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

Introduction: We measured the tiagabine-induced enhancement of the GABA_A receptor's affinity for benzodiazepine ligands ("GABA shift") using [¹⁸F]flumazenil (FMZ) PET with preclinical application of bolus plus constant infusion (B/I). Differences in quantified results of [¹⁸F]FMZ binding were compared to that of [¹⁸F]FMZ PET with single bolus injection (SB). Materials and methods: Sprague–Dawley rats underwent [¹⁸F]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. [¹⁸F]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), [¹⁸F]FMZ distribution in the various cortical and subcortical regions rapidly reached equilibrium. After the tiagabine treatment, [¹⁸F]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 [¹⁸F]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 [¹⁸F]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 [¹⁸F]FMZ PET.