title: [3H]methoxytetrabenazine: a high specific activity ligand for estimating monoaminergic neuronal integrity.
abstract: The properties as well as the distribution of high specific activity alpha-[O-methyl-3H]methyoxytetrabenazine binding to the synaptic vesicular monoamine transporter were studied autoradiographically in rat brain sections. Saturation analysis revealed [3H]methoxytetrabenazine interaction with a homogeneous population of striatal sites (Hill coefficient 1.00 +/- 0.05), with an apparent equilibrium dissociation binding constant of 3.9 +/- 0.4 nM and a maximal binding capacity of 1.2 +/- 0.1 fmol/micrograms protein. Highest levels of [3H]methoxytetrabenazine binding sites were observed in regions richly innervated by the monoamine systems. In the presence of 1 microM concentrations of a variety of competing drugs, only reserpine significantly inhibited [3H]methoxytetrabenazine binding. The presynaptic nigrostriatal location of [3H]methoxytetrabenazine binding was demonstrated by unilateral lesion of the median forebrain bundle with 6-hydroxydopamine. The resulting decrease of striatal [3H]methoxytetrabenazine binding showed an excellent correlation with tyrosine hydroxylase-positive neuron density in the substantia nigra pars compacta (r2 = 0.96; P < 0.001). The present studies demonstrate that in vitro [3H]methoxytetrabenazine binding is a reliable, quantitative marker of the synaptic vesicular monoamine transporter. Further, it is indicated that [3H]methoxytetrabenazine binding provides an accurate assessment of monoamine neuronal losses and may thus be of great value in future studies of neurodegenerative diseases.
authors.affiliation: Department of Internal Medicine (Division of Nuclear Medicine), University of Michigan, Ann Arbor 48109-0028, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Vander Borght
authors.forename: A A
authors.initials: AA
authors.lastname: Sima
authors.forename: M R
authors.initials: MR
authors.lastname: Kilbourn
authors.forename: T J
authors.initials: TJ
authors.lastname: Desmond
authors.forename: D E
authors.initials: DE
authors.lastname: Kuhl
authors.forename: K A
authors.initials: KA
authors.lastname: Frey
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000187:drug effects; D015306:Biogenic Monoamines / Q000502:physiology*; D007700:Kinetics; D008024:Ligands; D008474:Medial Forebrain Bundle / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D016627:Oxidopamine / Q000633:toxicity; D051381:Rats; D013747:Tetrabenazine / Q000031:analogs & derivatives*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D015306:Biogenic Monoamines; D008024:Ligands; C084867:5-O-methyldihydrotetrabenazine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D013747:Tetrabenazine