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 212Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate, 203Pb. 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 203Pb-L1-203Pb-L5 were performed on mice bearing PSMA(+) PC3 PIP and PSMA(-) PC3 flu flank xenografts. The absorbed radiation 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 0.10 to 17 nM. 203Pb-L1-203Pb-L5 were synthesized in high radiochemical yield and specific activity. Whole-body clearance of 203Pb-L1-203Pb-L5 was 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) 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 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 with 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. The antitumor efficacy of 212Pb-L2 supports the corresponding 203Pb/212Pb theranostic pair for PSMA-based α-particle TRT in advanced PC.

中文翻译：

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用于前列腺癌靶向放射性药物治疗的 203/212Pb 标记的低分子量化合物的临床前评价。

使用 α 粒子辐射的靶向放射性药物治疗 (TRT) 是治疗大转移和微转移病变的有前途的方法。我们通过评估匹配的 γ 发射替代物 203Pb，为前列腺癌 (PC) 患者的基于 212Pb 的 TRT 开发了前列腺特异性膜抗原 (PSMA) 靶向低分子量药物。方法：利用赖氨酸-尿素-谷氨酸支架合成5个设计合理的低分子量配体（L1-L5），并测定PSMA抑制常数。203Pb-L1-203Pb-L5 的组织生物分布和 SPECT/CT 成像在带有 PSMA(+) PC3 PIP 和 PSMA(-) PC3 流感侧腹异种移植物的小鼠上进行。使用生物分布数据确定相应的 212Pb 标记的类似物的吸收辐射剂量。在 PSMA(+) PC3 PIP 和 PSMA(-) PC3 流感肿瘤模型和 PSMA(+) 荧光素酶表达微转移模型中评估了 212Pb-L2 的抗肿瘤功效。还评估了 212Pb-L2 的剂量递增的长期毒性。结果：所有新配体均以高产率和纯度获得。PSMA 抑制活性范围为 0.10 至 17 nM。203Pb-L1-203Pb-L5 以高放化学产率和比活度合成。203Pb-L1-203Pb-L5的全身清除速度快。肿瘤和肾脏的吸收剂量系数 (mGy/kBq) 以 203Pb-L5 (31.0, 15.2) 最高，而 203Pb-L2 (8.0, 4.2) 最低。203Pb-L3 (3.2) 和 203Pb-L4 (3.6) 的肿瘤与肾脏吸收剂量比高于其他药物，但肿瘤与血液的比值较低。PSMA(+) 肿瘤病变早在 0 时就通过 SPECT/CT 可视化。注射后 5 小时。一项单次给药 212Pb-L2 的概念验证治疗研究表明，在 PSMA(+) 侧腹肿瘤模型中对肿瘤生长的抑制呈剂量依赖性。与 177Lu-PSMA-617 相比，212Pb-L2 在微转移模型中的生存​​获益也有所增加。对健康、免疫能力强的 CD-1 小鼠进行的长期毒性研究表明，肾脏是剂量限制器官。结论：203Pb-L1-203Pb-L5 对基于 212Pb 的 TRT 表现出良好的药代动力学。212Pb-L2 的抗肿瘤功效支持在晚期 PC 中基于 PSMA 的 α 粒子 TRT 的相应 203Pb/212Pb 治疗诊断对。与 177Lu-PSMA-617 相比，212Pb-L2 在微转移模型中的生存​​获益也有所增加。对健康、免疫能力强的 CD-1 小鼠进行的长期毒性研究表明，肾脏是剂量限制器官。结论：203Pb-L1-203Pb-L5 对基于 212Pb 的 TRT 表现出良好的药代动力学。212Pb-L2 的抗肿瘤功效支持在晚期 PC 中基于 PSMA 的 α 粒子 TRT 的相应 203Pb/212Pb 治疗诊断对。与 177Lu-PSMA-617 相比，212Pb-L2 在微转移模型中的生存​​获益也有所增加。对健康、免疫能力强的 CD-1 小鼠进行的长期毒性研究表明，肾脏是剂量限制器官。结论：203Pb-L1-203Pb-L5 对基于 212Pb 的 TRT 表现出良好的药代动力学。212Pb-L2 的抗肿瘤功效支持在晚期 PC 中基于 PSMA 的 α 粒子 TRT 的相应 203Pb/212Pb 治疗诊断对。