[F-18] FLUOROETHOXY-BENZOVESAMICOL, A PET RADIOTRACER FOR THE VESICULAR ACETYLCHOLINE TRANSPORTER AND CHOLINERGIC SYNAPSES

Loss of cholinergic transmission in the cortex and hippocampus is a ch aracteristic feature of Alzheimer's disease, and visualization of func tional cholinergic synapses in the brain with PET could be a useful me thod for studying this degenerative condition in living humans. We inv estigated [F-18]fluoroethoxybenzovesamicol, (-)-[F-18]-FEOBV, eridino) 5-(2-[F-18]fluoroethoxy)-1,2,3,4-tetralin, a high affinity positron em itting ligand for the vesicular acetylcholine transporter, as a potent ial in vivo cholinergic synapse mapping agent. Rodent biodistribution, dosimetry, stereospecificity of biological effects, pharmacologic blo cking studies, in vivo rodent brain autoradiography and metabolites we re examined. (-)-[F-18]FEOBV brain uptake following intravenous inject ion was robust, with 2.65% dose/brain in mice at 5 min, and the region al localization matched the known distributions of presynaptic choline rgic markers at later times. Both the cholinergic localization and cur are-like effects of FEOBV were associated with the ''(-)''-enantiomer exclusively. (-)[F-18]FEOBV regional brain distribution in rodents was changed little by pretreatment with haloperidol, (+)-3-PPP, or E-2020 , indicating FEOBV, unlike other vesamicol analogs, did not interact i n vivo with dopamine or sigma receptor systems. Autoradiography of rat brain 3 h following i.v. injection of (-)-[F-18]FEOBV showed high loc alization in brain areas rich in presynaptic cholinergic elements. Ill etabolic defluorination in rodents was modest, and analysis of brain t issue following tracer administration found FEOBV as the only extracta ble radioactive species. (-)-[F-18]FEOBV dosimetry calculated from rat data estimate 10 mCi doses can be given to humans. These studies show FEOBV maps cholinergic areas with high specificity in vivo, and may p rovide a noninvasive means to safely and accurately gauge the function al integrity of cholinergic synapses in man using PET. Synapse 30:263- 274, 1998. (C) 1998 Wiley-Liss, Inc.