PT - JOURNAL ARTICLE AU - Lindemann, Lothar AU - Jaeschke, Georg AU - Michalon, Aubin AU - Vieira, Eric AU - Honer, Michael AU - Spooren, Will AU - Porter, Richard AU - Hartung, Thomas AU - Kolczewski, Sabine AU - Büttelmann, Bernd AU - Flament, Christophe AU - Diener, Catherine AU - Fischer, Christophe AU - Gatti, Silvia AU - Prinssen, Eric P. AU - Parrott, Neil AU - Hoffmann, Gerhard AU - Wettstein, Joseph G. TI - CTEP: A Novel, Potent, Long-Acting, and Orally Bioavailable Metabotropic Glutamate Receptor 5 Inhibitor AID - 10.1124/jpet.111.185660 DP - 2011 Nov 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 474--486 VI - 339 IP - 2 4099 - http://jpet.aspetjournals.org/content/339/2/474.short 4100 - http://jpet.aspetjournals.org/content/339/2/474.full SO - J Pharmacol Exp Ther2011 Nov 01; 339 AB - The metabotropic glutamate receptor 5 (mGlu5) is a glutamate-activated class C G protein-coupled receptor widely expressed in the central nervous system and clinically investigated as a drug target for a range of indications, including depression, Parkinson's disease, and fragile X syndrome. Here, we present the novel potent, selective, and orally bioavailable mGlu5 negative allosteric modulator with inverse agonist properties 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP). CTEP binds mGlu5 with low nanomolar affinity and shows >1000-fold selectivity when tested against 103 targets, including all known mGlu receptors. CTEP penetrates the brain with a brain/plasma ratio of 2.6 and displaces the tracer [3H]3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-methyl-oxime (ABP688) in vivo in mice from brain regions expressing mGlu5 with an average ED50 equivalent to a drug concentration of 77.5 ng/g in brain tissue. This novel mGlu5 inhibitor is active in the stress-induced hyperthermia procedure in mice and the Vogel conflict drinking test in rats with minimal effective doses of 0.1 and 0.3 mg/kg, respectively, reflecting a 30- to 100-fold higher in vivo potency compared with 2-methyl-6-(phenylethynyl)pyridine (MPEP) and fenobam. CTEP is the first reported mGlu5 inhibitor with both long half-life of approximately 18 h and high oral bioavailability allowing chronic treatment with continuous receptor blockade with one dose every 48 h in adult and newborn animals. By enabling long-term treatment through a wide age range, CTEP allows the exploration of the full therapeutic potential of mGlu5 inhibitors for indications requiring chronic receptor inhibition.