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Targeted radiopharmaceutical therapy (TRT) using 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 agents for 212 Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate, 203 Pb. Methods: Five rationally designed low-molecular-weight ligands (L1-L5) were synthesized using the lysine-urea-glutamate scaffold, and PSMA inhibition constants were determined. Tissue biodistribution and SPECT/CT imaging of 203 Pb-L1- 203 Pb-L5 were performed on mice bearing PSMA(+) PC3 PIP and PSMA(-) PC3 flu flank xenografts. The absorbed radiation dose of the corresponding 212 Pb-labeled analogs was determined using the biodistribution data. Antitumor efficacy of 212 Pb-L2 was evaluated in PSMA(+) PC3 PIP and PSMA(-) PC3 flu tumor models and in the PSMA(+) luciferase-expressing micrometastatic model. 212 Pb-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 0.10 to 17 nM. 203 Pb-L1- 203 Pb-L5 were synthesized in high radiochemical yield and specific activity. Whole-body clearance of 203 Pb-L1- 203 Pb-L5 was fast. The absorbed dose coefficients (mGy/kBq) of the tumor and kidneys were highest for 203 Pb-L5 (31.0, 15.2) and lowest for 203 Pb-L2 (8.0, 4.2). The tumor-to-kidney absorbed dose ratio was higher for 203 Pb-L3 (3.2) and 203 Pb-L4 (3.6) than for the other agents, but with lower tumor-to-blood ratios. PSMA(+) tumor lesions were visualized through SPECT/CT as early as 0.5 h after injection. A proof-of-concept therapy study with a single administration of 212 Pb-L2 demonstrated dose-dependent inhibition of tumor growth in the PSMA(+) flank tumor model. 212 Pb-L2 also demonstrated an increased survival benefit in the micrometastatic model compared with 177 Lu-PSMA-617. Long-term toxicity studies in healthy, immunocompetent CD-1 mice revealed kidney as the dose-limiting organ. Conclusion:  203 Pb-L1- 203 Pb-L5 demonstrated favorable pharmacokinetics for 212 Pb-based TRT. The antitumor efficacy of 212 Pb-L2 supports the corresponding 203 Pb/ 212 Pb theranostic pair for PSMA-based α-particle TRT in advanced PC.

Preclinical Evaluation of 203/212Pb-Labeled Low-Molecular-Weight Compounds for Targeted Radiopharmaceutical Therapy of Prostate Cancer

Preclinical Evaluation of ^203/212Pb-Labeled Low-Molecular-Weight Compounds for Targeted Radiopharmaceutical Therapy of Prostate Cancer