No abstract

A single-tissue compartment model with plasma input is the established method for analysing [ 11 C]flumazenil ([ 11 C]FMZ) studies. However, arterial cannulation and measurement of metabolites are time-consuming. Therefore, a reference tissue approach is appealing, but this approach has not been fully validated for [11 C]FMZ. Dynamic [ 11 C]FMZ positron emission tomography scans with arterial blood sampling were performed in nine drug-free depressive patients and eight healthy subjects. Regions of interest were defined on co-registered magnetic resonance imaging scans and projected onto dynamic [11 C]FMZ images. Using a Hill-type metabolite function, single (1T) and reversible two-tissue (2T) compartmental models were compared. Simplified reference tissue model (SRTM) and full reference tissue model (FRTM) were investigated using both pons and (centrum semiovale) white matter as reference tissue. The 2T model provided the best fit in 59% of cases. Two-tissue V T values were on average 1.6% higher than 1T V T values. Owing to the higher rejection rate of 2T fits (7.3%), the 1T model was selected as plasma input method of choice. SRTM was superior to FRTM, irrespective whether pons or white matter was used as reference tissue. BP ND values obtained with SRTM correlated strongly with 1T V T (r = 0.998 and 0.995 for pons and white matter, respectively). Use of white matter as reference tissue resulted in 5.5% rejected fits, primarily in areas with intermediate receptor density. No fits were rejected using pons as reference tissue. Pons produced 23% higher BP ND values than white matter. In conclusion, for most clinical studies, SRTM with pons as reference tissue can be used for quantifying [ 11 C]FMZ binding.

The bilateral reduction in limbic parahippocampal and right temporal [(11)C]FMZ binding found in MDD indicates decreased GABA(A)-benzodiazepine receptor complex affinity and/or number. The inverse relationship between GABA(A) binding in the temporal lobe and HPA axis activity, suggests that HPA axis hyperactivity is partly due to reduced GABA-ergic inhibition.