PET imaging of norepinephrine transporter-expressing tumors using 76Br-meta-bromobenzylguanidine.
Meta-iodobenzylguanidine (MIBG) labeled with (123)I or (131)I has been widely used for the diagnosis and radiotherapy of norepinephrine transporter (NET)-expressing tumors. However, (123)I/(131)I-MIBG has limitations for detecting small lesions because of its lower spatial resolution than PET tracers. In this study, meta-bromobenzylguanidine (MBBG) labeled with (76)Br (half-life, 16.1 h), an attractive positron emitter, was prepared and evaluated as a potential PET tracer for imaging NET-expressing tumors.


METHODS
(76)Br-MBBG was prepared by a halogen-exchange reaction between the (76)Br and iodine of nonradioactive MIBG. The stability of MBBG was evaluated in vitro and in vivo by high-performance liquid chromatography analysis. Cellular uptake studies with or without NET inhibitors were performed in NET-positive PC-12 cell lines. Biodistribution studies were performed in PC-12 tumor-bearing nude mice by administration of a mixed solution of MBBG, MIBG, and (18)F-FDG. The tumor was imaged using (76)Br-MBBG and (18)F-FDG with a small-animal PET scanner.


RESULTS
MBBG was stable in vitro, but some time-dependent dehalogenation was observed after administration in mice. MBBG showed high uptake in PC-12 tumor cells that was significantly decreased by the addition of NET inhibitors. In biodistribution studies, MBBG showed high tumor accumulation (32.0 +/- 18.6 percentage injected dose per gram at 3 h after administration), and the tumor-to-blood ratio reached as high as 54.4 +/- 31.9 at 3 h after administration. The tumor uptake of MBBG correlated well with that of MIBG (r = 0.997) but not with that of (18)F-FDG. (76)Br-MBBG PET showed a clear image of the transplanted tumor, with high sensitivity, which was different from the lesion shown by (18)F-FDG PET.


CONCLUSIONS
(76)Br-MBBG showed high tumor accumulation, which correlated well with that of MIBG, and provided a clear PET image. These results indicated that (76)Br-MBBG would be a potential PET tracer for imaging NET-expressing neuroendocrine tumors and could provide useful information for determining the indications for (131)I-MIBG therapy.
Watanabe
Shigeki
S
Quantum Beam Science Directorate, Japan Atomic Energy Agency, Takasaki, Gunma, Japan. watanabe.shigeki@jaea.go.jp
Hanaoka
Hirofumi
H
Liang
Ji Xin
JX
Iida
Yasuhiko
Y
Endo
Keigo
K
Ishioka
Noriko S
NS
D000818:Animals; D001692:Biological Transport; D001969:Bromobenzenes / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D019788:Fluorodeoxyglucose F18; D015972:Gene Expression Regulation, Neoplastic; D006146:Guanidines / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016716:PC12 Cells; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D011941:Receptors, Adrenergic / Q000378:metabolism*
D001969:Bromobenzenes; D006146:Guanidines; D011941:Receptors, Adrenergic; D019788:Fluorodeoxyglucose F18; C083603:3-bromobenzylguanidine