholas PhD student male R Christer Halldin 

Liu Nancy PhD student female R Christer Halldin 

Andersson Jan PhD student male R Christer Halldin 

Sovago Judith PhD student female R Christer Halldin




Organisation legal name Commisariat à l’Energie Atomique, Program ImaGene, DSV, DRM 

Organisation short name CEA-ImaGene 

http://www-dsv.cea.fr/content/cea/d_dep/d_drm/d_shfj/d_lnt/ 


http://www-dsv.cea.fr/content/cea/d_dep/d_drm/d_shfj/d_uiibp/ 

http://www-dsv.cea.fr/content/cea/d_dep/d_drm/imagerie.htm/ 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Hantraye Philippe Director male I, R, S CNRS/CEA 

Déglon Nicole Co-Director, gene female I, R, S CEA 

transfer 

Brouillet Emmanuel PhD, animal male I, R, S CNRS/CEA 

models, PET 

Besret Laurent PhD, PET, imaging male I, R, S CNRS/CEA 

Lebon Vincent PhD, MRI/MRS male I, R, S CEA 

Delcescaux Thierry PhD, Image male R, S CEA 

processing 

Grégoire Marie-Claude PhD, Data 

female R, S CNRS/CEA 

modelling 

Dufour Noelle PhD, gene transfer female R, S CEA 

Trébossen Régine PhD, PET physicist female R, S CEA 

Comtat Claude PhD, PET physicist male R, S CEA 

Dollé Frédéric PhD, head of male R CEA 

radiochemistry 

Kunatz Bertrand PhD, radiochemist male R CEA 

Remy Philippe PhD, MD, 

neurologist 

male R CNRS/AP-HP 

Palfi Stéphane PhD, MD, 

neurosurgeon 

male R CNRS/AP-HP 

Gaura Véronique MD, neurologist female R CNRS/AP-HP 

Bonvento Gilles PhD, animal 

physiolgy 

male R CNRS/CEA 



male or 

female 



Activities 

(JPA) 



enrolled in 

Escartin Carole PhD student female R Philippe Hantraye 

Mauger Gweltas PhD student male R Philippe Hantraye 

Dauguet Julien PhD student male R Philippe Hantraye/ 

Thierry Delcescaux 

Boumezbeur Fawzi PhD student male R Vincent Lebon 

Valette Julien PhD student male R Vincent Lebon 

Dubois Albertine PhD student female R Thierry Delcescaux 

Jacquard Carine PhD student female R Emmanuel Brouillet 

Thévenot Etienne Post doctoral 

student 

male R Nicole Déglon




Organisation legal name Forschungszentrum Jülich GmbH 

Organisation short name FZJ 


http://www.fz-juelich.de 



male or 

female 

Bauer Andreas MD, neurologist, Head 

Molecular Neuroimaging 

Laboratory 

Zilles Karl Professor, Head 

Neuroscience 



Activities 

(JPA) 

male I, R, S, M FZJ 

male I, S, M FZJ 

Coenen Heinz H. Professor male I, R, M FZJ 

Dehnhardt Markus PhD, biologist male I, R, S, M FZJ 

Pietrzyk Uwe PhD, physicist, PET male I, R, S FZJ 


Matusch Andreas MD male R FZJ 

Khodaverdi Maryam PhD, physicist, PET female I, R, S FZJ 


Shah N. Jon PhD, physicist, MR male R FZJ 


Holschbach Marcus H. PhD, radiochemist male R FZJ 



male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 



enrolled in 

Posokhova Natalya MD student female R Andreas Bauer 

Langer Hartwig PhD student male R Uwe Pietrzyk




Organisation legal name Max-Planck-Institute for Neurological Research 

Organisation short name MPIfnF 


http://www.mpin-koeln.mpg.de 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Hoehn Mathias Professor, Head of male I, M, S, R MPI 

Research Unit 

Wegener Susanne MD female R MPI 

Wiedermann Dirk PhD, physicochemist 

male R MPI 

Himmelreich Uwe PhD, physicochemist 

male R MPI 

Cabrer Pedro Post-Doc male R MPI 

Mies Günter Professor male R MPI 

Weber Ralph MD male R MPI 



male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 



enrolled in 

Kandal Korinna PhD student female R Mathias Hoehn 

Wecker Stefan PhD student male R




Organisation legal name University of Maastricht 

Organisation short name UM 


http://www.unimaas.nl 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Reutelingsperger Chris Director male I, M UM/Carim 

