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Occupancy of human brain GABA A receptors by the novel a5 subtype-selective benzodiazepine site inverse agonist a5IA as measured using [ 11C]flumazenil PET imaging
journal contribution
posted on 2023-06-08, 14:40 authored by W Eng, J Atack, M Bergstrom, S Sanabria, L Appel, G R Dawson, G Sciberras, R J Hargreaves, B Langstrom, H D BurnsGABAA receptor a5-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 a5IA (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 a5-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 a5IA. One hour after dosing, mean occupancy levels were 53% and this fell to 16% by 8 h post-dose, with the plasma a5IA concentration corresponding to 50% occupancy being 10 ng/mL. These data clearly show that an a5-selective inverse agonist is not associated with anxiogenic-like side effects at doses that give ~50% occupancy.
History
Publication status
- Published
Journal
NeuropharmacologyISSN
0028-3908Publisher
ElsevierExternal DOI
Issue
7Volume
59Page range
635-639Department affiliated with
- Biochemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2013-04-09Usage metrics
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