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Occupancy of human brain GABAA receptors by the novel α5 subtype-selective benzodiazepine site inverse agonist α5IA as measured using [11C]flumazenil PET imaging

Eng, W., Atack, J.R., Bergstrom, M., Sanabria, S., Appel, L., Dawson, G.R., Sciberras, D., Hargreaves, R.J., Langstrom, B. and Burns, H.D. 2010. Occupancy of human brain GABAA receptors by the novel α5 subtype-selective benzodiazepine site inverse agonist α5IA as measured using [11C]flumazenil PET imaging. Neuropharmacology 59 (7-8) , pp. 635-639. 10.1016/j.neuropharm.2010.07.024

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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
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Elsevier
ISSN: 0028-3908
Date of Acceptance: 29 July 2010
Last Modified: 14 Nov 2017 21:02
URI: http://orca.cf.ac.uk/id/eprint/105896

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