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.

Variations in the Vesicular Monoamine Transporter 1 Gene (VMAT1/SLC18A1) are Associated with Bipolar I Disorder

“…Indirect evidence that the VMAT is involved in psychiatric disorders stems from positron emission tomography (PET) imaging studies. Binding of radiolabled dihydrotetrabenazine, a catecholamine depleter with higher VMAT2 than VMAT1 affinity (DaSilva et al, 1993(DaSilva et al, , 1994 was increased in thalamus and brainstem of BPD patients when compared to controls (Zubieta et al, 2000). Ventral brainstem binding was higher in BPD and SZ patients compared to controls (Zubieta et al, 2001).…”

Longitudinal noninvasive PET-based cell mass estimates in a spontaneous diabetes rat model

“…In feasibility studies, the biodistribution of [ 11 C]DTBZ in rats was obtained as previously reported by Kilbourn and colleagues (36). The in vivo biodistribution of DTBZ is higher in the pancreas than in many other abdominal organs (Table 1).…”

“…Biodistribution studies of [ 11 C]DTBZ in the Sprague-Dawley rats were performed as previously described (36). Briefly, rats were injected via the femoral vein with 150-650 μCi of [ 11 C]DTBZ.…”

Visualizing pancreatic β-cell mass with [11C]DTBZ

“…Specific activities of carbon-11-labeled radiotracers were >2000 mCi/μmol at the time of injection. Biodistribution studies of [ 11 C]DTBZ or [ 3 H]DTBZ in Lewis rats were performed as previously described [33]. Briefly, normal rats were injected via the tail vein with 0.5 μCi/g [ 3 H]DTBZ in saline.…”