Current Status of PSMA-Targeted Agents Based on Small Molecules for Prostate Cancer in Preclinical Studies

Prostate-specific membrane antigen (PSMA) has emerged as a clinically validated target for the diagnosis and treatment of prostate cancer using radioligand therapy (RLT). Among various PSMA-targeting ligands, urea-based small-molecules have gained limelight due to their favorable pharmacokinetic properties, high tumor penetration and convenient radiolabeling. Current preclinical research focuses on enhancing in vivo efficacy by optimizing ligand design, radionuclide selection, and improved pharmacokinetics. To reduce off-target toxicity in organs and enhance tumor accumulation, strategies involving the incorporation of albumin-binding moieties or linker modifications have been explored. Various studies have focused on PSMA-targeted therapies labeled with radionuclides, including β emitters (lutetium-177), α emitters (actinium-225 or astatine-211), and Auger electron emitters (iodine-125), that provide unique DNA damage mechanisms tailored to the tumor size and disease stage. This review summarizes recent approaches of PSMA-targeted small-molecules to optimize therapeutic efficacy while minimizing adverse effects on healthy tissues for RLT of prostate cancer.