uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
Show others and affiliations
2010 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 59, no 7-8, 635-639 p.Article in journal (Refereed) Published
Abstract [en]

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.
Keyword [en]
GABA(A) receptor, alpha 5-selective, Benzodiazepine, Inverse agonist, Positron emission tomography, [C-11]flumazenil
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-139387DOI: 10.1016/j.neuropharm.2010.07.024ISI: 000284436400010PubMedID: 20696179OAI: oai:DiVA.org:uu-139387DiVA: diva2:381315
Available from: 2010-12-27 Created: 2010-12-23 Last updated: 2013-03-14Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Appel, Lieuwe
By organisation
Section of Nuclear Medicine and PETDepartment of Biochemistry and Organic Chemistry
In the same journal
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 136 hits
ReferencesLink to record
Permanent link

Direct link