BENZODIAZEPINE RECEPTOR QUANTIFICATION IN-VIVO IN HUMANS USING [C-11]FLUMAZENIL AND PET - APPLICATION OF THE STEADY-STATE PRINCIPLE

Carbon-11-labeled flumazenil combined with positron emission tomograph y (PET) was used to measure the concentration (B-max) of the benzodiaz epine (Bz) receptor in the brain and its equilibrium dissociation cons tant (K-D) for flumazenil in five normal subjects. The steady-state ap proach was used injecting the tracer as a bolus of high specific activ ity. In each subject two studies were carried out. The first study was performed at essentially zero receptor occupancy, the tracer alone st udy. The second study was performed at a steady-state receptor occupan cy of about 50%, achieved by a prolonged constant infusion of nonlabel ed (''cold'') flumazenil starting 2 h before the bolus tracer injectio n and continuing until the end of the scanning period. In this second study the free concentration of unmetabolized flumazenil in plasma wat er was measured in multiple blood samples. The observed tissue and pla sma tracer curves, calibrated in the same units of radioactivity per m illimeter, were analyzed in two ways: (a) by the noncompartmental (sto chastic) approach making no assumptions regarding number of compartmen ts in the tissue, and (b) by the single-compartment approach assuming rapid exchange (mixing) of tracer between all tissue compartments. The noncompartmental and the compartmental analyses gave essentially the same values for the distribution volume of the tracer, the parameter u sed for quantitation of the Bz receptor. As the compartmental approach could be applied to a shorter observation period (60 min instead of 1 20 min) it was preferred. The five subjects had a mean K-D value of 12 nM/L of water and B-max values of the grey matter ranging from 39 +/- 11 in thalamus to 120 +/- 14 nM/L of brain in occipital cortex. Most previous studies have been based on the pseudoequilibrium approach usi ng the brain stem as a receptor-free reference region. This yields pra ctically the same K-D but lower B-max values than the steady-state app roach presented here.