title: In vivo receptor occupancy of mGlu5 receptor antagonists using the novel radioligand [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine).
abstract: In vivo receptor occupancy of mGlu5 receptor antagonists was quantified in rat and mouse brain using the mGlu5 receptor selective antagonist [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine) ([3H]methoxy-PEPy). Administration of [3H]methoxy-PEPy (50 microCi/kg i.v.) to mGlu5 receptor-deficient mice revealed binding at background levels in forebrain, whereas wild-type mice exhibited 14-fold higher binding in forebrain relative to cerebellum. Systemic administration of the mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) reduced the binding of [3H]methoxy-PEPy in rats and mice, reflecting mGlu5 receptor occupancy by these compounds. MPEP (10 mg/kg i.p.) and MTEP (3 mg/kg i.p.) maintained >75% receptor occupancy for 2 h in rats, while in mice MPEP and MTEP achieved >75% occupancy for only 30 and 15 min, respectively. Compound levels in plasma were substantially lower in mice suggesting species differences in receptor occupancy result from differences in absorption or metabolism of the compounds. These findings demonstrate that [3H]methoxy-PEPy is useful for determining the occupancy of mGlu5 receptors in the brain.
authors.affiliation: Department of Neuropharmacology, Merck Research Laboratories, MRLSDB1, 3535 General Atomics Court, San Diego, CA 92121, USA. jeffery_anderson@merck.com
authors.forename: Jeffery J
authors.initials: JJ
authors.lastname: Anderson
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Bradbury
authors.forename: Darlene R
authors.initials: DR
authors.lastname: Giracello
authors.forename: Deborah F
authors.initials: DF
authors.lastname: Chapman
authors.forename: Greg
authors.initials: G
authors.lastname: Holtz
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Roppe
authors.forename: Chris
authors.initials: C
authors.lastname: King
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
authors.forename: Mark A
authors.initials: MA
authors.lastname: Varney
mesh_terms: D000818:Animals; D001665:Binding Sites; D006624:Hippocampus / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016548:Prosencephalon / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors; D014316:Tritium
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; C474798:3-(3H)methoxy-5-(pyridin-2-ylethynyl)pyridine; D008024:Ligands; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; D014316:Tritium; C121465:6-methyl-2-(phenylethynyl)pyridine