Abstract：
The prostate-specific membrane antigen (PSMA)-targeted radiohybrid (rh) ligand [177Lu]Lu-rhPSMA-7.3 has recently been assessed in a pretherapeutic dosimetry study on prostate cancer patients. In comparison to [177Lu]Lu-PSMA I&T, application of [177Lu]Lu-rhPSMA-7.3 resulted in a significantly improved tumor dose but also higher kidney accumulation. Although rhPSMA-7.3 has been initially selected as the lead compound for diagnostic application based on the characterization of its gallium complex, a systematic comparison of the most promising 177Lu-labeled rhPSMA ligands is still missing. Thus, this study aimed to identify the rhPSMA ligand with the most favorable pharmacokinetics for 177Lu-radioligand therapy. Methods: The 4 isomers of [177Lu]Lu-rhPSMA-7 (namely [177Lu]Lu-rhPSMA-7.1, -7.2, -7.3, and -7.4), along with the novel radiohybrid ligands [177Lu]Lu-rhPSMA-10.1 and -10.2, were compared with the state-of-the-art compounds [177Lu]Lu-PSMA I&T and [177Lu]Lu-PSMA-617. The comparative evaluation comprised affinity studies (half-maximal inhibitory concentration) and internalization experiments on LNCaP cells, as well as lipophilicity measurements. In addition, we determined the apparent molecular weight (AMW) of each tracer as a parameter for human serum albumin (HSA) binding. Biodistribution studies and small-animal SPECT imaging were performed on LNCaP-tumor bearing mice at 24 h after injection. Results: 177Lu labeling of the radiohybrids was performed according to the established procedures for the currently established PSMA-targeted ligands. All ligands showed potent binding to PSMA-expressing LNCaP cells, with affinities in the low nanomolar range and high internalization rates. Surprisingly, the most pronounced differences regarded the HSA-related AMW. Although [177Lu]Lu-rhPSMA-7 isomers demonstrated the highest AMW and thus strongest HSA interactions, [177Lu]Lu-rhPSMA-10.1 showed an AMW lower than for [177Lu]Lu-rhPSMA-7.3 but higher than for the 177Lu-labeled references PSMA I&T and PSMA-617. In biodistribution studies, [177Lu]Lu-rhPSMA-10.1 exhibited the lowest kidney uptake and fastest excretion from the blood pool of all rhPSMA ligands while preserving a high tumor accumulation. Conclusion: Clinical investigation of [177Lu]Lu-rhPSMA-10.1 is highly warranted to determine whether the favorable pharmacokinetics observed in mice will also result in high tumor uptake and decreased absorbed dose to kidneys and other nontarget tissues in patients.
摘要：
前列腺特异性膜抗原（PSMA）靶向的放射杂交（rh）配体[177Lu]Lu-rhPSMA-7.3最近已在前列腺癌患者的治疗前剂量测定研究中进行了评估。与[177Lu]Lu-PSMAI&T相比，[177Lu]Lu-rhPSMA-7.3的应用导致显著改善的肿瘤剂量,但也导致更高的肾积累。尽管rhPSMA-7.3最初已根据其镓络合物的表征被选为诊断应用的先导化合物，最有希望的177Lu标记的rhPSMA配体的系统比较仍然缺失。因此，本研究旨在确定对177Lu-放射性配体治疗具有最有利药代动力学的rhPSMA配体。方法：[177Lu]Lu-rhPSMA-7的4种异构体（即[177Lu]Lu-rhPSMA-7.1，-7.2，-7.3和-7.4），与新的放射性混合配体[177Lu]Lu-rhPSMA-10.1和-10.2一起，与最新的化合物[177Lu]Lu-PSMAI＆T和[177Lu]Lu-PSMA-617进行了比较。比较评估包括对LNCaP细胞的亲和力研究（半最大抑制浓度）和内化实验，以及亲脂性测量。此外,我们确定了每种示踪剂的表观分子量（AMW）作为人血清白蛋白（HSA）结合的参数。在注射后24小时对LNCaP荷瘤小鼠进行生物分布研究和小动物SPECT成像。结果:对于目前建立的PSMA靶向配体,根据建立的程序进行放射性杂交体的177Lu标记。所有配体均显示与表达PSMA的LNCaP细胞的有效结合，具有低纳摩尔范围内的亲和力和高内在化率。令人惊讶的是,最明显的差异是与HSA相关的AMW。尽管[177Lu]Lu-rhPSMA-7异构体表现出最高的AMW，因此HSA相互作用最强，[177Lu]Lu-rhPSMA-10.1的AMW低于[177Lu]Lu-rhPSMA-7.3，但高于177Lu标记的参考文献PSMAI＆T和PSMA-617。在生物分布研究中，[177Lu]Lu-rhPSMA-10.1表现出最低的肾脏摄取和从所有rhPSMA配体的血池中最快的排泄，同时保留了高肿瘤积累。结论：[177Lu]Lu-rhPSMA-10.1的临床研究对于确定在小鼠中观察到的有利药代动力学是否也会导致高肿瘤摄取和减少患者肾脏和其他非靶组织的吸收剂量是非常有必要的。
