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.