Kenis Heidi Post-Doc female I, R UM 

Bitsch Nicole Head-technician female R UM/Carim 

Bennaghmouch Abdel Phd male R UM/Carim 

Kietselaer Bas Phd male R UM/Carim 

Hofstra Leonard MD male I, M, S, R UM/Carim 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Kietselaer Bas PhD student male R Leo Hofstra 

Bennaghmouch Abdel PhD student female R Leo Hofstra




Organisation legal name Center for Bio-Imaging, Sahlgrenska Akademin, Göteborg Universitet 

Organisation short name CBI 


http://www.swegene.org/bio_imaging 



male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Horn Michael Assoc.Prof male I, R, M, S CBI 

Ohlsson Claes Professor, scientific male I, R, M SU/SS 

manager CBI 

Bergström Göran Assoc. Prof male I, R, S HKI 

Forsell- Eva 

Professor, Head of female I, R, S SU/SS 

Aronsson 

Dept of Radiophysics 

Anderson Niklas Post-Doc male R SU/SS 

Skrtic Stanko MD male R SU/SS 

Bollano Entela MD female R HKI 

Tian Fei Post-Doc female R HKI 

Wickman Anna Post-Doc female I, R FYS, CMP 

Li-ming Gan MD male R Radfys 

Ljungberg Maria PhD physicist female R Radfys 

Larson Arne PhD physicist male R Radfys 

Orström Sven-Bertil PhD physicist male R Radfys 

Carlsson Åsa Phycisist female R Radfys 



male or 

female 



Activities 

(JPA) 



enrolled in 

Moverare Sofia PhD student female R Claes Ohlsson 

Barlind Anna PhD student female R Jörgen Isgaard 

Larsson Lisa PhD student female R Finn Waagstein 

Nyström Henrik PhD student male R Göran Bergström 

Wikström Johannes PhD student male R Göran Bergström 

Beckman Pia PhD student female R Jan Borén




Organisation legal name Centre National de la recherche Scientifique 

Organisation short name CNRS 


http://www.cnrs.fr 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Laugier Pascal PhD, Director male R CNRS 

Bridal Lori PhD, physicist female R CNRS 

Urbach Wladimir PhD, Professor male R Univ Paris V 

Correas Jean-Michel MD, PhD male R Hôpital Necker and 

Univ Paris V 

Spisar Monica Post-Doc female R Univ. Paris VI 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Ammi Azzdine PhD student male R Lori Bridal 

Kurtisovski Erol PhD student male R Wladimir Urbach




Organisation legal name Groningen University Hospital, the Netherlands 

Organisation short name AZG 


http://www.azg.nl/azg/nl 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Leenders Klaus Leonhard Professor male R, S AZG 

Laar van Teus MD male R, S AZG 

Jong de Bauke MD male S, R AZG 

Brunt Alexandra MD female S, R AZG 

Oostrom van Markus MD male S, R AZG 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Bartels Anna MD student female R Leenders 

Vries de Jeroen MD student male R Leenders 

Eshuis Silvia MD student female R Leenders 



enrolled in




Organisation legal name University Hospital Groningen, PET 

Organisation short name PET-AZG 



Status 


Gender: 

male or 

female 



Activities 

(JPA) 


Employer 

Elsinga Philip H. PhD male I,M PET-AZG 

Hendrikse N. Harry PhD male NDI PET-AZG 

Vaalburg Willem PhD, director male M PET-AZG 

Van Waarde Aren PhD male R PET-AZG 

Willemsen Antoon T.M. PhD male R PET-AZG 

Ishiwata Kiichi PhD male NDI Tokyo Metropolitan 

Institute of Gerontology




Organisation legal name Institut de Physique Nucléaire 

Organisation short name IPN 


http://iipnweb.in2p3.fr 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Mastrippolito Roland PhD. male I, M, S,R University Paris 11 

Pinot Laurent Ing. male I, R CNRS 

Lefebre Francoise Ing. female I,R CNRS 

Pain Frédéric PhD male I,R University Paris 11 

Lanièce Philippe PhD male I,R CNRS 

Gurden Hirac Biol. Dr male I,R CNRS 

Valentin Luc PhD male NDI University Paris 7 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Desbrée Aurélie PhD student female R Roland Mastrippolito




Organisation legal name University of Newcastle 

Organisation short name UNEW 


http://www.ncl.ac.uk 


Status 


Gender: 

male or 

female 

Connection 

with Joint 


Activities 

(JPA) 


