11C-MCG: synthesis, uptake selectivity, and primate PET of a probe for glutamate carboxypeptidase II (NAALADase)

Mol Imaging. Apr-Jun 2002;1(2):96-101. doi: 10.1162/153535002320162750.

Abstract

Imaging of glutamate carboxypeptidase II (GCP II), also known as N-acetylated alpha-linked L-amino dipeptidase (NAALADase), may enable study of glutamatergic transmission, prostate cancer, and tumor neovasculature in vivo. Our goal was to develop a probe for GCP II for use with positron emission tomography (PET). Radiosynthesis of 11C-MeCys-C(O)-Glu or 11C-(S)-2-[3-((R)-1-carboxy-2-methylsulfanyl-ethyl)-ureido]-pentanedioic acid (11C-MCG), an asymmetric urea and potent (Ki = 1.9 nM) inhibitor of GCP II, was performed by C-11 methylation of the free thiol. Biodistribution of 11C-MCG was assayed in mice, and quantitative PET was performed in a baboon. 11C-MCG was obtained in 16% radiochemical yield at the end of synthesis with specific radioactivities over 167 GBq/mmol (4000 Ci/mmol) within 30 min after the end of bombardment. At 30 min postinjection, 11C-MCG showed 33.0 +/- 5.1%, 0.4 +/- 0.1%, and 1.1 +/- 0.2% ID/g in mouse kidney (target tissue), muscle, and blood, respectively. Little radioactivity gained access to the brain. Blockade with unlabeled MCG or 2-(phosphonomethyl)pentanedioic acid (PMPA), another potent inhibitor of GCP II, provided sevenfold and threefold reductions, respectively, in binding to target tissue. For PET, distribution volumes (DVs) were 1.38 then 0.87 pre- and postblocker (PMPA). Little metabolism of 11C-MCG occurred in the mouse or baboon. These results suggest that 11C-MCG may be useful for imaging GCP II in the periphery.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Carbon Radioisotopes / pharmacokinetics*
  • Carboxypeptidases / metabolism*
  • Glutamate Carboxypeptidase II
  • Glutarates / pharmacokinetics*
  • Male
  • Methylation
  • Mice
  • Models, Animal
  • Papio
  • Tissue Distribution
  • Tomography, Emission-Computed / methods*

Substances

  • (S)-2-(3-((R)-1-carboxy-2-methylsulfanyl-ethyl)-ureido)pentanedioic acid
  • Carbon Radioisotopes
  • Glutarates
  • Carboxypeptidases
  • Glutamate Carboxypeptidase II