Development of Novel Radiotheranostic Ligand with Positively Charged Unit Targeting Prostate-Specific Membrane Antigen.

Prostate-specific membrane antigen (PSMA) is an ideal target of prostate cancer (PCa) for theranostics, combining diagnosis and therapy in the field of nuclear medicine. [177Lu]Lu-PSMA-617 is a gold standard in PSMA-targeting radioligands, whereas its rapid clearance from the tumor and high uptake in the kidney may compromise the efficacy of theranostics. In this study, we developed novel PSMA-targeting radioligands, [111In]In/[225Ac]Ac-PDI2 and [111In]In/[225Ac]Ac-PDI4, by introducing a positively charged diethylenetriamine (PEI2) or tetraethylenepentamine (PEI4) structure, respectively, to PSMA-617. In the biodistribution study, higher tumor retention and lower renal uptake of [111In]In-PDI2 and [111In]In-PDI4 were observed than those of [111In]In-PSMA-617, and [111In]In-PDI2 exhibited higher tumor-residualizing properties than [111In]In-PDI4. [111In]In-PDI2 and [111In]In-PDI4 clearly visualized PSMA-expressing tumors by single photon emission computed tomography/computed tomography (SPECT/CT). The administration of [225Ac]Ac-PDI2 led to a higher antitumor effect than [225Ac]Ac-PDI4 and [225Ac]Ac-PSMA-617. These findings suggest the utility of [111In]In/[225Ac]Ac-PDI2 as theranostic ligands for PCa.