Preclinical evaluation of [177Lu]Lu-M3-12: a novel PSMA-targeted radioligand with enhanced antitumor efficacy in prostate cancer

Despite the clinical success of [ 177 Lu]Lu-PSMA-617 in metastatic castration-resistant prostate cancer, heterogeneous responses and toxicities remain. M3-12 is a novel prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PSMA-RLT) featuring a linear, hydrophilic amide/urea-based linker conjugated to a DOTA chelator. This study compared the pharmacokinetics, target binding, cellular uptake, and antitumor efficacy of [ 177 Lu]Lu-M3-12 versus [ 177 Lu]Lu-PSMA-617 in preclinical models. [ 177 Lu]Lu-M3-12 was prepared and characterized. In vitro ADME and PSMA binding affinity were assessed. Cellular uptake and internalization were measured in LNCaP cells. In LNCaP tumor-bearing mice, biodistribution, SPECT/CT imaging, and therapeutic efficacy were evaluated for both radioligands. [ 177 Lu]Lu-M3-12 was prepared with 97.5% radiochemical purity. M3-12 exhibited superior PSMA inhibition (IC 50 : 2.24 vs. 4.07 nM) and cellular binding affinity versus PSMA-617, with comparable ADME profiles. In LNCaP mice, [ 177 Lu]Lu-M3-12 showed significantly higher tumor uptake at 24 h (44.69 vs. 24.09%ID/g, P = 0.0043) and a 2.73-fold higher tumor-to-kidney ratio. At the high dose (29.6 MBq), [ 177 Lu]Lu-M3-12 exhibited pronounced dose-dependent antitumor efficacy without significant toxicity. [ 177 Lu]Lu-M3-12 exhibited significantly higher PSMA binding affinity and tumor cell uptake than [ 177 Lu]Lu-PSMA-617, while demonstrating dose-dependent antitumor efficacy and favorable safety profiles. The unique, hydrophilic linker design contributed to a superior tumor-to-kidney ratio, highlighting its potential to reduce dose-limiting nephrotoxicity. These findings support further preclinical development. However, larger studies are warranted to validate these findings and to rigorously compare its efficacy with that of [ 177 Lu]Lu-PSMA-617.