We recently developed a chelating platform based on the macrocycle 1,4,7-triazacyclononane with up to three, five-membered azaheterocyclic arms for the development of 68Ga- and 64Cu-based radiopharmaceuticals. Here, a 68Ga-labelled conjugate comprising the bifunctional chelator NODIA-Me in combination with the αvß3-targeting peptide c(RGDfK) has been synthesized and characterized. The primary aim was to evaluate further the potential of our NODIA-Me chelating system for the development of 68Ga-labelled radiotracers. The BFC NODIA-Me was conjugated to c(RGDfK) by standard peptide chemistry to obtain the final bioconjugate NODIA-Me-c(RGDfK) 3 in 72% yield. Labelling with [68Ga]GaCl3 was accomplished in a fully automated, cGMP compliant process to give [68Ga]3 in high radiochemical yield (98%) and moderate specific activity (~ 8 MBq nmol− 1). Incorporation of the Ga-NODIA-Me chelate to c(RGDfK) 2 had only minimal influence on the affinity to integrin αvß3 (IC50 values [natGa]3 = 205.1 ± 1.4 nM, c(RGDfK) 2 = 159.5 ± 1.3 nM) as determined in competitive cell binding experiments in U-87 MG cell line. In small-animal PET imaging and ex vivo biodistribution studies, the radiotracer [68Ga]3 showed low uptake in non-target organs and specific tumor uptake in U-87 MG tumors. The results suggest that the bifunctional chelator NODIA-Me is an interesting alternative to existing ligands for the development of 68Ga-labelled radiopharmaceuticals.

中文翻译：

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包含双功能螯合剂 NODIA-Me 的 68Ga 标记的 c(RGDfK) 缀合物的制备和临床前评估。

我们最近开发了一个基于大环 1,4,7-三氮杂环壬烷的螯合平台，该平台具有多达三个、五元氮杂环臂，用于开发 68Ga 和 64Cu 基放射性药物。在这里，已经合成并表征了包含双功能螯合剂 NODIA-Me 与 αvß3 靶向肽 c(RGDfK) 的 68Ga 标记的偶联物。主要目的是进一步评估我们的 NODIA-Me 螯合系统开发 68Ga 标记的放射性示踪剂的潜力。BFC NODIA-Me 通过标准肽化学与 c(RGDfK) 缀合，以 72% 的产率获得最终的生物缀合物 NODIA-Me-c(RGDfK) 3。用 [68Ga]GaCl3 标记是在一个完全自动化的、符合 cGMP 的过程中完成的，从而以高放射化学产率 (98%) 和中等比活度 (~ 8 MBq nmol-1) 提供 [68Ga]3。Ga-NODIA-Me 螯合物与 c(RGDfK) 2 的结合对整合素 αvß3 的亲和力影响很小（IC50 值 [natGa]3 = 205.1 ± 1.4 nM，c(RGDfK) 2 = 159.5 ± 1.3 nM）如在 U-87 MG 细胞系的竞争性细胞结合实验中确定。在小动物 PET 成像和离体生物分布研究中，放射性示踪剂 [68Ga]3 在非靶器官中的摄取量较低，在 U-87 MG 肿瘤中显示出特定的肿瘤摄取。结果表明，双功能螯合剂 NODIA-Me 是现有配体的有趣替代品，可用于开发 68Ga 标记的放射性药物。在小动物 PET 成像和离体生物分布研究中，放射性示踪剂 [68Ga]3 在非靶器官中的摄取量较低，在 U-87 MG 肿瘤中显示出特定的肿瘤摄取。结果表明，双功能螯合剂 NODIA-Me 是现有配体的有趣替代品，可用于开发 68Ga 标记的放射性药物。在小动物 PET 成像和离体生物分布研究中，放射性示踪剂 [68Ga]3 在非靶器官中的摄取量较低，在 U-87 MG 肿瘤中显示出特定的肿瘤摄取。结果表明，双功能螯合剂 NODIA-Me 是现有配体的有趣替代品，可用于开发 68Ga 标记的放射性药物。