Preclinical evaluation of ^203/212Pb-labeled low-molecular-weight compounds for targeted radiopharmaceutical therapy of prostate cancer

Abstract

Targeted radiopharmaceutical therapy (TRT) employing α-particle radiation is a promising approach for treating both large and micrometastatic lesions. We developed prostate-specific membrane antigen (PSMA)-targeted low-molecular-weight (LMW) agents for ²¹²Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate, ²⁰³Pb. Methods: Five rationally designed LMW ligands (L1-L5) were synthesized using the lysine-urea-glutamate (Lys-urea-Glu) scaffold and PSMA inhibition constants (Ki) were determined. Tissue biodistribution and SPECT/CT imaging of ²⁰³Pb-L1-²⁰³Pb-L5 were performed in mice bearing PSMA(+) PC3 PIP and PSMA(-) PC3 flu flank xenografts. Radiation absorbed dose of the corresponding ²¹²Pb-labeled analogs was determined using the biodistribution data. Antitumor efficacy of ²¹²Pb-L2 was evaluated in PSMA(+) PC3 PIP and PSMA(-) PC3 flu tumor models and in the PSMA(+) luciferase-expressing micrometastatic model. ²¹²Pb-L2 was also evaluated for dose-escalated, long-term toxicity. Results: All new ligands were obtained in high yield and purity. PSMA inhibitory activities ranged from 0.1–17 nM. ²⁰³Pb-L1-²⁰³Pb-L5 were synthesized in high radiochemical yield and specific activity. Whole-body clearances of ²⁰³Pb-L1-²⁰³Pb-L5 were fast, the absorbed dose coefficients [mGy/kBq], of the tumor and kidneys were highest for ²⁰³Pb-L5 (31.0, 15.2), and lowest for ²⁰³Pb-L2 (8.0, 4.2). The tumor-to-kidney absorbed dose ratio was higher for ²⁰³Pb-L3 (3.2) and ²⁰³Pb-L4 (3.6) compared to the other agents, however, with lower tumor-to-blood ratios. PSMA(+) tumor lesions were visualized through SPECT/CT as early as 0.5 h post-injection. A proof-of-concept therapy study with a single administration of ²¹²Pb-L2 demonstrated dose-dependent inhibition of tumor growth in the PSMA(+) flank tumor model. ²¹²Pb-L2 also demonstrated an increased survival benefit in the micrometastatic model compared to ¹⁷⁷Lu-PSMA-617. Long-term toxicity studies in healthy, immunocompetent CD-1 mice revealed kidney as the dose-limiting organ. Conclusion: ²⁰³Pb-L1-²⁰³Pb-L5 demonstrated favorable pharmacokinetics for ²¹²Pb-based TRT. Antitumor efficacy of ²¹²Pb-L2 supports the corresponding ²⁰³Pb/²¹²Pb theranostic pair for PSMA-based α-particle TRT in advanced PC.