Alterations in the CNS noradrenergic system are important in the pathophysiology of depression, anxiety disorders and drug addiction. A positron emission tomography (PET) imaging agent for the norepinephrine transporter (NET) would provide a powerful tool for the study of the noradrenergic system in living humans and non-human primates. Such an imaging agent could be used to determine regional brain NET density distribution in psychiatric illnesses before and after treatment was well as to determine the in vivo pharmokinetic and pharmacodynamic properties of drugs with affinity for the NET. This proposal outlines four specific aims for developing a NET imaging agent. First candidate molecules will be synthesize and characterized in vitro for their affinity and selectivity for the NET. Second, radiolabeling methods will be developed to produce radioligands suitable for PET imaging studies. Third, radioligands will be evaluated for their imaging characteristics through autoradiography on brain slices and biodistrubution in rats. Finally, promising candidates will be used for PET studies in non-human primates for NET density quantitation and dose-occupancy studies with reboxetine, a new NET-selective antidepressant.
