title: Characterization of [11C]tetrabenazine as an in vivo radioligand for the vesicular monoamine transporter.
abstract: [11C]Tetrabenazine ([11C]TBZ) is a new in vivo radioligand for positron emission tomographic (PET) imaging of vesicular monoamine transporters. The in vivo distribution, metabolism and pharmacological specificity of [11C]TBZ has been determined in rodents. Regional mouse brain retention of [11C]TBZ is highest in brain regions with greatest monoaminergic innervation (striatum, hypothalamus) and can be reduced with ligands for the monoamine vesicular transporter (TBZ, ketanserin) but not haloperidol, a dopamine D2 receptor antagonist. Chromatographic analysis of rat blood demonstrated rapid metabolism of [11C]TBZ to radiolabeled metabolites (alpha- and beta -[11C]dihydrotetrabenazine) resulting from reduction of the 2-keto group. These metabolites, as well as a third potential metabolite, 9-O-desmethylTBZ, have been synthesized in unlabeled form and all three were shown to be capable of greatly reducing in vivo accumulation of [11C]TBZ in mouse striatum and hypothalamus. Whole body biodistribution of radioactivity after [11C]TBZ injection was determined in rats, and the data used to calculate the expected human dosimetry from this radiotracer. These studies demonstrated that [11C]TBZ can be safely administered for in vivo PET imaging and semi-quantitative determination of vesicular monoamine transporters in living human brain, but quantitative pharmacokinetic modeling of radioactivity distribution will be complicated by the presence of pharmacologically active metabolites.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0552, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: DaSilva
authors.forename: J E
authors.initials: JE
authors.lastname: Carey
authors.forename: P S
authors.initials: PS
authors.lastname: Sherman
authors.forename: T J
authors.initials: TJ
authors.lastname: Pisani
authors.forename: M R
authors.initials: MR
authors.lastname: Kilbourn
mesh_terms: D000042:Absorption; D000818:Animals; D001667:Binding, Competitive; D015306:Biogenic Monoamines / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D002250:Carbon Radioisotopes; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009410:Nerve Degeneration / Q000502:physiology; D011829:Radiation Dosage; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013747:Tetrabenazine / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D015306:Biogenic Monoamines; D002250:Carbon Radioisotopes; D008562:Membrane Glycoproteins; D013747:Tetrabenazine