PET measurement of “GABA shift” in the rat brain: A preclinical application of bolus plus constant infusion paradigm of [18F]flumazenil

Abstract Introduction We measured the tiagabine-induced enhancement of the GABA A receptor's affinity for benzodiazepine ligands (“GABA shift”) using [ 18 F]flumazenil (FMZ) PET with preclinical application of bolus plus constant infusion (B/I). Differences in quantified results of [ 18 F]FMZ binding were compared to that of [ 18 F]FMZ PET with single bolus injection (SB). Materials and methods Sprague–Dawley rats underwent [ 18 F]FMZ PET scans with B/I, which consisted of baseline and “GABA shift” sessions in a scan, or scans with SB one week apart. Tiagabine (10 mg/kg) was intravenously injected after the baseline session. [ 18 F]FMZ binding potentials (BP ND ) were calculated using an equilibrium ratio method and a modeling method for B/I and SB, respectively. Regional brain BP ND changes (%) before and after the tiagabine treatment were also calculated. Results In PET studies with B/I ( K bol  = 20 min), [ 18 F]FMZ distribution in the various cortical and subcortical regions rapidly reached equilibrium. After the tiagabine treatment, [ 18 F]FMZ BP ND were substantially increased across the regions of interest (the frontal cortex, hippocampus, thalamus, and striatum), ranging from 3% to 7% BP ND change (B/I) and 6–14% BP ND change (SB), respectively. In PET studies with SB, a statistically significant increase of [ 18 F]FMZ BP ND was found only in the striatum, due to the greater inter-individual variance compared to those with B/I. Conclusions Data demonstrated that an [ 18 F]FMZ PET study with B/I ( K bol  = 20 min) is both reliable and sensitive for the assessment of altered GABA A receptor function induced by tiagabine treatment in the rat brain. These results may help to improve the efficiency of the development of new GABA-targeting drugs in the preclinical stage using [ 18 F]FMZ PET.