title: Human PET studies of metabotropic glutamate receptor subtype 5 with 11C-ABP688.
abstract: 3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime (11C-ABP688), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent.
  
  
  METHODS
  Six healthy male volunteers (mean age, 25 y; range, 21-33 y) were studied. Brain perfusion (15O-H2O) was measured immediately before each 11C-ABP688 PET scan. For anatomic coregistration, T1-weighted MRI was performed on each subject. Arterial blood samples for the determination of the arterial input curve were obtained at predefined time points, and 11C-ABP688 uptake was assessed quantitatively using a 2-tissue-compartment model.
  
  
  RESULTS
  An initial rapid uptake of radioactivity followed by a gradual clearance from all examined brain regions was observed. Relatively high radioactivity concentrations were observed in mGluR5-rich brain regions such as the anterior cingulate, medial temporal lobe, amygdala, caudate, and putamen, whereas radioactivity uptake in the cerebellum and white matter, regions known to contain low densities of mGluR5, was low. Specific distribution volume as an outcome measure of mGluR5 density in the various brain regions ranged from 5.45 +/- 1.47 (anterior cingulate) to 1.91 +/- 0.32 (cerebellum), and the rank order of the corresponding specific distribution volumes of 11C-ABP688 in cortical regions was temporal > frontal > occipital > parietal. The metabolism of 11C-ABP688 in plasma was rapid; at 60 min after injection, 25% +/- 0.03% of radioactivity measured in the plasma of healthy volunteers was intact parent compound.
  
  
  CONCLUSIONS
  The results of these studies indicate that 11C-ABP688 has suitable characteristics and is a promising PET ligand for imaging mGluR5 distribution in humans. Furthermore, it could be of great value for the selection of appropriate doses of clinically relevant candidate drugs that bind to mGluR5 and for PET studies of patients with psychiatric and neurologic disorders.
authors.affiliation: Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, Zurich, Switzerland. simon.ametamey@pharma.ethz.ch
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
authors.forename: Valerie
authors.initials: V
authors.lastname: Treyer
authors.forename: Johannes
authors.initials: J
authors.lastname: Streffer
authors.forename: Matthias T
authors.initials: MT
authors.lastname: Wyss
authors.forename: Mark
authors.initials: M
authors.lastname: Schmidt
authors.forename: Milen
authors.initials: M
authors.lastname: Blagoev
authors.forename: Samuel
authors.initials: S
authors.lastname: Hintermann
authors.forename: Yves
authors.initials: Y
authors.lastname: Auberson
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gasparini
authors.forename: Uta C
authors.initials: UC
authors.lastname: Fischer
authors.forename: Alfred
authors.initials: A
authors.lastname: Buck
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism; D003627:Data Interpretation, Statistical; D006801:Humans; D007553:Isotope Labeling; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010091:Oximes / Q000138:chemical synthesis; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*
chemical_list: C510950:3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; D010091:Oximes; D011725:Pyridines; D019275:Radiopharmaceuticals; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate