A series of halogenated heterodimeric inhibitors of prostate specific membrane antigen (PSMA) as radiolabeled probes for targeting prostate cancer

J Med Chem. 2009 Jan 22;52(2):347-57. doi: 10.1021/jm800994j.


Prostate specific membrane antigen (PSMA) is a validated molecular marker for prostate cancer. A series of glutamate-urea (Glu-urea-X) heterodimeric inhibitors of PSMA were designed and synthesized where X = epsilon-N-(o-I, m-I, p-I, p-Br, o-Cl, m-Cl, p-Cl, p-F, H)-benzyl-Lys and epsilon-(p-I, p-Br, p-Cl, p-F, H)-phenylureido-Lys. The affinities for PSMA were determined by screening in a competitive binding assay. PSMA binding of the benzyllysine series was significantly affected by the nature of the halogen substituent (IC(50) values, Cl < I = Br << F = H) and the ring position of the halogen atom (IC(50) values, p-I < o-I << m-I). The halogen atom had little affect on the binding affinity in the para substituted phenylureido-Lys series. Two lead iodine compounds were radiolabeled with (123)I and (131)I and demonstrated specific PSMA binding on human prostate cancer cells, warranting evaluation as radioligands for the detection, staging, and monitoring of prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigens, Surface
  • Chromatography, High Pressure Liquid
  • Dimerization
  • Glutamate Carboxypeptidase II / antagonists & inhibitors*
  • Halogens / chemistry*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Male
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / immunology
  • Radioligand Assay
  • Spectrometry, Mass, Electrospray Ionization
  • Spectrophotometry, Ultraviolet


  • Antigens, Surface
  • Halogens
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II