The transporters involved in the reuptake and storage of monoamines in presynaptic neurons are important components of the synapse, and are targets for radiopharmaceutical development in the quest for in vivo markers of monoaminergic nerve termina densities in the brain. In vivo measures of monoaminergic nerve terminal densities, using Positron Emission Tomography (PEP), have important applications in studies of neurodegenerative diseases (e.g., Parkinson's) and psychiatric diseases where alterations of nerve terminal densities have been proposed. Quantitative measures in living human brain are needed to properly evaluate emerging therapeutic drug strategies for prevention of or intervention in neurodegenerative processes. This project will undertake a thorough examination of the in vivo characteristics of [11C] methoxytetrabenazine ([11C]MTBZ), a new high affinity and highly specific radioligand for the vesicular monoamine transporter (VMAT2). Studies in normal and neurotoxin-lesioned (unilateral 6-hydroxydopamine in rats, unilateral MPTP in monkeys, MPTP in mice) animals will address the following: (a) do DV/MTBZ measures correlate with in vitro measures of vesicular transporters: (b) are DV/MTBZ measures sensitive to competing drug (""""""""dose-response"""""""" analysis); (c) is DV/MTBZ sensitive to acute or chronic doses of commonly used therapeutic dopaminergic or cholinergic drugs; (d) does chronic pharmacologic manipulation of the dopamine system regulate vesicular monoamine transporters; and (e) how does DV/MTBZ compare with in vivo measures of dopamine synthesis or neuronal membrane transporters? Experimental methods include in vivo determination of regional brain DV/MTBZ using both tissue dissection (rodents) and PET imaging (monkeys), in vitro radioligand binding assays and immunohistochemistry. Equilibrium distribution volumes (DV/MTBZ) provide quantitative measures of the specific binding of a radioligand to a high affinity site. These experiments provide the first in vivo studies of vesicular transporters in animal lesion models of human disease, and the first in vivo studies of regulation of the vesicular transporter for monoamines. When completed, this project is expected to provide not only new and important information on the pharmacology and regulation of these transporters in normal and lesioned animals, but also provide complete characterization of [11C]MTBZ as a new and important addition to the group of radiopharmaceutical available for the in vivo study of monoaminergic nerve terminals in human brain in vivo.
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