Abstract
The two enantiomers of alpha-dihydrotetrabenazine were separated using chiral high performance liquid chromatography. The (+)-isomer showed high affinity in vitro (Ki = 0.97 +/- 0.48 nM) for the vesicular monoamine transporter (VMAT2) in rat brain striatum, whereas the (-)-isomer was inactive (Ki = 2.2 +/- 0.3 microM). Each isomer was then synthesized in carbon-11 labeled form, and regional brain biodistributions in mice determined after intravenous injection. Only (+)-alpha-dihydrotetrabenazine showed selective and specific accumulations in regions of dense monoaminergic innervation (e.g., striatum, hypothalamus), which could be blocked by coinjection of unlabeled tetrabenazine. Binding of alpha-dihydrotetrabenazine to the vesicular monoamine transporter is thus stereospecific.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Brain / metabolism
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Carbon Radioisotopes
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Drug Evaluation, Preclinical
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Female
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Glycoproteins / metabolism*
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Membrane Glycoproteins*
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Membrane Transport Proteins*
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Mice
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Mice, Inbred Strains
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Neuropeptides*
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Neurotransmitter Agents / metabolism*
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Stereoisomerism
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Tetrabenazine / analogs & derivatives*
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Tetrabenazine / chemistry
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Tetrabenazine / metabolism
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Tetrabenazine / pharmacology
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Vesicular Biogenic Amine Transport Proteins
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Vesicular Monoamine Transport Proteins
Substances
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Carbon Radioisotopes
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Glycoproteins
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Membrane Glycoproteins
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Membrane Transport Proteins
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Neuropeptides
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Neurotransmitter Agents
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Slc18a2 protein, mouse
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Vesicular Biogenic Amine Transport Proteins
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Vesicular Monoamine Transport Proteins
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dihydrotetrabenazine
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Tetrabenazine