Positron emission tomography (PET) studies of neurotransmitter systems in vivo in man hold great promise in helping to identify the role of receptor system defects in many diseases. This pilot project is aimed at developing radiopharmaceuticals which localize in discrete regions of the brain based upon their selective affinity for cerebral cholinergic neurons. The synthesized compounds will be labeled with the positron-emitting radionuclide 18F and utilized to quantitate cholinergic binding sites in control and lesioned rats. The gaol of this work is to demonstrate the applicability of these ligands for future in vivo studies in normal human subjects and subjects with Alzheimer's disease (AD) using PET. It is anticipated that the development of these radiopharmaceuticals, their in vivo characterization, and their use will eventually aid in the study of degenerative neurological disorders such as AD in which extensive deficits in the cholinergic system have been observed. Such an agent will provide a much needed tool to non-invasively map regional neuronal degeneration in AD using PET. The combination of the proposed agents and PET imaging is also well suited to monitor the efficacy of drug treatments aimed at sparing or protecting cholinergic function in AD. Non-radioactive 5-fluoroalkylbenzovesamicol compounds will be synthesized and characterized in vitro using competitive displacement autoradiographic techniques. Those agents possessing suitable in vitro binding properties will be further assessed in vivo to determine their potential as radiopharmaceuticals for quantitative PET studies of cholinergic innervation. The desired in vivo characteristics of these ligands include: good brain penetration to provide adequate counting statistics for PET studies; regional localization in brain areas rich in cholinergic innervation; retention of activity in those specific areas to allow for adequate PET data acquisition; rapid clearance of non-specific uptake in non-target areas; pharmacological specificity for the presynaptic vesamicol receptor; uptake site saturability; absence of lipophilic metabolites in the blood; and few metabolites in brain tissue. High specific activity 18F-fluoride (a positron emitteing radionuclide with a 110 min half-life) will be used to label the 5-fluoroalkylbenzovesamicol ligands, and these agents will be utilized in in vivo regional localization investigations in control and lesioned rats to determine their suitability as cholinergic radiopharmaceuticals. The uptake and retention of the 18F-labeled 5- fluoroalkylbenzovesamicol compounds will be compared to cholinergic markers (e.g., choline acetyltransferase) in the various brain regions to demonstrate that regional localization of the radiotracer is proportional to cholinergic innervation. These preliminary studies in animals will determine the efficacy of the compounds as cholinergic markers for future investigations in human subjects.
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