Radiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [177Lu]Lu-rhPSMA-10.1 and -10.2 have been synthesized and initially characterized in preclinical experiments with the aim to provide an optimized binding profile to human serum albumin, a reduction of charge, and thus accelerated kidney excretion, and unaffected or even improved tumor uptake. As both isomers showed similar in vitro characteristics and tumor uptake at 24 h post injection in tumor bearing mice and in order to identify the isomer with the most favorable pharmacokinetics for radioligand therapy, we carried out in-depth biodistribution and dosimetry studies in tumor-bearing and healthy mice. rhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (> 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3–0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [177Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [177Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6–11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2, respectively. Our preclinical data on biodistribution and dosimetry indicate a more favorable profile of [177Lu]Lu-rhPSMA-10.1 compared to [177Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [177Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [177Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918).

中文翻译：

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[177Lu]Lu-rhPSMA-10.1 和 [177Lu]Lu-rhPSMA-10.2 用于前列腺癌腔内放射治疗的临床前比较：生物分布和剂量测定研究

放射混合 PSMA 靶向配体 (rhPSMA) 已作为治疗诊断应用的新型平台推出。在为放射配体治疗开发的各种 rhPSMA 配体中，已合成了两种立体异构体 [177Lu]Lu-rhPSMA-10.1 和 -10.2，并在临床前实验中进行了初步表征，目的是提供与人血清白蛋白的优化结合特征，减少电荷，从而加速肾脏排泄，并且不影响甚至改善肿瘤摄取。由于这两种异构体在荷瘤小鼠体内注射后24小时表现出相似的体外特征和肿瘤摄取，为了鉴定对放射配体治疗最有利的药代动力学异构体，我们在荷瘤小鼠中进行了深入的生物分布和剂量测定研究和健康的小鼠。rhPSMA-10.1和-10.2根据其他基于DOTA的PSMA配体的既定程序用镥177进行放射性标记，并在所有缓冲液和人血清中表现出较高且相当的稳定性（> 97％，24小时）。生物分布研究表明，在 48 小时内可从血池（1 小时内为 0.3-0.6%ID/g）和其他背景组织中快速清除。在肾脏中发现了显着差异，其中 [177Lu]Lu-rhPSMA-10.1 与 [177Lu]Lu-rhPSMA-10.2 相比，表现出较低的初始摄取和更快的排泄动力学，在 1 小时和 1 小时时的摄取值分别低 1.5 倍和 9 倍。健康动物分别为24小时。两种异构体在 24 小时内的肿瘤摄取量相当，在 8.6–11.6%ID/g 范围内，并在 168 小时内保持在 2.2 ± 0.8 和 4.1 ± 1.4%ID/g（[177Lu]Lu-）的水平。分别为rhPSMA-10.1和[177Lu]Lu-rhPSMA-10.2。我们关于生物分布和剂量测定的临床前数据表明，与 [177Lu]Lu-rhPSMA-10.2 相比，[177Lu]Lu-rhPSMA-10.1 在 PSMA 靶向放射性配体治疗中具有更有利的特性。[ 177Lu]Lu-rhPSMA-10.1 显示出快速的肾脏清除动力学，从而在治疗相关时间过程中产生优异的肿瘤与器官比率。同时，[177Lu]Lu-rhPSMA-10.1目前正在mCRPC患者（NCT05413850）、高危局部PC患者（NCT06066437，Nautilus试验）和外照射放疗后（NCT06105918）的临床I/II期研究中进行研究）。