Discovery of ¹⁷⁷Lu-PSMA-MN4 as an improved PSMA-targeted radioligand with enhanced antitumor efficacy.

Abstract

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with ¹⁷⁷Lu-PSMA-617 improves outcomes in metastatic castration-resistant prostate cancer (mCRPC), yet a substantial subset of patients experiences disease progression, underscoring the need for next-generation agents with improved pharmacological profiles. Guided by the PSMA-617/PSMA co-crystal structure (PDB: 8BOW) and molecular dynamics (MD) simulations, the present study rationally designs seven novel PSMA-617 derivatives (PSMA-MN1-7) to enhance target engagement and pharmacokinetic behavior. Among these, ¹⁷⁷Lu-PSMA-MN4 demonstrates potent PSMA enzymatic inhibition (IC₅₀ = 1.72 nM), enhanced cellular internalization (110.67 ± 2.60% relative to PSMA-617), and a favorable biodistribution profile marked by sustained tumor retention and rapid renal clearance in LNCaP tumor-bearing mice. In both hormone-sensitive LNCaP and castration-resistant 22RV1 xenograft models, ¹⁷⁷Lu-PSMA-MN4 achieves superior tumor growth inhibition and survival prolongation compared with ¹⁷⁷Lu-PSMA-617. Single-dose administration at doses up to 0.6 mCi/animal is well tolerated, with no clinically significant hematological changes, renal biochemical abnormalities, or histopathological findings within the observation period of this study. These findings should be interpreted in light of several limitations: absorbed-dose estimates were derived from mouse biodistribution data and require allometric scaling before comparison with clinical organ constraints; therapeutic efficacy was evaluated under a single-dose regimen rather than a fractionated or multi-cycle schedule; and long-term toxicity, including delayed renal and hematopoietic effects, was not assessed. These findings position ¹⁷⁷Lu-PSMA-MN4 as a promising candidate for next-generation PSMA-targeted radioligand therapy. Collectively, this work establishes a structure-guided linker-optimization paradigm for PSMA radioligands and identifies ¹⁷⁷Lu-PSMA-MN4 as a promising preclinical candidate that warrants further translational evaluation.