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 Pb-212-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 Bi-212 and Po-212. 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 Pb-212 using a Ra-224/Pb-212-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 Ra-224. Compared with [Pb-212]Pb-PSMA-617, [Pb-212]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 Bi-212 was not detected in mice. In conclusion, the obtained results warrant further preclinical studies to evaluate the therapeutic efficacy of [Pb-212]Pb-NG001.