Background: New treatments combating bone and extraskeletal metastases are needed for
patients with metastatic castration-resistant prostate cancer. The majority of metastases overexpress
prostate-specific membrane antigen (PSMA), making it an ideal candidate for targeted radionuclide
Objective: The aim of this study was to test a novel liquid 224Ra/212Pb-generator for the rapid preparation
of a dual-alpha targeting solution. Here, PSMA-targeting ligands are labelled with 212Pb in the
224Ra-solution in transient equilibrium with daughter nuclides. Thus, natural bone-seeking 224Ra targeting
sclerotic bone metastases and 212Pb-chelated PSMA ligands targeting PSMA-expressing tumour
cells are obtained.
Methods: Two PSMA-targeting ligands, the p-SCN-Bn-TCMC-PSMA ligand (NG001), specifically
developed for chelating 212Pb, and the most clinically used DOTA-based PSMA-617 were labelled with
212Pb. Radiolabelling and targeting potential were investigated in situ, in vitro (PSMA-positive C4-2
human prostate cancer cells) and in vivo (athymic mice bearing C4-2 xenografts).
Results: NG001 was rapidly labelled with 212Pb (radiochemical purity >94% at concentrations of ≥15
μg/ml) using the liquid 224Ra/212Pb-generator. The high radiochemical purity and stability of [212Pb]Pb-
NG001 were demonstrated over 48 hours in the presence of ascorbic acid and albumin. Similar binding
abilities of the 212Pb-labelled ligands were observed in C4-2 cells. The PSMA ligands displayed comparable
tumour uptake after 2 hours, but NG001 showed a 3.5-fold lower kidney uptake than PSMA-
617. Radium-224 was not chelated and, hence, showed high uptake in bones.
Conclusion: A fast method for the labelling of PSMA ligands with 212Pb in the 224Ra/212Pb-solution
was developed. Thus, further in vivo studies with dual tumour targeting by alpha-particles are warranted.