Employer 

Morris Christopher Head of Unit male I, M, R, S Medical Research Council 

Molecular Biology 

Gibson Alison Laboratory female R Medical Research Council 

Scientist 

Alder Tracy Research Associate female R UNEW 

Edwardson James Director, Professor male R, M Medical Research Council 

O’Brien John Professor male R UNEW 

Firbanks Michael Research Associate male R UNEW 

Burton Emma Research Associate female R UNEW 

McKeith Ian Professor male R UNEW 

Mossman Urs Research Associate male R UNEW 

Burn David Head of Unit 

Neurology 

Kalaria Raj Professor male R UNEW 

Kenny Rose Ann Professor female R UNEW 

Polvikoski Tuomo Research Associate male R UNEW 

Male R National Health Service 

Thomas Alan Head of Unit male R National Health Service 

Psychiatry 

Piggott Margaret Research Associate female R Medical Research Council 

Perry Elaine Professor female R Medical Research Council 

Jenny Court Head of Unit female R Medical Research Council 

Perry Robert Professor male R National Health Service 

Jaros Evelyn Research Associate female R National Health Service 

Keith Alexander Research Associate male R UNEW 



male or 

female 

Connection 

with Joint 


Activities 

(JPA) 



enrolled in 

Wilson Kate BSc(Hons) female R Christopher Morris 

Colloby Sean BSc(Hons) male R John O’Brien 

Keverne Jessica BSc(Hons) female R Raj Kalaria 

Ray Melissa BSc(Hons) female R Jenny Court 

Fairlie John BSc(Hons) male R Raj Kalaria 

Miller Veronica BSc(Hons) female R Rose Ann Kenny 

Barlow Emelia BSc(Hons) female R Tuomo Polvikoski 

Stephens Sally BA female R Rose Ann Kenny




Organisation legal name Technische Universiteit Eindhoven 

Organisation short name TU/e 


http://www.tue.nl 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Nicolay Klaas Professor male I, M, S, R TU/e + MU 

Smits Jos Professor male R Maastricht University 

Meijer Bert Professor male R TU/e 

Ter Haar Romeny Bart Professor male R TU/e + MU 

Van Engelshoven Jos MD, Professor male R Maastricht University 

Strijkers Gustav PhD, physicist male R TU/e 

Prompers Jeanine PhD, chemist female R TU/e 

Florack Luc PhD, 

male R TU/e 

mathematician 

Vilanova ì Bartroli Anna PhD, physicist female R TU/e 

Van Genderen Marcel PhD, chemist male R TU/e 

Hackeng Tilman PhD, chemist male R Maastricht University 

Blankesteijn Matthijs PhD, biology male R Maastricht University 

Van Zandvoort Marc PhD, physicist male R Maastricht University 

Kooi Eline PhD, physicist female R Maastricht University 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Van Tilborg Geralda PhD student female R Klaas Nicolay 

Van der Schans Veerle PhD student female R Jos Smits 

Lutgens Suzanne PhD student female R Jos van Engelshoven 

Mulder Willem PhD student male R Klaas Nicolay 

Heijman Edwin PhD student male R Klaas Nicolay 

Langereis Sander PhD student male R Bert Meijer 

De Lussanet Quido PhD student male R Jos van Engelshoven 

Cappendijk Vincent PhD student male R Jos van Engelshoven 

Lobbes Marc PhD student male R Klaas Nicolay 

Megens Remco PhD student male R Marc van Zandvoort 

Platel Bram PhD student male R Bart ter Haar Romeny




Organisation legal name Klinikum at the University of Cologne (Medizinische Einrichtungen Koeln) 

Organisation short name MEK 


http://www.medizin.uni-koeln.de 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Nordberg Agneta Professor female I,R KI Neurotec 

Stefanova Elka Post doc female R KI Neurotec 

Almkvist Ove Assoc prof male R KI Neurotec 

Långström Bengt Professor male I, R Uppsala Imanet 

Blomqvist Gunnar Assoc prof male R Uppsala Imanet 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Forsberg Anton PhD student male R Agneta Nordberg 

Kadir Ahmadul PhD student male R Agneta Nordberg 

Engler Henry PhD student male R Bengt Långström




Organisation legal name Consiglio Nazionale delle Ricerche 

Organisation short name CNR-IBB 


http://www.cnr.it 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Brunetti Arturo Professor male I, M, S, R CNR-IBB 

