Analogues of exogenous L-dopa will be labeled with 18F and evaluated as PET probes of the dopaminergic nigrostriatal nerve terminals in the brains of anesthetized rhesus macaques. Three tracers will be studied, 6-fluoro-L-dopa (6-FD), 6-fluoro-L-m-tyrosine (6-FMT), and 6-fluoro-beta-fluoromethylene-L-m-tyrosine (6-FMMT). All are transported into brain by the neutral amino acid carrier system and decarboxylated to their respective amines. The subsequent fates of the tracers are expected to be sensitive to various striatal enzymes and mechanisms associated with the storage, release, and metabolism of dopamine. A total of 22 subjects will be drawn from colonies at the Wisconsin Regional Primate Center. Of these, 4 will receive unilateral lesions of the nigrostriatal pathway by infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The other 18 will be drawn equally from two age groups: 10-15 years and greater that 25 years. Some studies in intact animals will be performed following pharmacological manipulation of aspects of dopa and dopamine transport and metabolism including inhibitions of amino acid transport, decarboxylation, monoamine oxidases, and the storage of dopamine in vesicles. Dynamic PET imaging will be performed over a 4 hr period following bolus administration of tracer; brain regions will be established by correlation with MRI image data in the same subjects and the regional time courses combined with measurements of plasma concentrations of tracer and metabolites and analyzed by a variety of mathematical data reduction and modeling tools. The particular focus will be to perform both model-independent and model-dependent characterization the slowly-clearing, long-term kinetic components of the striatal time courses of each tracer label, to establish their physiological and neurochemical interpretation, and to investigate the stability of the loss rates of such components in the face of aging and of neuron loss due to lesioning. The validated non-invasive tracer methods arising from this project would be of critical importance in the study of early-stage Parkinson's disease, and for the tracking of prospective neuroprotective therapies.
| Dejesus, O T; Endres, C J; Shelton, S E et al. (2001) Noninvasive assessment of aromatic L-amino acid decarboxylase activity in aging rhesus monkey brain in vivo. Synapse 39:58-63 |
| Holden, J E; Doudet, D; Endres, C J et al. (1997) Graphical analysis of 6-fluoro-L-dopa trapping: effect of inhibition of catechol-O-methyltransferase. J Nucl Med 38:1568-74 |
| Endres, C J; Swaminathan, S; DeJesus, O T et al. (1997) Affinities of dopamine analogs for monoamine granular and plasma membrane transporters: implications for PET dopamine studies. Life Sci 60:2399-406 |
| DeJesus, O T; Endres, C J; Shelton, S E et al. (1997) Evaluation of fluorinated m-tyrosine analogs as PET imaging agents of dopamine nerve terminals: comparison with 6-fluoroDOPA. J Nucl Med 38:630-6 |
