QUANTIFICATION OF BENZODIAZEPINE RECEPTORS IN HUMAN BRAIN USING PET, [C-11] FLUMAZENIL, AND A SINGLE-EXPERIMENT PROTOCOL

A kinetic method using a multiinjection protocol, positron emission to mography (PET), and [C-11]flumazenil as a specific ligand was used to study in vivo the flumazenil-benzodiazepine receptor interactions in t he human brain. The model structure is composed of three compartments (plasma, free, and bound ligand) and five parameters (including the be nzodiazepine receptor concentration). The arterial plasma concentratio n, after correction for metabolites, was used as the input function. T he experimental protocol, which consisted of three injections of label ed and/or unlabeled ligand, allowed the evaluation of the five model p arameters in various brain regions from a single experiment. In partic ular, the concentration of receptor sites available for binding (B'(ma x)) and the equilibrium dissociation constant (KDVR, V-R being the vol ume of reaction) were estimated in five brain regions, including the p ens, in which these parameters are identified for the first time (B'(m ax) = 4.7 +/- 1.7 pmol/ml and KDVR = 4.4 +/- 1.3 pmol/ml). Due to the large range of measured receptor concentrations, a linear correlation between B'(max) and KDVR was pointed out (r = 0.88, p < 0.0005) and wa s interpreted as a linear relationship between B'(max) and V-R, the pa rameter K-D being assumed constant. This result and its concordance wi th the published data are discussed. Simulation of the usual two-exper iment Scatchard analysis, using the pens as a reference region, showed that the bias on the receptor concentration estimates introduced by t his method is significant (from 20 to 40%) but can be corrected using an estimate of the receptor concentration in the pens. Furthermore, we propose a new experimental protocol, based on a Scatchard analysis of the PET data obtained with a partial-saturation experiment. This sing le-injection protocol is entirely noninvasive, and thus the estimation of the benzodiazepine receptor concentration and of the flumazenil af finity is now possible in human patients using a single 1-h experiment without blood sampling.