Salvatore Marco Professor male I, M,S CNR-IBB-University 

Federico II 

Pappata Sabina MD female I, M, S, R CNR-IBB 

Varrone Andrea MD male R CNR-IBB 

Alfano Bruno Res Director male I, M, S, R CNR-IBB 

Quarantelli Mario MD male R CNR-IBB 

Prinster Anna Engineer female R CNR-IBB 

Larobina Michele Physicist male R CNR-IBB 

Panico Maria R Radiochemist female R CNR-IBB 

Speranza Antonio Chemical eng male R CNR-IBB 

Postiglione Alfredo Professor male R, I, S CNR-IBB + University 

Federico II 

Paternò Roberto MD male R University Federico II 

+ CNR-IBB 



degree 

Sansone Valeria Resident Nucl 

Med 

Mollica Carmine Resident 

Radiology 

Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

female R Marco Salvatore 

male R Marco Salvatore




Organisation legal name Fondazione Telethon (Institute of Genetics and Medicine, Naples) 

Organisation short name FTELE.IGEM 


www.telethon.it 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Auricchio Alberto MD male R TIGEM 

Rugarli Elena MD female R TIGEM 

Pirozzi Marinella PhD female R TIGEM 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Allocca Mariacarmela PhD student female R Alberto Auricchio




Organisation legal name Durham University 

Organisation short name DUR 


http://www.dur.ac.uk/chemistry 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Parker David Professor male I, M, S DUR 

Yu Jun Hua PhD chemist male R DUR 

Gaillard Stephane PhD male R DUR 

Dickins Rachel Sarah Research fellow female R DUR 

Fulton David Post-Doc male R DUR 

Senanayake Kanthi Post-doc female R DUR 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 



enrolled in 

Atkinson Paul PhD student male R David Parker 

Pal Robert PhD student male R David Parker 

Kielar Filip PhD student male R David Parker 

Poole Robert PhD student male R David Parker




Organisation legal name Università Vita-Salute San Raffaele 

Organisation short name UVita-P 


www.unihsr.it 


Status 


Gender: 

male or 

female 

Connection 

with Joint 


Activities 

(JPA) 


Employer 

Fazio Ferruccio Professor male M Milano-Bicocca University 

Perani Daniela Professor female I, M, S, R UVita-P 

Abutalebi Jubin MD male R, S UVita-P 

Anchisi Davide MD male R, S UVita-P 

Tettamanti Marco Post-Doc male R, S IRCCS San Raffaele Hospital 

Garibotto Valentina MD female R Milano-Bicocca University 

Cappa Stefano Professor male R, S UVita-P 

Marcone Alessandra MD female R IRCCS San Raffaele Hospital 

Zamboni Michele MD male R IRCCS San Raffaele Hospital 

Ortelli Paola MD female R UVita-P 

Gilardi Maria Carla Professor female R, S Milano-Bicocca University 

Bettinardi Valentino physic male R, S IRCCS San Raffaele Hospital 

Castiglioni Isabella physic female R IBFH-CNR 

Scifo Paola engineer female R IRCCS San Raffaele Hospital 

Rizzo Giovanna engineer female R, S IBFH-CNR 

Matarrese Mario radiochemist male R, S IBFH-CNR 

Todde Sergio radiochemist male R, S Milano-Bicocca University 

Minotti Maria Grazia radiochemist female R, S IRCCS San Raffaele Hospital 

Perugini Francesco radiochemist male R, S IRCCS San Raffaele Hospital 

Carpinelli Assunta radiochemist female R, S IBFH-CNR 

Moresco Rosa Maria pharmachologist female R Milano-Bicocca University 

Panzacchi Andrea MD male R IRCCS San Raffaele Hospital 

Belloli Sara biotechnologist female R IRCCS San Raffaele Hospital 


degree 


Gender: 

male or 

female 

Connection 

with Joint 


Activities 

(JPA) 

Organiser of course doctoral 

Student is enrolled in 

Vitali Paolo PhD student female R Stefano Cappa 

Brambati Simona PhD student female R Stefano Cappa 

Turolla Elia Anna PhD student male R Mario Matarrese 

Filannino Azzurra PhD studenti female R Mario Matarrese 

Pietra Lucia PhD student female R Rosa Maria Moresco




Organisation legal name Leiden University Medical Center 

Organisation short name LUMC 


http://www.LUMC.nl 

Last name 

First 

name(s) 


Professional Status 

Gender: 

male or 

female 

Connection 

with Joint 


Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Gittenberger-de Adriana Professor, head Anatomy female I, S, M LUMC 

