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 [⁶⁸Ga]Ga-P16-093 demonstrates high tumor uptake and low urinary background in clinical studies. Its success has enabled the development of therapeutic counterparts, including [¹⁷⁷Lu]Lu-P17-087 which shows rapid in vivo kinetics, and [¹⁷⁷Lu]Lu-P17-088 which exhibits improved tumor retention and prolonged circulation compared with [¹⁷⁷Lu]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.