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PET Studies of Neuroendcrine Tumors by
Using 76 Br-m-Bromobenzylguanidine ( 76 Br-MBBG)
Sh. Watanabe a) , H. Hanaoka b) , J. X. Liang a) , Y. Iida b) , Sa. Watanabe a) ,
K. Endo b) and N. S. Ishioka a)
a) Radiation-Applied Biology Division, QuBS, JAEA,
b) Graduate School of Medicine, Gunma University
Introduction
131 I-m-Iodobenzylgunanidine ( 131 I-MIBG), functional
analogue of norepinephrine, has been employed for the
therapy of neuroendcrine tumors which express
norepinephrine transporter (NET). 123 I-MIBG scintigraphy
has been also used for diagnosis of NET positive tumors
such as detecting metastasis, investigating suitability and
monitoring response to the treatment with 131 I-MIBG.
However, 123 I-MIBG scintigraphy has limitation to diagnose
small legions due to lower sensitivity and resolution. Since
positron emission tomography (PET) is superior to spatial
resolution and quantitative capability compared to
scintigraphy, positron emitter labeled MIBG has potential to
improve diagnostic ability of NET positive neuroendcrine
tumors. Then, we have reveal the utility of positron emitter
76 Br (t1/2 = 16.1 h, + = 57% labeled m-bromobenzyl-
guanidine ( 76 Br-MBBG) as a PET tracer for NET positive
tumor. In this study, we have performed PET imaging by
using 76 Br-MBBG and 18 F-FDG.
Materials and Methods
No-carrier-added 76 Br was produced using enriched
Cu2 76 Se target (99.7% enrichment, 365 mg) at
76
JAEA-TIARA AVF cyclotron. Br-MBBG was
synthesized from MIBG in the presence of in situ generated
Cu + catalyst 2) . Characterization was carried out with
HPLC analysis. (Mobile phase: 15% acetonitrile in 0.01 M
Na2HPO4 solution; Flow rate: 3 mL/min.; Column:
μBondapak C-18 300 mm × 7.6 mm i.d., Waters). For PET
studies, rat pheochromocytoma (PC-12) xenografted mice
were intravenously administered 5 MBq of FDG. The
mice were anesthetized with sodium pentobarbital solution,
and PET scans were performed at 1 h after administration by
using an animal PET scanner (Inveon; Siemens) with 20 min
emission scanning. Two days after FDG-PET, the
tumor-bearing mice were intravenously administered 7 MBq
76
of Br-MBBG and also anesthetized with sodium
pentobarbital solution. PET scans were then performed at
1 h, 3 h, and 6 h after administration.
Results and Discussions
76 Br-MBBG was synthesized with 20-50% of labeling
efficiency. Retention time of 76 Br-MBBG in HPLC
analysis was 27 min, which are identical to non-radioactive
MBBG. Radiochemical purity was >97%. Animal PET
demonstrated that the transplanted PC-12 tumor was
successfully imaged at 3 h after administration (Fig. 1).
In mouse A, high accumulation was also observed at this
time point in the bladder, after which 76 Br-MBBG was
gradually cleared from these non- target organs. On the
other hand, FDG failed to detect an even larger tumor.
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In mouse B, however, there were two tumors which showed
differential uptake of 76 Br-MBBG and FDG. That is,
76 Br-MBBG showed high accumulation in the lower tumor,
but FDG showed high accumulation in the upper tumor
(Fig. 1B). Animal PET studies demonstrated that
76 Br-MBBG could image NET expressing tumors clearly at
3 h after administration. The accumulation patterns of
MBBG and FDG in the tumors differed from mouse to
mouse and even from lesion to lesion within individual
animals. Histological staining of the excised tumors after
PET studies indicated that MBBG-strong and FDG-weak
tumors were well-differentiated and MBBG-weak and
FDG-strong tumors were poorly differentiated, which agrees
well with the clinical data. Thus, the variation of tumor
differentiation was considered to have contributed to the
variation in the accumulation level of MBBG.
Conclusion
In the present study, MBBG showed a higher level of
tumor accumulation than MIBG. In PET studies, MBBG
provided a clear image with high sensitivity, and its
accumulation pattern was distinct from that of FDG. These
results indicated that 76 Br-MBBG would be a potential tracer
for imaging NET-expressing neuroendocrine tumors.
Fig. 1 PET imaging of PC-12 xenografted nude-mice
A and B by using 76 Br-MBBG and 18 F-FDG. Yellow
allows indicate the position of xenografted tumor, and
red allows show the tumor detected by PET imaging.
References
1) S. Watanabe et al., JAEA Takasaki Ann. Rep. 2008
(2009) 107.
2) S. Watanabe et al., J. Nucl. Med. (2010) in press.