Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos" , GR-153 10 Athens, Greece.
J Med Chem. 2013 Nov 14;56(21):8579-87. doi: 10.1021/jm4010237. Epub 2013 Oct 23.
Radiolabeled analogs of the frog tetradecapeptide bombesin (BBN) have been proposed for diagnosis and therapy of gastrin releasing peptide receptor (GRPR)-expressing tumors. Following a different and yet unexplored approach, we have developed four novel (111)In-labeled truncated analogs of the human 27-mer GRP after conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) at the N-terminus of GRP(13/14/17/18-27) fragments. Analog affinities for the human GRPR determined against [(125)I-Tyr(4)]BBN were at the nanomolar level and dependent on truncation site. The respective (111)In radioligands specifically internalized in GRPR-expressing PC-3 cells. The shorter chain [(111)In-DOTA]GRP(17/18-27) analogs showed higher metabolic stability in mice. Radioligands specifically localized in human PC-3 xenografts in SCID mice, with [(111)In-DOTA]GRP(17-27) exhibiting the most favorable pharmacokinetic profile. This study has demonstrated the efficacy of human GRP-based radiopeptides to target GRPR-positive lesions in vivo and has revealed the impact of GRP chain length on key biological parameters of resulting radiotracers.
蛙十四肽缩胆囊素（BBN）的放射性标记类似物已被提议用于胃泌素释放肽受体（GRPR）表达肿瘤的诊断和治疗。采用一种不同且尚未探索的方法，我们在 GRP（13/14/17/18-27）片段的 N 末端缀合了 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）后，开发了四个新型的（111）In 标记的人 27 肽 GRP 截断类似物。针对 [(125)I-Tyr(4)]BBN 测定的人 GRPR 亲和力为纳摩尔级，并且依赖于截断位点。相应的（111）In 放射性配体特异性地在表达 GRPR 的 PC-3 细胞中内化。较短链 [(111)In-DOTA]GRP(17/18-27)类似物在小鼠中表现出更高的代谢稳定性。放射性配体特异性地定位于 SCID 小鼠中的人 PC-3 异种移植物中，其中 [(111)In-DOTA]GRP(17-27)表现出最有利的药代动力学特征。这项研究证明了基于人 GRP 的放射性肽能够在体内靶向 GRPR 阳性病变，并揭示了 GRP 链长对所得放射性示踪剂关键生物学参数的影响。
