title: Radiosynthesis and preclinical evaluation of 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5.
abstract: (11)C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-(11)C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent.
  
  
  METHODS
  ABP688 was radiolabeled with (11)C by reacting (11)C-methyl iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime). The affinity of (11)C-ABP688 for mGluR5 was determined by Scatchard analysis using rat whole-brain membranes (without cerebellum). Ex vivo autoradiography, biodistribution, and PET studies with (11)C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice.
  
  
  RESULTS
  The overall synthesis time was 45-50 min from the end of radionuclide production. (11)C-ABP688 was obtained in good radiochemical yield (35% +/- 8%, n = 17, decay corrected), and the specific radioactivity was 150 +/- 50 GBq/mumol (n = 17) at the end of the synthesis. Scatchard analysis revealed a single high-affinity binding site with a dissociation constant of 1.7 +/- 0.2 nmol/L and a maximum number of binding sites of 231 +/- 18 fmol/mg of protein. Ex vivo autoradiography in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of (11)C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynyl-pyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of (11)C-ABP688 was observed. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of (11)C-ABP688 binding to mGluR5.
  
  
  CONCLUSIONS
  (11)C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.
authors.affiliation: Center for Radiopharmaceutical Science of ETH, PSI and USZ and Department of Chemistry and Applied Biosciences of ETH, CH-8093 Zurich, Switzerland. simon-ametamey@pharma.ethz.ch
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
authors.forename: Lea J
authors.initials: LJ
authors.lastname: Kessler
authors.forename: Michael
authors.initials: M
authors.lastname: Honer
authors.forename: Matthias T
authors.initials: MT
authors.lastname: Wyss
authors.forename: Alfred
authors.initials: A
authors.lastname: Buck
authors.forename: Samuel
authors.initials: S
authors.lastname: Hintermann
authors.forename: Yves P
authors.initials: YP
authors.lastname: Auberson
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gasparini
authors.forename: Pius A
authors.initials: PA
authors.lastname: Schubiger
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D005260:Female; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010091:Oximes / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: C510950:3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime; D002250:Carbon Radioisotopes; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D010091:Oximes; D011725:Pyridines; D019275:Radiopharmaceuticals; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate