Radiohalogenated prostate-specific membrane antigen (PSMA)-based ureas as imaging agents for prostate cancer

J Med Chem. 2008 Dec 25;51(24):7933-43. doi: 10.1021/jm801055h.

Abstract

To extend our development of new imaging agents targeting the prostate-specific membrane antigen (PSMA), we have used the versatile intermediate 2-[3-(5-amino-1-carboxy-pentyl)-ureido]-pentanedioic acid (Lys-C(O)-Glu), which allows ready incorporation of radiohalogens for single photon emission computed tomography (SPECT) and positron emission tomography (PET). We prepared 2-[3-[1-carboxy-5-(4-[(125)I]iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid ([(125)I]3), 2-[3-[1-carboxy-5-(4-[(18)F]fluoro-benzoylamino)-pentyl]-ureido]-pentanedioic acid ([(18)F]6), and 2-(3-[1-carboxy-5-[(5-[(125)I]iodo-pyridine-3-carbonyl)-amino]-pentyl]-ureido)-pentanedioic acid ([(125)I]8) in 65-80% (nondecay-corrected), 30-35% (decay corrected), and 59-75% (nondecay-corrected) radiochemical yields. Compound [(125)I]3 demonstrated 8.8 +/- 4.7% injected dose per gram (%ID/g) within PSMA(+) PC-3 PIP tumor at 30 min postinjection, which persisted, with clear delineation of the tumor by SPECT. Similar tumor uptake values at early time points were demonstrated for [(18)F]6 (using PET) and [(125)I]8. Because of the many radiohalogenated moieties that can be attached via the epsilon amino group, the intermediate Lys-C(O)-Glu is an attractive template upon which to develop new imaging agents for prostate cancer.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Animals
  • Antigens, Surface / biosynthesis*
  • Antigens, Surface / chemistry
  • Binding Sites
  • Chemistry, Pharmaceutical / methods
  • Computational Biology / methods
  • Diagnostic Imaging / instrumentation
  • Diagnostic Imaging / methods
  • Drug Design
  • Glutamate Carboxypeptidase II / biosynthesis*
  • Glutamate Carboxypeptidase II / chemistry
  • Humans
  • Male
  • Models, Molecular
  • Molecular Conformation
  • Prostatic Neoplasms / metabolism*
  • Protein Binding
  • Radiopharmaceuticals / pharmacology

Substances

  • Antigens, Surface
  • Radiopharmaceuticals
  • Adenosine Triphosphate
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II