Characterization of [11C]tetrabenazine as an in vivo radioligand for the vesicular monoamine transporter.

[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.