title: Occupancy of human brain GABA(A) receptors by the novel α5 subtype-selective benzodiazepine site inverse agonist α5IA as measured using [¹¹C]flumazenil PET imaging.
abstract: GABA(A) receptor α5-selective inverse agonists enhance cognitive performance in pre-clinical species. However, a key aspect of the clinical development of such compounds is the demonstration that in man such compounds are devoid of the anxiogenic-like activity associated with non-selective inverse agonists such as FG 7142. The triazolophthalazine α5IA (3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo[3,4-a]phthalazine) is an α5-selective inverse agonist which enhances cognitive performance in rodents and encouragingly in human Phase I Safety and Tolerability studies it was devoid of the anxiogenic-like activity associated with FG 7142. However, in order to appropriately interpret this latter observation, it was considered important to demonstrate that the absence of anxiogenic-like activity occurs at significant levels of receptor occupancy. Consequently, the occupancy of human brain GABA(A) receptors was measured using [¹¹C]flumazenil positron emission tomography in three healthy normal young male volunteers following a single oral dose of 2 mg α5IA. One hour after dosing, mean occupancy levels were 53% and this fell to 16% by 8 h post-dose, with the plasma α5IA concentration corresponding to 50% occupancy being 10 ng/mL. These data clearly show that an α5-selective inverse agonist is not associated with anxiogenic-like side effects at doses that give ~50% occupancy.
authors.affiliation: Imaging Department, Merck & Co. Inc., West Point, PA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Eng
authors.forename: J R
authors.initials: JR
authors.lastname: Atack
authors.forename: M
authors.initials: M
authors.lastname: Bergstrom
authors.forename: S
authors.initials: S
authors.lastname: Sanabria
authors.forename: L
authors.initials: L
authors.lastname: Appel
authors.forename: G R
authors.initials: GR
authors.lastname: Dawson
authors.forename: D
authors.initials: D
authors.lastname: Sciberras
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
authors.forename: B
authors.initials: B
authors.lastname: Langstrom
authors.forename: H D
authors.initials: HD
authors.lastname: Burns
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D054314:Drug Inverse Agonism; D005442:Flumazenil / Q000378:metabolism*; D058785:GABA-A Receptor Agonists / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D010793:Phthalazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D021122:Protein Subunits / Q000819:agonists / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D014230:Triazoles / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C555638:3-(5-methylisoxazol-3-yl)-6-((1-methyl-1,2,3-triazol-4-yl)methyloxy)-1,2,4-triazolo(3,4-a)phthalazine; D002250:Carbon Radioisotopes; D058785:GABA-A Receptor Agonists; D010793:Phthalazines; D021122:Protein Subunits; D011963:Receptors, GABA-A; D014230:Triazoles; D005442:Flumazenil