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.
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.
Van Laere
Koen
K
Division of Nuclear Medicine, K.U.Leuven, Belgium. koen.vanlaere@uz.kuleuven.ac.be
Bormans
Guy
G
Sanabria-Bohórquez
Sandra M
SM
de Groot
Tjibbe
T
Dupont
Patrick
P
De Lepeleire
Inge
I
de Hoon
Jan
J
Mortelmans
Luc
L
Hargreaves
Richard J
RJ
Atack
John R
JR
Burns
H Donald
HD
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects*; D002250:Carbon Radioisotopes; D004311:Double-Blind Method; D005442:Flumazenil; D018755:GABA Agonists / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008297:Male; D049268:Positron-Emission Tomography; D011724:Pyridazines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism*; D014230:Triazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*
C507018:7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo(4,3-b)pyridazine; D002250:Carbon Radioisotopes; D018755:GABA Agonists; D011724:Pyridazines; D011963:Receptors, GABA-A; D014230:Triazoles; D005442:Flumazenil