Synthesis and evaluation of technetium-99m- and rhenium-labeled inhibitors of the prostate-specific membrane antigen (PSMA)

J Med Chem. 2008 Aug 14;51(15):4504-17. doi: 10.1021/jm800111u. Epub 2008 Jul 19.


The prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for imaging and therapy of cancer. We prepared seven (99m)Tc/Re-labeled compounds by attaching known Tc/Re chelating agents to an amino-functionalized PSMA inhibitor (lys-NHCONH-glu) with or without a variable length linker moiety. K i values ranged from 0.17 to 199 nM. Ex vivo biodistribution and in vivo imaging demonstrated the degree of specific binding to engineered PSMA+ PC3 PIP tumors. PC3-PIP cells are derived from PC3 that have been transduced with the gene for PSMA. Despite demonstrating nearly the lowest PSMA inhibitory potency of this series, [(99m)Tc(CO)3( L1)] (+) ( L1 = (2-pyridylmethyl)2N(CH2) 4CH(CO2H)NHCO-(CH2) 6CO-NH-lys-NHCONH-glu) showed the highest, most selective PIP tumor uptake, at 7.9 +/- 4.0% injected dose per gram of tissue at 30 min postinjection. Radioactivity cleared from nontarget tissues to produce a PIP to flu (PSMA-PC3) ratio of 44:1 at 120 min postinjection. PSMA can accommodate the steric requirements of (99m)Tc/Re complexes within PSMA inhibitors, the best results achieved with a linker moiety between the epsilon amine of the urea lysine and the chelator.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Chelating Agents / chemical synthesis
  • Chelating Agents / chemistry
  • Electrons
  • Glutamate Carboxypeptidase II / antagonists & inhibitors*
  • Glutamate Carboxypeptidase II / metabolism
  • Male
  • Mice
  • Molecular Structure
  • Neoplasm Transplantation
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*
  • Protein Binding
  • Rhenium / chemistry
  • Structure-Activity Relationship
  • Technetium / chemistry
  • Urea / chemistry


  • Chelating Agents
  • Protease Inhibitors
  • Rhenium
  • Technetium
  • Urea
  • Glutamate Carboxypeptidase II