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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

journal contribution
posted on 2023-06-08, 14:40 authored by Koen Van Laere, Guy Bormans, Sandra M Sanabria-Bohórquez, Tjibbe de Groot, Patrick Dupont, Inge De Lepeleire, Jan de Hoon, Luc Mortelmans, Richard J Hargreaves, John R Atack, H Donald Burns
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.

History

Publication status

  • Published

Journal

Biological Psychiatry

ISSN

0006-3223

Publisher

Elsevier

Issue

2

Volume

64

Page range

153-161

Department affiliated with

  • Biochemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2013-04-09

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