TY - JOUR T1 - Synthesis and Preclinical Evaluation of <sup>177</sup>Lu-labeled Radiohybrid PSMA Ligands (rhPSMAs) for Endoradiotherapy of Prostate Cancer JF - Journal of Nuclear Medicine JO - J Nucl Med DO - 10.2967/jnumed.121.263371 SP - jnumed.121.263371 AU - Alexander Wurzer AU - Jan-Philip Kunert AU - Sebastian Fischer AU - Veronika Felber AU - Roswitha Beck AU - Francesco De Rose AU - Calogero D'Alessandria AU - Wolfgang Andreas Weber AU - Hans-Jürgen Wester Y1 - 2022/01/01 UR - http://jnm.snmjournals.org/content/early/2022/01/27/jnumed.121.263371.abstract N2 - Introduction: The prostate-specific membrane antigen (PSMA)-targeted radiohybrid (rh) ligand [177Lu]Lu-rhPSMA-7.3 has recently been assessed in a pretherapeutic dosimetry study in prostate cancer patients. In comparison to [177Lu]Lu-PSMA I&amp;T, application of [177Lu]Lu-rhPSMA-7.3 resulted in a significantly improved tumor dose, but also higher kidney accumulation. Aim: 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 most favorable pharmacokinetics for 177Lu-radioligand therapy. Methods: The four 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 to the state-of-the-art compounds [177Lu]Lu-PSMA I&amp;T and [177Lu]Lu-PSMA-617. The comparative evaluation comprised affinity studies (IC50) 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 µSPECT imaging was performed in LNCaP-tumor bearing mice at 24 h post injection. Results: 177Lu-labeling of the radiohybrids was carried out 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, most pronounced differences were identified regarding the HSA-related AMW. While [177Lu]Lu-rhPSMA-7 isomers demonstrated the highest AMW and thus strongest HSA-interactions, [177Lu]Lu-rhPSMA-10.1 showed an AMW lower than [177Lu]Lu-rhPSMA-7.3 but higher than the 177Lu-labeled references PSMA I&amp;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 in order to determine if the favorable pharmacokinetics observed in mice will also result in high tumor uptake and decreased absorbed dose to kidneys and other non-target tissues in patients. ER -