Development and Advantages of O -(Carboxymethyl)- L -tyrosine-Based PSMA-Targeting Theranostics for Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a well-established target for diagnostic imaging and radioligand therapy (RLT) in prostate cancer (PCa). This Perspective highlights PSMA-targeting agents incorporating the O -(carboxymethyl)- L -tyrosine scaffold, a versatile linker that enhances binding affinity and optimizes pharmacokinetics. The PET tracer [ 68 Ga]Ga–P16–093 demonstrates high tumor uptake and low urinary background in clinical studies. Its success has enabled the development of therapeutic counterparts, including [ 177 Lu]Lu–P17–087 which shows rapid in vivo kinetics, and [ 177 Lu]Lu–P17–088 which exhibits improved tumor retention and prolonged circulation compared with [ 177 Lu]Lu-PSMA-617 (PLUVICTO). The modular scaffold supports structural diversification, including alternative chelators and dual-targeting strategies. Incorporating a bisphosphonate moiety in P17–079 enables simultaneous targeting of PSMA and bone metastases. This adaptable platform facilitates the development of next-generation radiopharmaceuticals as theranostics for the treatment of PCa.