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

Eng, W, Atack, J, Bergstrom, M, Sanabria, S, Appel, L, Dawson, G R, Sciberras, G, Hargreaves, R J, Langstrom, B and Burns, H D (2010) 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. Neuropharmacology, 59 (7). pp. 635-639. ISSN 0028-3908

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Abstract

GABAA 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 GABAA 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science
Depositing User: Deeptima Massey
Date Deposited: 09 Apr 2013 08:42
Last Modified: 09 Apr 2013 08:42
URI: http://sro.sussex.ac.uk/id/eprint/44155
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