Development of PSMA-1007-Related Series of 18F-Labeled Glu-Ureido-Type PSMA Inhibitors

J Med Chem. 2020 Oct 8;63(19):10897-10907. doi: 10.1021/acs.jmedchem.9b01479. Epub 2020 Sep 22.

Abstract

In recent years, a number of drugs targeting the prostate-specific membrane antigen (PSMA) have become important tools in the diagnosis and treatment of prostate cancer. In the present work, we report on the synthesis and preclinical evaluation of a series of 18F-labeled PSMA ligands for diagnostic application based on the theragnostic ligand PSMA-617. By applying modifications to the linker structure, insight into the structure-activity relationship could be gained, highlighting the importance of hydrophilicity and stereoselectivity on interaction with PSMA and hence the biodistribution. Selected compounds were co-crystallized with the PSMA protein and analyzed by X-rays with mixed results. Among these, PSMA-1007 (compound 5) showed the best interaction with the PSMA protein. The respective radiotracer [18F]PSMA-1007 was translated into the clinic and is, in the meantime, subject of advanced clinical trials.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Surface
  • Fluorine Radioisotopes / chemistry*
  • Glutamate Carboxypeptidase II / antagonists & inhibitors*
  • Humans
  • Ligands
  • Male
  • Niacinamide / analogs & derivatives*
  • Niacinamide / chemistry
  • Niacinamide / pharmacology
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacology
  • Positron-Emission Tomography
  • Prostatic Neoplasms / diagnostic imaging
  • Radiopharmaceuticals / pharmacology

Substances

  • Antigens, Surface
  • Fluorine Radioisotopes
  • Ligands
  • Oligopeptides
  • PSMA-1007
  • Radiopharmaceuticals
  • Niacinamide
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II