Prostate-specific membrane antigen (PSMA)–targeted radiotherapy of prostate cancer (PCa) has emerged recently as a promising approach to the treatment of disseminated disease. A small number of ligands have been evaluated in patients, and although early tumor response is encouraging, relapse rate is high and these compounds localize to the parotid, salivary, and lacrimal glands as well as to the kidney, leading to dose-limiting toxicities and adverse events affecting quality of life. We envision that dual-target binding ligands displaying high affinity for PSMA and appropriate affinity for human serum albumin (HSA) may demonstrate a higher therapeutic index and be suitable for treatment of PCa by targeted α-therapy. Methods: Six novel urea-based ligands with varying affinities for PSMA and HSA were synthesized, labeled with ¹³¹I, and evaluated by in vitro binding and uptake assays in LNCaP cells. Four compounds were advanced for further evaluation in a preclinical model of PCa. The compounds were compared with MIP-1095, a PSMA ligand currently in clinical evaluation. Results: The compounds demonstrated affinity for PSMA on the order of 4–40 nM and affinity for HSA in the range of 1–53 μM. Compounds with relatively high affinity for HSA (≤2 μM) showed high and sustained blood-pool activity and reduced uptake in the kidneys. ¹³¹I-RPS-027, with a 50% inhibitory concentration (PSMA) of 15 nM and a dissociation constant (HSA) of 11.2 μM, cleared from the blood over the course of 48 h and showed good tumor uptake (10 percentage injected dose per gram) and retention and a greater than 5-fold decrease in kidney uptake relative to MIP-1095. The tumor-to-kidney ratio of ¹³¹I-RPS-027 was greater than 3:1 at 24 h after injection, increasing to 7:1 by 72 h. Conclusion: RPS-027 shows dual targeting to PSMA and albumin, resulting in a high tumor uptake, highly favorable tissue distribution, and promising therapeutic profile in a preclinical model of prostate cancer. In comparison to existing ligands proposed for targeted therapy of prostate cancer, RPS-027 has tumor-to-tissue ratios that predict a significant reduction in side effects during therapy. Using iodine/radioiodine as a surrogate for the radiohalogen ²¹¹At, we therefore propose dual-target binding ligands such as RPS-027 as next-generation radiopharmaceuticals for targeted α-therapy using ²¹¹At.

前列腺特异性膜抗原（PSMA）靶向的前列腺癌（PCa）放射疗法最近作为一种治疗散播性疾病的有前途的方法而出现。已在患者中评估了少数配体，尽管早期肿瘤反应令人鼓舞，但复发率很高，而且这些化合物位于腮腺，唾液和泪腺以及肾脏，从而限制了剂量和毒性。影响生活质量的不良事件。我们设想显示对PSMA具有高亲和力和对人血清白蛋白（HSA）具有适当亲和力的双靶结合配体可能显示出更高的治疗指数，并适合通过靶向α-疗法治疗PCa。方法：合成了六个对PSMA和HSA具有不同亲和力的新型脲基配体，用¹³¹ I标记，并通过LNCaP细胞中的体外结合和吸收测定进行了评估。在PCa的临床前模型中对四种化合物进行了进一步评估。将该化合物与目前在临床评估中的PSMA配体MIP-1095进行了比较。结果：这些化合物对PSMA的亲和力约为4–40 nM，对HSA的亲和力约为1–53μM。对HSA的亲和力相对较高（≤2μM）的化合物显示出高且持续的血池活性，并减少了肾脏的摄取。¹³¹I-RPS-027的50％抑制浓度（PSMA）为15 nM，解离常数（HSA）为11.2μM，在48小时内从血液中清除，并显示出良好的肿瘤吸收率（每剂量10％注射剂量克）和保留，相对于MIP-1095，肾脏摄取减少了5倍以上。注射后24 h ¹³¹ I-RPS-027的肿瘤与肾脏比率大于3：1，到72 h增加至7：1。结论：RPS-027对PSMA和白蛋白具有双重靶向性，在前列腺癌的临床前模型中可导致较高的肿瘤吸收，高度有利的组织分布和有希望的治疗情况。与提议用于前列腺癌靶向治疗的现有配体相比，RPS-027具有肿瘤与组织的比率，可预测治疗期间的副作用显着减少。因此，使用碘/放射性碘作为放射性卤素²¹¹ At的替代物，因此，我们提出了双靶结合配体，例如RPS-027，作为使用²¹¹ At靶向α治疗的下一代放射性药物。