Occupancy of human brain GABA(A) receptors by the novel alpha 5 subtype-selective benzodiazepine site inverse agonist alpha 5IA as measured using [C-11]flumazenil PET imaging
2010 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 59, no 7-8, 635-639 p.Article in journal (Refereed) Published
GABA(A) receptor alpha 5-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 alpha 5IA (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 alpha 5-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 [C-11]flumazenil positron emission tomography in three healthy normal young male volunteers following a single oral dose of 2 mg alpha 5IA. One hour after dosing, mean occupancy levels were 53% and this fell to 16% by 8 h post-dose, with the plasma alpha 5IA concentration corresponding to 50% occupancy being 10 ng/mL. These data clearly show that an alpha 5-selective inverse agonist is not associated with anxiogenic-like side effects at doses that give 50% occupancy.
Place, publisher, year, edition, pages
2010. Vol. 59, no 7-8, 635-639 p.
GABA(A) receptor, alpha 5-selective, Benzodiazepine, Inverse agonist, Positron emission tomography, [C-11]flumazenil
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-139387DOI: 10.1016/j.neuropharm.2010.07.024ISI: 000284436400010PubMedID: 20696179OAI: oai:DiVA.org:uu-139387DiVA: diva2:381315