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. ORCID: https://orcid.org/0000-0002-3410-791X, 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

Full text not available from this repository.

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:	03 Nov 2022 09:45
URI:	https://orca.cardiff.ac.uk/id/eprint/105896

Citation Data

Cited 16 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item