Synthesis and evaluation of 76Br labeled compound for tumor diagnosis with PET

13 <18>F-FDG是PET诊断肿瘤最有价值的工具，但13 F-FDG<18>因其半衰期短（110分钟）而被限制使用。通常，半衰期长的放射性药物使用方便。目前用于PET诊断的正电子发射体都不适合标记抗体。与这些放射性核素相比，~（13）<76>Br和~<64>（13）Cu具有合适的性质（~（13）<76>Br：T_（1/2）= 16.1hr，~（13）<64>Cu：T_（1/2）= 12.7hr），在免疫PET中有很大的应用潜力。~<76>（13）Br或~<64>（13）Cu标记的抗体适用于肿瘤诊断。特别地，^<76>Br是放射性卤素，例如^<18>F或^<123>I，并且其适合于标记为用^ F或^ I标记而开发的各种化合物<18><123>。因此，我们希望开发出用于PET肿瘤诊断的~（14）Br标记放射性药物<76>。本研究合成了抗CD 20单克隆抗体NuB 2，并对其进行了溴<76>化或<64>铜化标记，以评价其在肿瘤诊断中的应用价值。直接 ...更多信息 与蛋白质的碘化类似的溴化已被用于<76>NuB 2的^ Br标记。为了用12 Cu标记<64>，通过使NuB 2与1，4，8，11-四氮杂环十四烷-N，N '，N'，N '-四乙酸（TETA）反应来制备稳定的免疫缀合物，TETA是一种对12 Cu表现出高亲和力的螯合剂<64>。对于小动物中的体内生物分布和肿瘤定位研究，制备13 <76>Br或13 <64>Cu标记的NuB 2并施用于携带CD 20+肿瘤的SCID小鼠。我们还在注射放射性标记的NuB 2后24小时用PET进行成像研究。放射化学产率<76>为10%左右，<64>Cu-TETA-NuB 2为90%左右。肿瘤定位研究的结果表明，两种化合物的肿瘤放射性浓度在整个实验过程中稳定增加，并且在第2天达到10%剂量/g（对于15 <76>Br-NuB 2）和13%剂量/g（对于15 <64>Cu-TETA-NuB 2）。PET研究也获得了相同的结果。在这项研究中，我们成功地制备了用于PET的放射性标记的mAb，对CD 20+肿瘤表现出高亲和力。~<76>（13）Br-NuB_2和~<64>（13）Cu-TETA-NuB_2在肿瘤中高度蓄积，PET能清晰显示这些图像，与离体研究结果一致。肿瘤对4 Br-NuB 2的摄取<76>低于对4Cu-TETA<64>-NuB 2的摄取似乎是由于脱卤作用。从这些数据来看，用于免疫PET的^<76>Br和^<64>Cu在肿瘤诊断中具有很大的潜力。少

^<18>F-FDG is most valuable tool for tumor diagnosis with PET, but ^<18> F is limited to use for its short half-life, 110 minutes. Usually, radiopharmaceuticals with long half-life are convenient to use. All positron emitters, now using for PET diagnosis, don't suit for labeling of antibody. Compared with these radionuclides, ^<76> Br and ^<64> Cu have appropriate properties ( ^<76> Br: T_<1/2> = 16.1hr, ^<64> Cu: T_1/2 = 12.7hr) and they may have great potentials for immuno-PET. ^<76> Br or ^<64> Cu labeled antibody is suitable for tumor diagnosis. Especially, ^<76> Br is a radioactive halogen such as ^<18> F or ^<123> I, and it is suitable for labeling of various compounds developed for labeling with ^<18> F or ^<123> I. So we hoped to develop radiopharmaceuticals labeled with ^<76> Br for tumor diagnosis with PET. In this study, we synthesized anti-CD20 monoclonal antibody (mAb), NuB2, labeled with ^<76> Br or ^<64> Cu, and evaluated potential for in vivo diagnosis of tumor. Direct … More bromination similar with iodination of proteins has been applied for ^<76> Br labeling of NuB2. For labeling with ^<64> Cu, a stable immunoconjugate was prepared by reacting NuB2 with 1, 4, 8, 11-tetraazacyclotetradecan-N, N', N', N'-tetraacetic acid (TETA), a chelator exhibiting high affinity for ^<64> Cu. For in vivo biodistribution and tumor localization studies in small animals, ^<76> Br or ^<64> Cu labeled NuB2 was prepared and administered to SCID mice bearing CD20+ tumor. We also performed imaging study with PET at 24hr after injection of radiolabeled NuB2. Radiochemical yield of ^<76> Br-NuB2 was approximately 10 % and that of ^<64> Cu-TETA-NuB2 was approximately 90 %. The results of tumor localization studies show that the tumor concentration of radioactivity increased steadily throughout the course of experiment for both compounds, and reached to 10 %dose/g for ^<76> Br-NuB2 and 13 %dose/g for ^<64> Cu-TETA-NuB2 at 2 days. Same results were also obtained from PET studies. In this study, we successfully prepared radiolabeled mAbs for PET, exhibiting high affinity for CD20+ tumor. ^<76> Br-NuB2 and ^<64> Cu-TETA-NuB2 were highly accumulated to tumor, and PET could show these images clearly, which were same results with ex vivo studies. Lower tumor uptake of ^<76> Br-NuB2 than that of ^<64> Cu-TETA-NuB2 seems to be owing to dehalogenation. From these data, the use of ^<76> Br and ^<64> Cu for immuno-PET has great potential for tumor diagnosis. Less