In Vivo Characterization and Dynamic Receptor Occupancy Imaging of TPA023B, an α2/α3/α5 Subtype Selective γ-Aminobutyric Acid–A Partial Agonist

Background: A novel, high-affinity (.7–2.0 nmol) compound that selectively activates the α2, α3, and α5 (but not α1) γ-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 [11C]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 VT) and of occupancy. Results: The GABAA receptor occupancy as determined from [11C]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 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. [Copyright &y& Elsevier]