Groot 

Poelmann Robert Professor, devel. biology male I, R, S, M LUMC 

project leader 

Hogers Bianca PhD, female I, S, R LUMC 

Van Ginneken Vincent Post-Doc male I, S, R LUMC 

De Groot Huub Professor physical chemistry male I, S, M University of Leiden 

Van der Maarel Johan PhD male R UL 

Kiihne Suzanne PhD female R UL 

Erkelens Kees Head of NMR facility male R, M UL 

Van der Laarse Arnoud Professor biochemistry male R, S LUMC 

Steendijk Paul PhD male R LUMC 

Van der Wall Ernst Prof Head of Cardiology male S, M LUMC 

Schalij Martin Professor cardiology male R, S, M LUMC 

Atsma Douwe cardiologist male R LUMC 

Jukema Wouter cardiologist male R LUMC 

De Roos Albert Prof Head of Radiology male S, M LUMC 

Reiber Johan Prof. Imaging male R, S, M LUMC 

Doornbos Joost PhD male R, S LUMC 

Van der Geest Rob PhD male R LUMC 

Emeis Sjef PhD male R TNO 

De Vries Antoin PhD male R LUMC 

Knaan Shosh PhD female R LUMC 

Lie-Venema Heleen PhD female R LUMC 

Havekes Louis Professor biochemistry male R, S LUMC 

Willems van Dijk Ko PhD male R LUMC 

Frants Rune Professor genetics male R, S LUMC 

Van den Arn PhD male R LUMC 

Maagdenberg 

Ferrari Michel Professor neurology male R, S LUMC 

Buchem Mark Professor radiology male R, S LUMC 

Last name 

First 

name(s) 


University degree 

Gender: 

male or 

female 

Connection 

with Joint 


Activities 

(JPA) 



enrolled in 

Van den Akker Nynke MD student female R Gittenberger-de Groot 

Eralp Ismail MD student male R Gittenberger-de Groot 

Molhoek Sander MD student male R Atsma


Van der Heiden Kim MD student female R Poelmann 

Van der Ven Rob MD student male R Frants




Organisation legal name Commissariat à ľ énergie atomique 

Organisation short name CEA 


http://www-leti.cea.fr/uk/index-uk.htm 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Rizo Philippe Lab. Director male I, R CEA/LETI 

Moy Jean-Pierre Project coord. male I, R CEA/LETI 

Peltié Philippe Project coord male I, R CEA/LETI 

Da Silva Aanabela Post-Doc female I, R CEA/LETI 

Plannat-Chrétien Anne PhD, 

female I,R CEA/LETI 

modeling 

Texier-Nogues Isabelle PhD, 

female I,R CEA/LETI 

Photochemist 

Berger Michel Optics male I,R CEA/LETI 

Rustique Emilie Cemist female I,R CEA/LETI 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Laidevant Aurélie PhD Student female R Boccara Claude




Organisation legal name Université de Liège 

Organisation short name ULG 


http://www.ulg.ac.be 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Luxen André Director male I, M, S ULg 

Salmon Eric Medical Director male I, M, S, R ULg 

Collette Fabienne Head, Cognitive female I, M, R FNRS 

Aging 

Plenevaux Alain Head, 

male I, M, S, R FNRS 


Lemaire Christian PhD male R ULg 

Delfiore Guy PhD male R Province 

Peigneux Philippe PhD male R CRC 

Lekeu Françoise PhD female R ULg 

Aerts Joël Head, Pharmacy male R CRC 

Cantarini Claudia PhD female R CRC 

Mela Christine PhD female R CRC 

Degueldre Christian Responsible PET male R CRC 

Phillips Christophe PhD male R FNRS 

Majerus Steve PhD male R FNRS 

Lassance Damien Responsible, QA male R CRC 

Garraux Gaëtan PhD male R FNRS 

Laureys Steve Phd male R FNRS 



male or 

female 



Activities 

(JPA) 



enrolled in 

Baltiau Evelyne PhD student female NDI A. Luxen 

Defraiteur Caroline PhD student female R A. Luxen 

Hogge Michael PhD student male R F. Collette 

Wouters Ludovic PhD Student male R A. Luxen 

Brichard Laurent PhD Student male R A. Luxen 

Peeters Frederic PhD student male R F. Collette




Organisation legal name Universitätsklinikum Münster 

Organisation short name UKM 


http://www.nuklearmedizin.uni-muenster.de 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Schäfers Michael Professor, project male I, M, S, R UKM 

