Occupancy of human brain GABA(A) receptors by the novel α5 subtype-selective benzodiazepine site inverse agonist α5IA as measured using [¹¹C]flumazenil PET imaging.
Neuropharmacology
; 59(7-8): 635-9, 2010 Dec.
Article
en En
| MEDLINE
| ID: mdl-20696179
ABSTRACT
GABA(A) 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 GABA(A) 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ftalazinas
/
Triazoles
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Flumazenil
/
Receptores de GABA-A
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Agonistas de Receptores de GABA-A
Límite:
Adult
/
Humans
/
Male
Idioma:
En
Revista:
Neuropharmacology
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos