Research progress on prostate-specific membrane antigen-targeted small-molecule radioligands

Prostate-specific membrane antigen (PSMA) is markedly overexpressed on prostate cancer cell membranes—particularly in advanced, metastatic, and metastatic castration-resistant prostate cancer (mCRPC) lesions—but is present at only low levels in healthy tissues and organs, such as the salivary glands, kidneys, and proximal small intestine. This unique characteristic makes PSMA a highly promising target for precision radiopharmaceutical-based theranostics of prostate cancer. In recent years, the rapid development of radionuclides, such as 68Ga, 18F, 90Y, 64Cu, 177Lu, and 225Ac, together with continuous advances in bifunctional chelators including 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), has enabled a seamless transition from diagnosis to therapy for targeted radiotheranostic strategies. Notably, [177Lu]Lu-PSMA-617 (brand name: Pluvicto) has been approved by the United States Food and Drug Administration for the treatment of patients with PSMA-positive mCRPC based on the groundbreaking findings from the Phase III VISION trial, which has fundamentally transformed the treatment landscape of this disease. Nevertheless, current PSMA-targeted radiopharmaceuticals still face multiple challenges: temporal and spatial heterogeneity of tumor PSMA expression, mechanisms of acquired drug resistance, and adverse reactions induced by dose-limiting toxicities. This review systematically reviews the latest preclinical advances and clinical translation outcomes of PSMA-targeted ligands, covering molecular design strategies, optimization of pharmacokinetic profiles, exploration of novel radionuclides, and evaluation of radiopharmaceuticals. It aims to provide a valuable reference for researchers engaged in PSMA-targeted theranostic studies.