Idiopathic Parkinson's disease (IP) is a progressive neurodegenerative disorder characterized by a severe depletion of nigrostriatal dopamine neurons and distinct neurological deficits. Management of the disease continues to pose major diagnostic and therapeutic challenges. The overall goals of this project are to develop improved markers and therapeutic approaches to IP. Preliminary studies in this laboratory have generated promising leads for each of these goals. We have identified CFT (WIN 35,428; 2beta carbomethoxy -3beta-4-(fluorophenyl) tropane) as a sensitive marker for the pathophysiological changes in Parkinson's disease. [3H] CTF binds to the dopamine transporter and binding is markedly reduced in postmortem Parkinson's diseased brains in vitro. In vivo, positron emission tomographic imaging (PET) with [11C] CTF suggests that it is an accurate indicator of dopamine neuron degeneration in MPTP-treated monkeys and in humans, as reported by others.
Our first aim i s to establish a quantitative assay of [11C] CFT in vivo with PET. Pilot studies with [11C] CFT have indicated the feasibility of quantifying the density of the dopaniine transporter with PET. We then will relate the density of [11C] CFT to progressive changes in motor in MPTP treated monkeys.
Our second aim i s to establish a quantitative assay of [11] CFT in humans. We will quantify [11C] CTT uptake in normal human subjects and utilize this information for imaging of patients with 1P. We will evaluate the efficacy of [11C] CFT as an in vivo imaging agent for the pathophysiology of 1P both to differentiate patients from age-matched controls and as a tool for monitoring the progression of the disease. Our third goal is to utilize PET imaging in monkeys to relate the therapeutic potential of D1 dopamine receptor agonists with the degree of dopamine neuron degeneration. A selective D1 agonist improved motor function in MPTP -treated cynomolgus monkeys and we will extend these studies to other drugs administered acutely and chronically. These results will be compared with findings using D2 agonists. These studies will provide fundamental information on the usefulness of the dopamine transporter as a marker for Parkinson's disease and clarify whether dopamine agonists targeted to D1 dopamine receptors represent important leads for the therapeutic management of Parkinson's disease.
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