Preclinical Evaluation of Bi- and Ac-Labeled Low-Molecular-Weight Compounds for Radiopharmaceutical Therapy of Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical therapy is a new option for patients with advanced prostate cancer refractory to other treatments. Previously, we synthesized a β-particle-emitting low-molecular-weight compound, Lu-L1 which demonstrated reduced off-target effects in a xenograft model of prostate cancer. Here, we leveraged that scaffold to synthesize α-particle-emitting analogs of L1, Bi-L1 and Ac-L1, to evaluate their safety and cell kill effect in PSMA-positive (+) xenograft models. The radiochemical synthesis, cell uptake, cell kill, and biodistribution of Bi-L1 and Ac-L1 were evaluated. The efficacy of Ac-L1 was determined in human PSMA+ subcutaneous and micrometastatic models. Subacute toxicity at 8 wk and chronic toxicity at 1 y after administration were evaluated for Ac-L1. The absorbed radiation dose of Ac-L1 was determined using the biodistribution data and α-camera imaging. Bi- and Ac-L1 demonstrated specific cell uptake and cell kill in PSMA+ cells. The biodistribution of Bi-L1 and Ac-L1 revealed specific uptake of radioactivity within PSMA+ lesions. Treatment studies of Ac-L1 demonstrated activity-dependent, specific inhibition of tumor growth in the PSMA+ flank tumor model. Ac-L1 also showed an increased survival benefit in the micrometastatic model compared with Lu-L1. Activity-escalated acute and chronic toxicity studies of Ac-L1 revealed off-target radiotoxicity, mainly in kidneys and liver. The estimated maximum tolerated activity was about 1 MBq/kg. α-Camera imaging of Ac-L1 revealed high renal cortical accumulation at 2 h followed by fast clearance at 24 h. Ac-L1 demonstrated activity-dependent efficacy with minimal treatment-related organ radiotoxicity. Ac-L1 is a promising therapeutic for further clinical evaluation.