Background:
New treatments combating bone and extraskeletal metastases are needed for patients with metastatic castrationresistant prostate cancer. The majority of metastases overexpress prostate-specific membrane antigen (PSMA), making it an ideal candidate
for targeted radionuclide therapy.
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.
Method:
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/212Pbgenerator. 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.