This project will apply an established equilibrium binding method for estimation of regional brain benzodiazepine binding site (""""""""benzOdiazepine receptor""""""""; BZR) numbers to normal human subjects and to patients with anxiety disorders. It will employ positron emission tomography (PET) and the radiotracer [11C]flumazenil to image and quantify cerebral BZR in vivo. The project has three major divisions: the first is devoted to calculation of specific radioligand binding maps, and for their summation across individuals to produce population-average data; the second concerns evaluation of benzodiazepine binding site occupancy estimation following administration of pharmacologic doses of unlabeled drugs; the third will explore the possibility of altered benzodiazepine receptors in patients with anxiety disorders. These studies will yield new information on the central nervous system actions of benzodiazepines in humans, and will permit the direct testing of hypothesized psychiatric disease mechanisms. Experiments are proposed to further investigate quantification of high- affinity ligand binding to the BZR by application of less-invasive procedures. The experimental design will make use of venous blood sampling and continuous tracer infusion to achieve a true equilibrium between blood and brain. Successful implementation may lead to more widespread application of the method, particularly in populations where arterial sampling may not be feasible. Analytic methods will be developed to quantify and display changes in BZR availability resulting from administration of pharmacologic doses of unlabeled benzodiazepines. The relationships between plasma levels of midazolam, brain BZR occupancy, and behavioral and physiologic measures of drug action will be investigated in normal subjects following subacute intravenous infusion. Evidence for dose-response relationships between plasma drug levels and PET BZR occupancy, power spectral changes in the EEG, and altered performance on neuropsychometric testing will be sought. Our overall goal is to advance unbiased, quantitative, yet relatively simple procedures for the study of neuroreceptors in human brain with emission tomography. The methodology developed in this project will have widespread applicability to a variety of ligands and binding sites.
