New PET Radiotracers-Monoamine Transporters

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DESCRIPTION (provided by applicant): In vivo imaging of the biochemistry of the neuronal membrane dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) are two important methods for non-invasively measuring the losses of dopaminergic function in Parkinson's disease (PD). Both measures may prove useful as biomarkers for clinical trials of new drugs or gene therapy approaches to prevention or reversal of the losses of dopaminergic nerve terminals in Parkinson's and other degenerative diseases of the dopaminergic system. In this Project, the relative sensitivity of these two measures will be directly and simultaneously compared in the acute MPTP, unilateral 6-hydroxydopamine, and chronic rotenone animal models of PD. Losses of in vivo DAT and VMAT2 binding sites will be determined using dual-radiotracer in vivo studies employing tritiated and carbon-11 forms of the specific radioligands d-threo-methylphenidate and dihydrotetrabenazine. Quantitative measures of radioligand binding in rat brain will be determined using a newly developed dual radiotracer infusion to equilibrium protocol. The time-dependent differential losses of in vivo measures of the two transporter binding sites will first be determined for each animal model. Possible alterations of these sites upon growth factor treatment will be determined in control animals. Subsequently, the two different in vivo radioligand measures of DAT and VMAT2 sites will be evaluated as markers of neuroprotection or neurorescue of dopaminergic nerve terminals in the brain, following administration of important new growth factor (e.g., glial-derived neurotrophic factor, GDNF, and erythropoeitin, EPO). These studies will provide crucial information regarding the proper selection of one or both of these in vivo radioligand methods (DAT and/or VMAT2) as optimal in vivo biomarkers to be employed in clinical trials of emerging new drug and gene therapy approaches to the prevention or reversal of the dopaminergic neurodegeneration found in Parkinson's disease.