DOPAMINE TRANSPORTER IMAGING BY PET IN AGING AND DISEASE

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The dopaminergic system is known to undergo mild degeneration during the course of normal aging and, at an accelerated rate, in certain movement disorders. Positron emission tomography (PET) represents an excellent method to noninvasively measure the loss of dopaminergic neurons in normal aging and movement disorders due to the high chemically specificity that can be achieved using currently available radiotracers. We have recently developed IIC-WIN 35,428 as a tracer ligand for imaging and quantitation of the dopamine transporter by PET. IIC-WIN 35,428 is radio synthesized by the reaction of 11C-methyliodide with an appropriate des-methyl precursor at a specific activity of greater than 1000 Ci/mmole. We have previously demonstrated that 11C-WIN 35428 binding to the dopamine transporter is reduced in Parkinson disease (PD), and we now propose to extend our results to the study of very mild PD with the long-term goals of improving our understanding the deficits in the dopamine system and developing a PET imaging method for the early biochemical identification of PD. This aim is significant based on the current use of neuroprotective therapy for slowing the progression of PD. The early-possibly pre-clinical biochemical discrimination of PD from normal individuals, and those with other disorders such as progressive supranuclear palsy and essential tremor, would permit earlier institution of neuroprotective therapy than is possible by clinical diagnosis alone. Normal aging and associated reductions in 11C-WLN 35,428 binding is a focus of this proposal since some movement disorders may represent acceleration of the changes observed as part of the normal aging process. Whereas other PET tracers have not reliably detected the age-associated loss of pre-synaptic dopaminergic neurons, 11C-WIN 35,428 has the potential to achieve the sensitivity needed to detect the subtle changes in the dopaminergic system that occur in normal aging. Elucidation of age- associated changes in the brain dopamine system would be significant for understanding how normal aging may predispose to certain diseases and. for the development and use of drugs that interact with dopamine-containing neurons.