coordinator 

Levkau Bodo Professor male I, M, S, R University of Essen 

Schober Otmar Head Nuclear male S, R UKM 

Medicine 

Schäfers Klaus PhD male M, S, R UKM 

Kopka Klaus PhD male R UKM 

Wagner Stefan PhD male R UKM 

Breyholz Hans-Jörg PhD male I, M, S, R UKM 

Theilmeier Gregor MD male NDI UKM 

Law Marilyn BSc female M, R UKM 

Riemann Burkhard MD male R UKM 



male or 

female 



Activities 

(JPA) 



enrolled in 

Range Felix MD student male R Michael Schäfers 

Hoffmeier Anne-Nadine MD student female R Michael Schäfers 

Papavassilis Philipp MD student male R Michael Schäfers 

Dawood Mohammed PhD student male R Klaus Schäfers




Organisation legal name University of Muenster 

Organisation short name UKM 


http://medweb.uni-muenster.de/institute/ikr 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Heindel Walter Director male I, M UKM 

Bremer Christoph MD, project male I, R, M, S UKM 

coordinator 

von Wallbrunn Angelika PhD, Molecular female I, R, M, S UKM 

Biologist 

Höltke Carsten PhD, Radiochemist male I, S, R UKM 

Faust Andreas PhD, Biochemist male I, S, R UKM 

Matuszewski Lars MD, Radiologist male I, R UKM 

Wall Alexander MD, Radiologist male I, R UKM 

Persigehl Thorsten MD, Radiologist male I, R UKM 



male or 

female 



Activities 

(JPA) 



enrolled in 

Kuhlpeter Rebekka MD student female R Christoph Bremer 

Eisenblätter Michel MD student male R Christoph Bremer




Organisation legal name Katholieke Universiteit Leuven, Nuclear Medicine and Radiopharmacy 

Organisation short name KUL 


http://www.kuleuven.ac.be/nucmed/ 



male or 

female 

Connection 

with Joint 


Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Mortelmans Luc Department Head male R,S,M UZ Leuven/KUL 

Van Laere Koenraad MD PhD DSc, coordinator male R,I,M UZ Leuven/KUL 

Nuclear Medicine 

Verbruggen Alfons Professor head 

male R, I, M, S KUL 

radiopharmacy 

Bormans Guy Professor, radiopharmacy male I, M, S, R KUL 

De Groot Tjibbe PhD, chemist male R UZ Leuven 

Van Billoen Bert PhD, radiopharmacy male R UZ Leuven 

Rattat Dirk PhD, chemist male R KUL 

Nuyts Johan Professor, engineer male R KUL 

Dupont Patrick PhD, physicist male R KUL 

Vandenberghe Rik MD PhD male R UZ Leuven/KUL 

Dom René Professor, Neurology male R UZ Leuven/KUL 

De Cuyper Marcel Professor, engineer male R KUL/KULAK 

Noppe Wim PhD male R KUL/KULAK 



male or 

female 

Connection 

with Joint 


Activities 

(JPA) 



enrolled in 

Deroose Christophe MD; PhD student male R Luc Mortelmans 

Van den Eynden Jimmy MD; PhD student male R Koen Van Laere 

Bequé Dirk PhD student male R Johan Nuyts 

Baete Kristof PhD student male R Patrick Dupont 

Vanderghinste Dominique PhD student male R Alfons Verbruggen 

Verduyckt Tom PhD Student male R Guy Bormans 

Kieffer Davy PhD student male R Alfons Verbruggen 

Fonge Humphrey PhD Student male R Alfons Verbruggen 

Kumar Satish PhD Student male R Alfons Verbruggen 

Vandenbulcke Matthieu MD; PhD student male R Rik Vandenberghe 

Goffin Karolien MD; PhD student female R Koen Van Laere




Organisation legal name Cyceron 

Organisation short name CYM 


http://www.cyceron.fr 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Mazoyer Bernard Professor male I, M, S University/CNRS/CEA 

Barré Louisa Director female I, M, S CEA/CNRS 

Eustache Francis Director male I, M, S DE EPHE, Inserm 

MacKenzie Eric Director male I, M, S, CNRS 

Sobrio Franck PhD male R CEA 

Perrio Cecile PhD female M, R CNRS 

Gourand Fabienne Ingineer female R CEA 

Desgranges Beatrice PhD female R Inserm 

Chetelat Gael PhD female R Inserm 

Crivello Fabrice PhD male R CEA 

Jolliot Marc PhD male R CEA 

Petit Laurent PhD male R CEA 

Buisson Alains Professor male I, M, R University/CNRS 

Vivien Denis Professor male I, M, R University/CNRS 

Touzani Omar phD male R University/CNRS 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Kalpouzos Gregoria PhD student female R Francis Eustache 

