Preparation of the alpha‐emitting prostate‐specific membrane antigen targeted radioligand [212Pb]Pb‐NG001 for prostate cancer

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 (NG001) and compare it with the commonly used DOTA‐based PSMA‐617. The PSMA‐targeting ability of the 212Pb‐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 212Bi and 212Po. 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 212Pb using a 224Ra/212Pb‐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 224Ra. Compared with [212Pb]Pb‐PSMA‐617, [212Pb]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 cell internalization, any significant translocalization of 212Bi was not detected in mice. In conclusion, the obtained results warrant further preclinical studies to evaluate the therapeutic efficacy of [212Pb]Pb‐NG001.