The central hypothesis of this work is that radiolabeled enzyme markers of presynaptic dopaminergic function used with positron emission tomography (PET) are not linear indicators of nigrostriatal cell losses. It is expected that axonal sprouting with synapses would respond quickly to early signs of nigrostriatal dopaminergic degeneration as part of the compensatory mechanisms at play to maintain functional activity. If so, substantial changes in aromatic amino acid decarboxylase (AAAD) activities and dopamine reuptake sites are not expected to occur during this adjustment period and, therefore, the AAAD-dependent kinetics and dopamine reuptake ligand binding will not be sensitive to these initial changes. To test this hypothesis, we will use the MPTP-monkey-model of Parkinson's disease (both symptomatic and asymptomatic) to correlate in a controlled environment the graded effects of nigrostriatal cell loss on presynaptic function with the biochemistry and central kinetics of the radiolabeled probes. We will focus our in on the initial stages of cell degeneration, with the aim of providing probes that will detect vestigation neurochemical deficiencies preceding clinical symptoms. We will combine the unique expertise and resources of two leading centers in the world, namely the Parkinson's Institute (Dr. W. Langston, ector) in I methyl-4- phenyl- I ,2,3,6 tetrahydropyridine (MPTP)-exposure to non-humans primates and humans, and UCLA, in functional imaging with positron emission tomography. With a """"""""gold standard"""""""" provide-by concomitant cytological and neurochemical information, in-vivo PET data will be correlated with the functional integrity of the dopaminergic system. If this work is successful, we will have developed new in-vivo approaches to: 1) unveil otherwise undetected, early signs of nigrostriatal cell degeneration; 2) trace striatal AAAD activity allowing for evaluation of specific pharmacological interactions (e.g., methamphetamine) and the effects of cell degeneration. The combination of dopamine enzyme probes and, net dopamine re-uptake ligands (""""""""cocaine receptor"""""""" ligands), will provide the necessary tools and contribute to the logic necessary for the non-invasive evaluation of the functional activity of central dopaminergic mechanisms in health disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033356-04
Application #
2714545
Study Section
Neurology A Study Section (NEUA)
Program Officer
Murphy, Diane
Project Start
1995-06-01
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
2000-05-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Yee, R E; Cheng, D W; Huang, S C et al. (2001) Blood-brain barrier and neuronal membrane transport of 6-[18F]fluoro-L-DOPA. Biochem Pharmacol 62:1409-15
Yee, R E; Irwin, I; Milonas, C et al. (2001) Novel observations with FDOPA-PET imaging after early nigrostriatal damage. Mov Disord 16:838-48
Stout, D B; Huang, S C; Namavari, M et al. (2000) Distribution volume of 3-O-methyl-6. J Cereb Blood Flow Metab 20:1717-24
Yee, R E; Huang, S C; Stout, D B et al. (2000) Nigrostriatal reduction of aromatic L-amino acid decarboxylase activity in MPTP-treated squirrel monkeys: in vivo and in vitro investigations. J Neurochem 74:1147-57
Shoghi-Jadid, K; Huang, S C; Stout, D B et al. (2000) Striatal kinetic modeling of FDOPA with a cerebellar-derived constraint on the distribution of volume of 30MFD: a PET investigation using non-human primates. J Cereb Blood Flow Metab 20:1134-48
Lacan, G; Satyamurthy, N; Barrio, J R (1999) Synthesis of stereo (R and S) and geometric (E and Z) isomers of [18F]fluoro-beta-fluoromethylene-m-tyrosine derivatives: in vivo probes of central dopaminergic function. Nucl Med Biol 26:359-63
Stout, D; Petric, A; Satyamurthy, N et al. (1999) 2Beta-carbomethoxy-3beta-(4- and 2-[18F]fluoromethylphenyl)tropanes: specific probes for in vivo quantification of central dopamine transporter sites. Nucl Med Biol 26:897-903
Petric, A; Barrio, J R; Namavari, M et al. (1999) Synthesis of 3beta-(4-[18F]fluoromethylphenyl)- and 3beta-(2-[18F] fluoromethylphenyl)tropane-2beta-carboxylic acid methyl esters: new ligands for mapping brain dopamine transporter with positron emission tomography. Nucl Med Biol 26:529-35
Huang, S C; Quintana, J; Satyamurthy, N et al. (1999) [18F]Fluoro-beta-fluoromethylene-m-tyrosine derivatives show stereo, geometrical, and regio specificities as in vivo central dopaminergic probes in monkeys. Nucl Med Biol 26:365-70
Stout, D B; Huang, S C; Melega, W P et al. (1998) Effects of large neutral amino acid concentrations on 6-[F-18]Fluoro-L-DOPA kinetics. J Cereb Blood Flow Metab 18:43-51

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