In vivo characterization and dynamic receptor occupancy imaging of TPA023B, an alpha 2/alpha 3/alpha 5 subtype selective gamma-aminobutyric acid-a partial agonist

Van Laere, Koen, Bormans, Guy, Sanabria-Bohórquez, Sandra M, de Groot, Tjibbe, Dupont, Patrick, De Lepeleire, Inge, de Hoon, Jan, Mortelmans, Luc, Hargreaves, Richard J, Atack, John R and Burns, H Donald (2008) In vivo characterization and dynamic receptor occupancy imaging of TPA023B, an alpha 2/alpha 3/alpha 5 subtype selective gamma-aminobutyric acid-a partial agonist. Biological Psychiatry, 64 (2). pp. 153-161. ISSN 0006-3223

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Abstract

BACKGROUND:

A novel, high-affinity (.7-2.0 nmol) compound that selectively activates the alpha2, alpha 3, and alpha 5 (but not alpha1) gamma-aminobutyric acid-A (GABA(A)) receptor subtypes, TPA023B (2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl) imidazo[1,2-b][1,2,4]triazin-7-yl][1,1'-biphenyl]-2-carbonitrile) was pharmacologically characterized and studied by means of positron emission tomography (PET) to determine dynamic occupancies of the benzodiazepine binding site of human brain GABA(A) receptors after a single oral dose.

METHODS:

Four healthy male volunteers were studied in a double-blind, randomized placebo-controlled study of which three were given a single dose of 1.5 mg TPA023B and the fourth received placebo. The time course of GABA(A) receptor occupancy was determined with multiple dynamic [(11)C]flumazenil PET studies at pre-dose baseline and 5 and 24 hours after dose. Arterial sampling and full kinetic modeling with a two-compartment model was used to calculate parametric maps of receptor availability (distribution volume V(T)) and of occupancy.

RESULTS:

The GABA(A) receptor occupancy as determined from [(11)C]flumazenil V(T) values in all brain regions was reduced homogeneously, on average by 52.5 +/- 1.2% after 5 hours and 46.4 +/- 6.0% after 24 hours. No serious adverse events were encountered in humans.

CONCLUSIONS:

Single oral doses of 1.5 mg of TPA023B correspond to average receptor occupancies in neocortical regions of 52% and 46% after 5 and 24 hours, respectively. Provided suitable ligands and quantification methods are available for the appropriate target, quantitative PET offers a unique tool for dynamic in vivo measurement of relevant on-site receptor occupancy.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science
Depositing User: Deeptima Massey
Date Deposited: 09 Apr 2013 08:41
Last Modified: 09 Apr 2013 08:41
URI: http://srodev.sussex.ac.uk/id/eprint/44156
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