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Abstract：
BACKGROUND: 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.
RESULTS: 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.
CONCLUSIONS: 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).
RESULTS: 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.
CONCLUSIONS: 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).
摘要：
背景：放射性杂化PSMA靶向配体（rhPSMA）已被引入作为治疗应用的新型平台。在为放射性配体治疗开发的各种rhPSMA配体中，已经合成了两种立体异构体[177Lu]Lu-rhPSMA-10.1和-10.2，并在临床前实验中初步表征，旨在提供与人血清白蛋白的优化结合图，减少电荷，从而加速肾脏排泄，并且不受影响甚至改善肿瘤摄取。由于两种异构体在荷瘤小鼠注射后24小时显示出相似的体外特征和肿瘤摄取，并且为了鉴定具有最有利的药代动力学的异构体用于放射性配体治疗，我们在荷瘤小鼠和健康小鼠中进行了深入的生物分布和剂量学研究。
结果：rhPSMA-10.1和-10.2根据其他基于DOTA的PSMA配体的既定程序用lutium-177进行放射性标记，并在所有缓冲液和人血清中显示出较高且相当的稳定性（>97％，24h).生物分布研究显示，在48小时内从血池（1小时时0.3-0.6%ID/g）和其他背景组织中快速清除。在肾脏中发现了明显的差异，其中[177Lu]Lu-rhPSMA-10.1与[177Lu]Lu-rhPSMA-10.2相比，显示出较低的初始摄取和较快的排泄动力学，在健康动物中在1小时和24小时时表达的摄取值低1.5倍和九倍，分别。两种异构体的肿瘤摄取在24小时内具有可比性，在8.6-11.6％ID/g的范围内，对于[177Lu]Lu-rhPSMA-10.1和[177Lu]Lu-rhPSMA-10.2，分别保持在2.2±0.8和4.1±1.4％ID/g的水平长达168小时。
结论：我们关于生物分布和剂量学的临床前数据表明，与[177Lu]Lu-rhPSMA-10.2相比，[177Lu]Lu-rhPSMA-10.2对于PSMA靶向放射性配体治疗具有更有利的特征。[177Lu]Lu-rhPSMA-10.1显示出快速的肾脏清除动力学，从而在治疗相关的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患者的临床I/II期研究中进行研究（NCT05413850），在高风险的局部PC（NCT06066437，Nautilus试验）和外部束放疗后（NCT06105918）的患者中。
结果：rhPSMA-10.1和-10.2根据其他基于DOTA的PSMA配体的既定程序用lutium-177进行放射性标记，并在所有缓冲液和人血清中显示出较高且相当的稳定性（>97％，24h).生物分布研究显示，在48小时内从血池（1小时时0.3-0.6%ID/g）和其他背景组织中快速清除。在肾脏中发现了明显的差异，其中[177Lu]Lu-rhPSMA-10.1与[177Lu]Lu-rhPSMA-10.2相比，显示出较低的初始摄取和较快的排泄动力学，在健康动物中在1小时和24小时时表达的摄取值低1.5倍和九倍，分别。两种异构体的肿瘤摄取在24小时内具有可比性，在8.6-11.6％ID/g的范围内，对于[177Lu]Lu-rhPSMA-10.1和[177Lu]Lu-rhPSMA-10.2，分别保持在2.2±0.8和4.1±1.4％ID/g的水平长达168小时。
结论：我们关于生物分布和剂量学的临床前数据表明，与[177Lu]Lu-rhPSMA-10.2相比，[177Lu]Lu-rhPSMA-10.2对于PSMA靶向放射性配体治疗具有更有利的特征。[177Lu]Lu-rhPSMA-10.1显示出快速的肾脏清除动力学，从而在治疗相关的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患者的临床I/II期研究中进行研究（NCT05413850），在高风险的局部PC（NCT06066437，Nautilus试验）和外部束放疗后（NCT06105918）的患者中。
