177 Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy

Purpose To develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and minimized toxicity employing the β-particle radiation of 177 Lu. Methods We synthesized 14 new PSMA-targeted, 177 Lu-labeled radioligands ( 177 Lu-L1– 177 Lu-L14) using different chelating agents and linkers. We evaluated them in vitro using human prostate cancer PSMA(+) PC3 PIP and PSMA(−) PC3 flu cells and in corresponding flank tumor models. Efficacy and toxicity after 8 weeks were evaluated at a single administration of 111 MBq for 177 Lu-L1, 177 Lu-L3, 177 Lu-L5 and 177 Lu-PSMA-617. Efficacy of 177 Lu-L1 was further investigated using different doses, and long-term toxicity was determined in healthy immunocompetent mice. Results Radioligands were produced in high radiochemical yield and purity. Cell uptake and internalization indicated specific uptake only in PSMA(+) PC3 cells. 177 Lu-L1, 177 Lu-L3 and 177 Lu-L5 demonstrated comparable uptake to 177 Lu-PSMA-617 and 177 Lu-PSMA-I&T in PSMA-expressing tumors up to 72 h post-injection. 177 Lu-L1, 177 Lu-L3 and 177 Lu-L5 also demonstrated efficient tumor regression at 8 weeks. 177 Lu-L1 enabled the highest survival rate. Necropsy studies of the treated group at 8 weeks revealed subacute damage to lacrimal glands and testes. No radiation nephropathy was observed 1 year post-treatment in healthy mice receiving 111 MBq of 177 Lu-L1, most likely related to the fast renal clearance of this agent. Conclusions 177 Lu-L1 is a viable clinical candidate for radionuclide therapy of PSMA-expressing malignancies because of its high tumor-targeting ability and low off-target radiotoxic effects.