Piflufolastat F-18, Illuccix, Posluma, Pluvicto, and beyond: the development of radiopharmaceuticals for prostate cancer theranostics

Prostate cancer (PCa) is a common malignancy in men worldwide. Radiopharmaceuticals have demonstrated significant utility in the diagnosis and treatment of PCa. Targeted radionuclide therapy and radionuclide drug conjugate are currently prominent strategies in radiopharmaceuticals, aiming to precisely target specific molecular markers expressed in tumor cells or tumor microenvironments for imaging and therapy. Prostate-specific membrane antigen (PSMA) is a membrane enzyme highly expressed specifically in PCa cells, which has been widely utilized as a drug delivery target. PSMA-based radiopharmaceuticals have been widely developed, such as Food and Drug Administration-approved Flutarstat F-18, Illuccix, Posluma for the diagnosis and monitoring of PCa, and Pluvicto for treating PSMA-positive metastatic castration-resistant PCa. Here, we comprehensively analyze the selection and optimization strategies of four elements of nuclear drug technology: targeting ligands, linkers, chelators, and radionuclides, and discuss the origin of toxicity of radiopharmaceuticals, offering suggestions for the future development of radiopharmaceuticals.