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Occupancy of human ...
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
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Eng, W. (author)
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Atack, J. R. (author)
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- Bergström, M. (author)
- Uppsala universitet,Enheten för nuklearmedicin och PET
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Sanabria, S. (author)
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- Appel, Lieuwe (author)
- Uppsala universitet,Enheten för nuklearmedicin och PET
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Dawson, G. R. (author)
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Sciberras, D. (author)
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Hargreaves, R. J. (author)
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- Långström, Bengt (author)
- Uppsala universitet,Institutionen för biokemi och organisk kemi
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Burns, H. D. (author)
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(creator_code:org_t)
- Elsevier BV, 2010
- 2010
- English.
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In: Neuropharmacology. - : Elsevier BV. - 0028-3908 .- 1873-7064. ; 59:7-8, s. 635-639
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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.
Keyword
- GABA(A) receptor
- alpha 5-selective
- Benzodiazepine
- Inverse agonist
- Positron emission tomography
- [C-11]flumazenil
- MEDICINE
- MEDICIN
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Eng, W.
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Atack, J. R.
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Bergström, M.
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Sanabria, S.
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Appel, Lieuwe
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Dawson, G. R.
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show more...
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Sciberras, D.
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Hargreaves, R. J ...
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Långström, Bengt
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Burns, H. D.
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show less...
- Articles in the publication
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Neuropharmacolog ...
- By the university
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Uppsala University