Preclinical Evaluation of 213Bi- and 225Ac-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 b-particle-emitting low-molecular-weight compound, 177Lu-L1 which demonstrated reduced off-target effects in a xenograftmodel of prostate cancer. Here, we leveraged that scaffold to synthesize a-particle-emitting analogs of L1, 213Bi-L1 and 225Ac-L1, to evaluate their safety and cell kill effect in PSMApositive (1) xenograftmodels.Methods: The radiochemical synthesis, cell uptake, cell kill, and biodistribution of 213Bi-L1 and 225Ac-L1 were evaluated. The efficacy of 225Ac-L1 was determined in human PSMA1subcutaneous andmicrometastaticmodels. Subacute toxicity at 8 wk and chronic toxicity at 1 y after administrationwere evaluated for 225Ac-L1. The absorbed radiation dose of 225Ac-L1 was determined using the biodistribution data and a-camera imaging. Results: 213Bi- and 225Ac-L1 demonstrated specific cell uptake and cell kill in PSMA1 cells. The biodistribution of 213Bi-L1 and 225Ac-L1 revealed specific uptake of radioactivity within PSMA1 lesions. Treatment studies of 225Ac-L1 demonstrated activitydependent, specific inhibition of tumor growth in the PSMA1 flank tumor model. 225Ac-L1 also showed an increased survival benefit in the micrometastatic model compared with 177Lu-L1. Activityescalated acute and chronic toxicity studies of 225Ac-L1 revealed off-target radiotoxicity, mainly in kidneys and liver. The estimated maximumtolerated activitywas about 1MBq/kg.a-Camera imaging of 225Ac-L1 revealed high renal cortical accumulation at 2 h followed by fast clearance at 24 h. Conclusion: 225Ac-L1 demonstrated activity-dependent efficacy with minimal treatment-related organ radiotoxicity. 225Ac-L1 is a promising therapeutic for further clinical evaluation.