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

INTRODUCTION: We measured the tiagabine-induced enhancement of the GABAA 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 (10mg/kg) was intravenously injected after the baseline session. [18 F]FMZ binding potentials (BPND ) were calculated using an equilibrium ratio method and a modeling method for B/I and SB, respectively. Regional brain BPND changes (%) before and after the tiagabine treatment were also calculated.

RESULTS: In PET studies with B/I (Kbol =20min), [18 F]FMZ distribution in the various cortical and subcortical regions rapidly reached equilibrium. After the tiagabine treatment, [18 F]FMZ BPND were substantially increased across the regions of interest (the frontal cortex, hippocampus, thalamus, and striatum), ranging from 3% to 7% BPND change (B/I) and 6-14% BPND change (SB), respectively. In PET studies with SB, a statistically significant increase of [18 F]FMZ BPND 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 (Kbol =20min) is both reliable and sensitive for the assessment of altered GABAA 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.