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The prostate-specific membrane antigen (PSMA)–targeted radiohybrid (rh) ligand 177LuLu-rhPSMA-7.3 has recently been assessed in a pretherapeutic dosimetry study on prostate cancer patients. In comparison to 177LuLu-PSMA I&T, application of 177LuLu-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 177LuLu-rhPSMA-7 (namely 177LuLu-rhPSMA-7.1, -7.2, -7.3, and -7.4), along with the novel radiohybrid ligands 177LuLu-rhPSMA-10.1 and -10.2, were compared with the state-of-the-art compounds 177LuLu-PSMA I&T and 177LuLu-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 177LuLu-rhPSMA-7 isomers demonstrated the highest AMW and thus strongest HSA interactions, 177LuLu-rhPSMA-10.1 showed an AMW lower than for 177LuLu-rhPSMA-7.3 but higher than for the 177Lu-labeled references PSMA I&T and PSMA-617. In biodistribution studies, 177LuLu-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 177LuLu-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.
Wurzer et al. (Thu,) studied this question.