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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS030556-01A3
Application #
2268512
Study Section
Neurology A Study Section (NEUA)
Project Start
1994-12-01
Project End
1997-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Madras, Bertha K; Fahey, Michele A; Goulet, Martin et al. (2006) Dopamine transporter (DAT) inhibitors alleviate specific parkinsonian deficits in monkeys: association with DAT occupancy in vivo. J Pharmacol Exp Ther 319:570-85
Jassen, Amy K; Brown, Jeffrey M; Panas, Helen N et al. (2005) Variants of the primate vesicular monoamine transporter-2. Brain Res Mol Brain Res 139:251-7
Madras, Bertha K; Miller, Gregory M; Fischman, Alan J (2002) The dopamine transporter: relevance to attention deficit hyperactivity disorder (ADHD). Behav Brain Res 130:57-63
Miller, G M; Madras, B K (2002) Polymorphisms in the 3'-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression. Mol Psychiatry 7:44-55
Meschler, J P; Howlett, A C; Madras, B K (2001) Cannabinoid receptor agonist and antagonist effects on motor function in normal and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-treated non-human primates. Psychopharmacology (Berl) 156:79-85
Goulet, M; Madras, B K (2000) D(1) dopamine receptor agonists are more effective in alleviating advanced than mild parkinsonism in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated monkeys. J Pharmacol Exp Ther 292:714-24
Bonab, A A; Fischman, A J; Alpert, N M (2000) Comparison of 4 methods for quantification of dopamine transporters by SPECT with [123I]IACFT. J Nucl Med 41:1086-92
Dougherty, D D; Bonab, A A; Spencer, T J et al. (1999) Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 354:2132-3
Madras, B K; Meltzer, P C; Liang, A Y et al. (1998) Altropane, a SPECT or PET imaging probe for dopamine neurons: I. Dopamine transporter binding in primate brain. Synapse 29:93-104
Madras, B K; Gracz, L M; Fahey, M A et al. (1998) Altropane, a SPECT or PET imaging probe for dopamine neurons: III. Human dopamine transporter in postmortem normal and Parkinson's diseased brain. Synapse 29:116-27

Showing the most recent 10 out of 17 publications