The goals of this project are the design, synthesis and preliminary in vitro and in vivo evaluation of new radiolabeled ligands for the picrotoxin binding site of the GABAA receptor. In particular, we seek the identification and characterization of ligands that display sensitivity to the functional state of the GABAA receptor in vivo. The GABAA receptor is present at a very high proportion of synapses in the brain, and dysfunction of this receptor has been implicated in a wide variety of neurological, psychiatric and drug abuse conditions. The new radioligands to be prepared will be based on the recently reported dithiane and dithiane oxide structural class of high affinity picotoxin site ligands. Preliminary in vivo studies with 11C- and 18F- labeled dithiane oxides have demonstrated blood-brain-barrier permeability, metabolic stability in the blood, and some-dependent alterations of in vivo uptake in brain after administration of a GABA agonist. New compounds will be examined for in vitro binding affinities (inhibition of binding of [35S]TBPS to rodent cortical membranes. High affinity compounds (Ki<20 nM) will then be prepared in carbon-11 or fluorine-18 form, and the regional brain pharmacokinetics in rodents determined. These distributions will also be examined in the presence of drugs known to alter the functioning of the GABAA receptor, such as GABA agonists, benzodiazepines, and beta-carbolines. The optimal compounds will then be examined for reproducibility and sensitivity to GABAergic perturbations using PET imaging and quantification of radiotracer pharmacokinetics in the monkey brain. The goal will be the development of radioligands with appropriate pharmacokinetics and pharmacological specificity to be suitable for in vivo studies of the picrotoxin site as a functional marker of the human brain GABAA receptor using Positron Emission Tomography (PET). In combination with existing radioligands for measurement of the numbers of benzodiazepine sites, these new functional radioligands will allow more complete characterization of GABAergic neurotransmission in the normal and diseased human brain.
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