Molecular Radiopharmacy, Institute of Radioisotopes-Radiodiagnostic Products, National Center for Scientific Research Demokritos, Ag. Paraskevi Attikis, GR-153 10 Athens, Greece.
J Med Chem. 2012 Oct 11;55(19):8364-74. doi: 10.1021/jm300741f. Epub 2012 Sep 26.
The synthesis and preclinical evaluation of [(99m)Tc]Demomedin C in GRPR-expressing models are reported. Demomedin C resulted by coupling a Boc-protected N(4)-chelator to neuromedin C (human GRP(18-27)), which, after (99m)Tc-labeling, afforded [(99m)Tc]Demomedin C. Demomedin C showed high affinity and selectivity for the GRPR during receptor autoradiography on human cancer samples (IC(50) in nM: GRPR, 1.4 ± 0.2; NMBR, 106 ± 18; and BB(3)R, >1000). It triggered GRPR internalization in HEK-GRPR cells and Ca(2+) release in PC-3 cells (EC(50) = 1.3 nM). [(99m)Tc]Demomedin C rapidly and specifically internalized at 37 °C in PC-3 cells and was stable in mouse plasma. [(99m)Tc]Demomedin C efficiently and specifically localized in human PC-3 implants in mice (9.84 ± 0.81%ID/g at 1 h pi; 6.36 ± 0.85%ID/g at 4 h pi, and 0.41 ± 0.07%ID/g at 4 h pi block). Thus, human GRP-based radioligands, such as [(99m)Tc]Demomedin C, can successfully target GRPR-expressing human tumors in vivo while displaying attractive biological features--e.g. higher GRPR-selectivity--vs their frog-homologues.
报道了在表达 GRPR 的模型中[(99m)Tc]Demomedin C 的合成和临床前评价。Demomedin C 通过将 Boc 保护的 N(4)-螯合剂偶联到神经调节素 C（人 GRP(18-27)）上得到，后者在（99m)Tc 标记后得到[(99m)Tc]Demomedin C。在对人癌症样本进行受体放射自显影时，Demomedin C 对 GRPR 表现出高亲和力和选择性（IC50，nM：GRPR，1.4±0.2；NMBR，106±18；和 BB(3)R，>1000）。它在 HEK-GRPR 细胞中触发 GRPR 内化，并在 PC-3 细胞中释放 Ca(2+)（EC50=1.3 nM）。[(99m)Tc]Demomedin C 在 37°C 下在 PC-3 细胞中快速且特异性地内化，并且在小鼠血浆中稳定。[(99m)Tc]Demomedin C 在小鼠中的人 PC-3 植入物中有效且特异性地定位（注射后 1 h 为 9.84±0.81%ID/g；注射后 4 h 为 6.36±0.85%ID/g，注射后 4 h 阻断为 0.41±0.07%ID/g）。因此，基于人 GRP 的放射性配体，如[(99m)Tc]Demomedin C，可成功地在体内靶向表达 GRPR 的人类肿瘤，同时表现出有吸引力的生物学特征-例如，与它们的蛙同源物相比，GRPR 选择性更高。
