PET Imaging of Norepinephrine Transporter-Expressing Tumors Using 76Br-meta-Bromobenzylguanidine
PET Imaging of Norepinephrine Transporter-Expressing Tumors Using 76Br-meta-Bromobenzylguanidine
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DOI：
10.2967/jnumed.110.075465
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发表时间：
2010-09-01
影响因子：
9.3
通讯作者：
Ishioka, Noriko S.
中科院分区：
文献类型：
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作者：
Watanabe, Shigeki;Hanaoka, Hirofumi;Ishioka, Noriko S.
碘-123或碘-131标记的间碘苄胍（MIBG）已广泛用于去甲肾上腺素转运蛋白（NET）表达肿瘤的诊断和放射治疗。然而，由于I-123/I-131-MIBG的空间分辨率低于PET示踪剂，因此其在检测小病变方面存在局限性。在这项研究中，间溴苄基胍（MBBG）标记的Br-76（半衰期，16.1小时），一个有吸引力的正电子发射体，制备和评价作为一个潜在的PET示踪剂成像NET表达肿瘤。方法：以溴化76为原料，与非放射性碘代异丁基胍（MIBG）中的碘进行卤素交换反应，制备溴化76-甲基异丁基胍（Br-76-MBBG）。采用高效液相色谱法对MBBG的体内外稳定性进行了评价。在NET阳性PC-12细胞系中进行了有或无NET抑制剂的细胞摄取研究。通过给予MBBG、MIBG和F-18-FDG的混合溶液，在PC-12荷瘤裸鼠中进行生物分布研究。使用Br-76-MBBG和F-18-FDG用小动物PET扫描仪对肿瘤进行成像。结果：MBBG在体外稳定，但在小鼠体内给药后观察到一定的时间依赖性脱卤。MBBG在PC-12肿瘤细胞中显示出高摄取，其通过添加NET抑制剂而显著降低。在生物分布研究中，MBBG显示出高肿瘤蓄积（给药后3小时，每克注射剂量为32.0 +/-18.6%），给药后3小时，肿瘤-血液比高达54.4 +/- 31.9。肿瘤对MBBG的摄取与对MIBG的摄取呈良好的相关性（r = 0.997），而与对F-18-FDG的摄取无相关性。Br-76-MBBG PET显示移植瘤图像清晰，灵敏度高，与F-18-FDG PET显示的病灶不同。结论：Br-76-MBBG显示高肿瘤蓄积，其与MIBG具有良好的相关性，并且提供了清晰的PET图像。这些结果表明，Br-76-MBBG将是一种潜在的PET示踪剂，用于成像NET表达的神经内分泌肿瘤，并可为确定I-131-MIBG治疗的适应症提供有用的信息。
Meta-iodobenzylguanidine (MIBG) labeled with I-123 or I-131 has been widely used for the diagnosis and radiotherapy of norepinephrine transporter (NET)-expressing tumors. However, I-123/I-131-MIBG has limitations for detecting small lesions because of its lower spatial resolution than PET tracers. In this study, meta-bromobenzylguanidine (MBBG) labeled with Br-76 (half-life, 16.1 h), an attractive positron emitter, was prepared and evaluated as a potential PET tracer for imaging NET-expressing tumors. Methods: Br-76-MBBG was prepared by a halogen-exchange reaction between the Br-76 and iodine of non-radioactive 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 F-18-FDG. The tumor was imaged using Br-76-MBBG and F-18-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 F-18-FDG. Br-76-MBBG PET showed a clear image of the transplanted tumor, with high sensitivity, which was different from the lesion shown by F-18-FDG PET. Conclusion: Br-76-MBBG showed high tumor accumulation, which correlated well with that of MIBG, and provided a clear PET image. These results indicated that Br-76-MBBG would be a potential PET tracer for imaging NET-expressing neuroendocrine tumors and could provide useful information for determining the indications for I-131-MIBG therapy.