Inhibitors of prostate-specific membrane antigen in the diagnosis and therapy of metastatic prostate cancer - a review of patent literature

Introduction Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II, is a potential target protein for imaging and treatment of patients with prostate cancer because of its overexpression during metastasis. Various PSMA-targeted imaging and therapeutic probes have been designed and synthesized based on the Lys-urea-Glu motif. Structural modifications have been made exclusively in the linker region, while maintaining the Lys-urea-Glu structure that interacts with S1 and S1MODIFIER LETTER PRIME pockets. Area Covered This review includes WIPO-listed patents (from January 2017 to June 2020) reporting PSMA-targeted probes based on the Lys-urea-Glu or Glu-urea-Glu structure. Expert opinion : PSMA-targeted imaging agents labeled with radionuclides such as fluorine-18, copper-64, gallium-68, and technetium-99m have been successfully translated into clinical phase for the early diagnosis of metastatic prostate cancer. Recently, PSMA-targeted therapeutic agents labeled with iodine-131, lutetium-177, astatine-211, and lead-212 have also been developed with notable progress. Most PSMA-targeted agents are based on the Lys-urea-Glu or Glu-urea-Glu structure, demonstrate strong PSMA-binding affinity in nanomolar range, and achieve diverse structural modifications in the non-pharmacophore pocket. By exploiting the S1 accessory pocket or the tunnel region of the PSMA active site, the in vivo efficacy and pharmacokinetic profiles of the PMSA-targeted agents can be effectively modulated.

Automated summary

PSMA-targeted probes based on the Lys-urea-Glu structure have been successfully translated into clinical use, including imaging agents labeled with radionuclides and therapeutic agents with structure modifications in the non-pharmacophore pocket.