Prostate-specific membrane antigen (PSMA) is the most promising target for radioligand therapy of prostate cancer. The aim of this study was to prepare a small molecular ligand p-SCN-Bn-TCMC-PSMA ligand (NG001), and compare it with the commonly used DOTA-based PSMA-617. The PSMA-targeting ability of 212 Pb-labelled ligands was evaluated using PSMA-positive C4-2 human prostate cancer cells. Lead-212 is an in vivo generator of alpha particles by its daughter nuclides 212 Bi and 212 Po. NG001 was synthesized by conjugating the isothiocyanato group of p-SCN-Bn-TCMC to the amino group of a glutamate-urea-based PSMA binding entity. Molecular size, chelator unit and chelator linking method are different in NG001 and PSMA-617. Both ligands were efficiently labelled with 212 Pb using a 224 Ra/212 Pb-solution generator in transient equilibrium with progeny. Lead-212-labelled NG001 was purified with a yield of 85.9±4.7% and with 0.7±0.2% of 224 Ra. Compared with [212 Pb]Pb-PSMA-617, [212 Pb]Pb-NG001 displayed a similar binding and internalization in C4-2 cells, with comparable tumour uptake in mice bearing C4-2 tumours, but almost a 2.5-fold lower kidney uptake. Due to the rapid normal tissue clearance and tumour internalisation, any significant translocalization of 212 Bi was not detected in mice. In conclusion, the obtained results warrant further preclinical studies to evaluate the therapeutic efficacy of [212 Pb]Pb-NG001.

中文翻译：

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用于前列腺癌的 α 发射 PSMA 靶向放射性配体 [212 Pb]Pb-NG001 的制备


前列腺特异性膜抗原（PSMA）是前列腺癌放射配体治疗最有希望的靶标。本研究的目的是制备小分子配体p-SCN-Bn-TCMC-PSMA配体（NG001），并将其与常用的基于DOTA的PSMA-617进行比较。使用 PSMA 阳性 C4-2 人前列腺癌细胞评估 212 个 Pb 标记配体的 PSMA 靶向能力。 Lead-212 是一种通过其子核素 212 Bi 和 212 Po 产生 α 粒子的体内发生器。 NG001 是通过将 p-SCN-Bn-TCMC 的异硫氰酸根基团与基于谷氨酸-尿素的 PSMA 结合实体的氨基基团缀合而合成的。 NG001 和 PSMA-617 的分子大小、螯合剂单元和螯合剂连接方法不同。两种配体均使用 224 Ra/212 Pb 溶液发生器在与子代的瞬时平衡中被有效地标记为 212 Pb。铅212标记的NG001经纯化，产率为85.9±4.7%，并含有0.7±0.2%的224 Ra。与 [212 Pb]Pb-PSMA-617 相比，[212 Pb]Pb-NG001 在 C4-2 细胞中表现出相似的结合和内化，在携带 C4-2 肿瘤的小鼠中具有类似的肿瘤摄取，但几乎低 2.5 倍肾脏摄取。由于快速的正常组织清除和肿瘤内化，在小鼠中未检测到 212 Bi 的任何显着易位。总之，所获得的结果值得进一步的临床前研究来评估[212 Pb]Pb-NG001的治疗效果。