Guillaume Cécile MD student female R Francis Eustaches 

Herve Pierre-yves MD student male R Bernard Mazoyer 

Beaucousin Virgine PhD student female R Bernard Mazoyer 

Castel Hervé PhD student male R Denis Vivien 

Leblond Clothilde MD student female R Omar Touzani




Organisation legal name MiceTech 

Organisation short name MT 



Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Carlsen Harald Post-doc male I, R, S, M MT/UiO 

Moskaug Jan Oivind Assistant male R MT/UiO 

professor 

Ebihara Kanae Post-doc female R MT/UiO




Organisation legal name Universidad de Navarra - Fundación Para La Investigación Médica Aplicada 

Organisation short name UNAV-FIMA 


http://www.unav.es/neurologia/neurology/default.html 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Masdeu Joseph Director male M, S, R Clínica Univ. Navarra 

Pastor Maria MD, PhD female R Clínica Univ. Navarra 

Arbizu Javier MD male R Clínica Univ. Navarra 

Martínez-Lage Pablo MD male R Clínica Univ. Navarra 

Penuelas Ivan PhD, radiochemist male R Clínica Univ. Navarra 

Zubieta Jose Luis MD male R Clínica Univ. Navarra 



male or 

female 



Activities 

(JPA) 



enrolled in 

Lamet Gil Isabel PhD student female R Joseph Masdeu 

Reynoso Cesar Alberto PhD student male R Joseph Masdeu




Organisation legal name Laboratoire Biophysique Médicale et pharmaceutique, Université de Tours 

Organisation short name UnivTours 



Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Benderbous Soraya Professor female R University 

Nadal-Desbarats Lydie PhD female R University 

Ouahabi Abdeljalil Professor male R University 

Barantin Laurent PhD male R University 

Lejeune Bernard PhD male R University 

Beloeil Jean-Claude Research Dir male R CNRS 

Bich Thuy Doan PhD female R CNRS 

Szeremeta Frederic PhD male R CNRS 

Meme Sandra PhD female R CNRS 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Kribeche Ali PhD Student male R S Benderbous 

Brahimi Yacine PhD Student male R S Benderbous




Organisation legal name CYCLOPHARMA Laboratoires 

Organisation short name Cyclopharma 


www.cyclopharma.fr 



male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Deloye Jean Bernard General Manager male M S Cyclopharma 

Askienazy Serge Professor male R S Cyclopharma 

Viot Gilles Application Manager male R I Cyclopharma 

Lambert Elisa Regulatory Affairs female M S Cyclopharma




Organisation legal name medres – medical research GmbH 

Organisation short name medres 


http://www.medres.de 



male or 

female 

Connection 

with Joint 


Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Wecker Stefan Head of the company male I, R medres – medical 

research GmbH 

Radermacher Bernd R&D male R medres – medical 

research GmbH




Organisation legal name Visgenyx Ltd 

Organisation short name Visgenyx 


http://www.visgenyx.com 



male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Vasar Eero Head of Board, 


male I, M, S Visgenyx + Univ of 

Tartu 

Karis Alar Member of Board, 


male I, M, S Visgenyx + Agricult 

Univ of Tartu 

Kõks Sulev CSO, sen res male I, M, S, R Visgenyx + Univ of 

Tartu 

Võikar Vootele Post-Doc male I, S, R Visgenyx + Univ of 

Tartu 

Plaas Mario injectionist male R Visgenyx 

Talts Kaia researcher female R Visgenyx 

Meier Riho senior res male R Visgenyx 



male or 

female 



Activities 

(JPA) 



enrolled in 

Tõnissoo Tambet PhD student male R Alar Karis 

Abramov Urho PhD student male R Eero Vasar 

Kurrikoff Kaido PhD student male R Sulev Kõks 

Luuk Hendrik PhD student male R Sulev Kõks 

Areda Tarmo PhD student male R Eero Vasar 

Philips Mari-Anne PhD student female R Sulev Kõks 

Raud Sirli PhD student female R Eero Vasar 

Koido Kati PhD student female R Sulev Kõks




Organisation legal name Universita Karlova, Charles University, Faculty of Science) 

