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UNLABELLED Radiolabeled amino acids are superior PET tracers for the imaging of malignant tumors, and amino acids labeled with (76)Br, an attractive positron emitter because of its relatively long half-life (16.2 h), could potentially be a widely usable tumor imaging tracer. In this study, in consideration of its stability and tumor specificity, we designed two (76)Br-labeled amino acid derivatives, 2-(76)Br-bromo-α-methyl-l-phenylalanine (2-(76)Br-BAMP) and 4-(76)Br-bromo-α-methyl-l-phenylalanine (4-(76)Br-BAMP), and investigated their potential as tumor imaging agents. METHODS Both (76)Br- and (77)Br-labeled amino acid derivatives were prepared. We performed in vitro and in vivo stability studies and cellular uptake studies using the LS180 colon adenocarcinoma cell line. Biodistribution studies in normal mice and in LS180 tumor-bearing mice were performed, and the tumors were imaged with a small-animal PET scanner. RESULTS Both (77)Br-BAMPs were stable in the plasma and in the murine body. Although both (77)Br-BAMPs were taken up by LS180 cells and the uptake was inhibited by L-type amino acid transporter 1 inhibitors, 2-(77)Br-BAMP exhibited higher uptake than 4-(77)Br-BAMP. In the biodistribution studies, 2-(77)Br-BAMP showed more rapid blood clearance and lower renal accumulation than 4-(77)Br-BAMP. More than 90% of the injected radioactivity was excreted in the urine by 6 h after the injection of 2-(77)Br-BAMP. High tumor accumulation of 2-(77)Br-BAMP was observed in tumor-bearing mice, and PET imaging with 2-(76)Br-BAMP enabled clear visualization of the tumors. CONCLUSION 2-(77)Br-BAMP exhibited preferred pharmacokinetics and high LS180 tumor accumulation, and 2-(76)Br-BAMP enabled clear visualization of the tumors by PET imaging. These findings suggest that 2-(76)Br-BAMP could constitute a potential new PET tracer for tumor imaging and may eventually enable the wider use of amino acid tracers.

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.(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.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.(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.