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

作者：Van Laere Koen^*; Bormans Guy; Sanabria Bohorquez Sandra M; de Groot Tjibbe; Dupont Patrick; De Lepeleire Inge; de Hoon Jan; Mortelmans Luc; Hargreaves Richard J; Atack John R; Burns H Donald

来源：Biological Psychiatry, 2008, 64(2): 153-161.

DOI：10.1016/j.biopsych.2008.01.021

• anxioselectivity
• flumazenil
• GABA-A receptor subtypes
• occupancy
• positron emission tomography

Background: A novel, high-affinity (.7-2.0 nmol) compound that selectively activates the alpha 2, alpha 3, and alpha 5 (but not alpha 1) gamma-aminobutyric acid-A(GABAA) 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 GABAA 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 GABAA receptor occupancy was determined with multiple dynamic [C-11]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 GABAA receptor occupancy as determined from[C-11]flumazenil VT 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 T-P A023B 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.

• 出版日期2008-7-15