Organisation short name Charles University 


http://www.natur.cuni.cz/~petrh/19.htm 



male or 

female 

Connection 

with Joint 


Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Lukes Ivan Professor of inorganic male R, M Charles University 

chemistry 

Hermann Petr PhD, doz. male R Charles University 

Kotek Jan PhD male R Charles University 

Trnka Tomas Professor, organic chemistry male R Charles University 

Polakova Jana PhD female R Charles University 

Kubicek Vojtech M.Sc. male R Charles University 



male or 

female 

Connection 

with Joint 


Activities 

(JPA) 



enrolled in 

Polasek Milos PhD student male R Petr Hermann 

Rudovsky Jakub PhD student male R Ivan Lukes 

Foerstrova Michaela PhD student female R Ivan Lukes 

Vitha Tomas PhD student male R Petr Hermann




Organisation legal name Radioisotope Centre POLATOM, Otwock – Swierk, Poland 

Organisation short name POLATOM 


http://www.polatom.pl 


Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Mikolajczak Renata Director female I, R, M, S POLATOM 

Byszewska- Ewa PhD female I, R, S POLATOM 

Szpocinska 

Michalik Joanna PhD female I, M, S, R POLATOM 

Parus Joseph L. Prof. Dr male I, M, S, R POLATOM 

Karczmarczyk Urszula PhD female R, S POLATOM 

Iller Edward PhD male R, M POLATOM 

Janota Barbara MSc female I, R, S POLATOM 

Korsak Agnieszka MSc female I, R POLATOM 

Kulicki Pawl technologist male R, S POLATOM 

Jakubowska Elzbieta technologist female R POLATOM 

Wawryniuk Tomasz MSC male R POLATOM 

Sasinowska Iwona MSc female R POLATOM 


degree 


Gender: 

male or 

female 



Activities 

(JPA) 



enrolled in 

Edyta Zakrzewskaa PhD student female R Joanna Michalik 

Izabela Cieszykowska PhD student female R Mieczyslaw Mielcarski 

Pawlak Dariuszs PhD student male R Edward Iller




Organisation legal name Institute of Experimental Medicine, Academy of Sciences of the Czech Republic 

Organisation short name IEM ASCR 


http://uemweb.biomed.cas.cz 



male or 

female 

Connection 

with Joint 


Activities 

(JPA) 


Employer 

Sykova Eva Professor, Research female I, R, S, M IEM ASCR 

Director, MD 

Chvatal Alexandr Assoc. Prof. male R IEM ASCR 

Jendelova Pavla Head of research unit female R, S IEM ASCR 

Anderova Miroslava Post-Doc female R IEM ASCR 

Vargova Lydia Post-Doc, MD female R IEM ASCR 

Hajek Milan Head of research unit male I, R, S Institute for Clinical and 

Experimental Medicine 

Saudek Frantisek Head of research unit, 

MD 

male R, S Institute for Clinical and 


Tintera Jaroslav Post-Doc male R Institute for Clinical and 


Herynek Vit Post-Doc male R Institute for Clinical and 


Dezortova Monika Post-Doc female R Institute for Clinical and 




male or 

female 

Connection 

with Joint 


Activities 

(JPA) 



enrolled in 

Andersson Benita PhD student female R Eva Sykova 

Lesny Petr PhD student male R Eva Sykova 

Homola Ales PhD student male R Eva Sykova 

Glogarova Katerina PhD student female R Eva Sykova 

Urdzikova Lucia PhD student female R Eva Sykova 

Slais Karel PhD student male R Eva Sykova 

Jirak Daniel PhD student male R Milan Hajek 

Burian Martin PhD student male R Milan Hajek 

Dolezal Jiri PhD student male R Milan Hajek 

Skoch Antonín PhD student male R Milan Hajek 

Girman Petr PhD student male R Frantisek Saudek 

Kriz Jan PhD student male R Frantisek Saudek 

Berkova Zuzana PhD student female R Frantisek Saudek 

Slavickova Klara PhD student female R Frantisek Saudek 

Koblas Tomas PhD student male R Frantisek Saudek




Organisation legal name Image Guided Therapy SA 

Organisation short name IGT 



Status 


Gender: 

male or 

female 



Activities 

(JPA) 

Dumont Erik PhD, Research male M,R IGT 

Director 

Quesson Bruno PhD, physicist male R IGT 



male or 

female 



Activities 

(JPA) 

Legal name 

researcher's 

Employer 

Organiser of 

course doctoral 

Student is enrolled 

in 

Dennis de Senneville Baudouin PhD student male R Pascal Desbarats 

Kabongo Luis PhD student male R Pascal Desbarats

Annex I - âDescription of Workâ - European Society for Molecular ...

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Annex I - âDescription of Workâ - European Society for Molecular ...