title: Binding of alpha-dihydrotetrabenazine to the vesicular monoamine transporter is stereospecific.
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.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kilbourn
authors.forename: L
authors.initials: L
authors.lastname: Lee
authors.forename: T
authors.initials: T
authors.lastname: Vander Borght
authors.forename: D
authors.initials: D
authors.lastname: Jewett
authors.forename: K
authors.initials: K
authors.lastname: Frey
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D004353:Drug Evaluation, Preclinical; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D009479:Neuropeptides; D018377:Neurotransmitter Agents / Q000378:metabolism*; D013237:Stereoisomerism; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
chemical_list: D002250:Carbon Radioisotopes; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; C493453:Slc18a2 protein, mouse; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D013747:Tetrabenazine