Presynaptic monoaminergic vesicles in Parkinson's disease and normal aging

Abstract

We present development and human application of a method for determining the regional cerebral density of the type 2 vesicular monoamine transporter (VMAT2) using positron emission tomography (PET) and [11C]dihydrotetrabenazine (DTBZ). Previous animal studies indicate striatal VMAT2 density is linearly related to the integrity of substantia nigra dopamine neurons and is not subject to drug- or lesion-compensatory regulation. In the present studies, kinetic compartmental modeling was employed to estimate blood-brain [11C]DTBZ transport (K1) and VMAT2 binding site density (tissue-to-plasma DTBZ distribution volume, DV) from the cerebral and plasma DTBZ time courses after intravenous tracer injection. In controls, we found reductions of putamen DTBZ DVwith advancing age, corresponding to losses of 0.77% per year in specific VMAT2 binding. Parkinson's disease (PD) patients had reduction in specific DTBZ DV in the putamen (-61%) and in the caudate nucleus (-43%). There was no overlap of lowest specific putamen DTBZ DV between individual elderly controls and PD patients. The present results indicate the suitability of [11C]DTBZ PET for objective quantification of nigrostriatal integrity, including evaluation of PD progression and its possible therapeutic modification.

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

“…The expression of VMAT2 protein in PC12 and cultured chromaffin cells can be regulated by lithium ions [53] and high extracellular concentrations of potassium ions [54] and gastrin [55], respectively. In a broader context, the density of VMAT2 expression in the CNS (as determined by PET and [ 11 C]DTBZ) is reduced in Parkinson's disease [56] and is increased in Tourette's syndrome and bipolar disorders [57,58]. In ex vivo experiments, using purified human islets, we found that glucose stimulation of islets did not affect the binding of [ 3 H]DTBZ to membrane preparations (data not shown).…”

Distribution of Vesicular Monoamine Transporter 2 Protein in Human Brain: Implications for Brain Imaging Studies

“…Tetrabenazine or its metabolite dihydrotetrabenazine (DTBZ) is a specific inhibitor of the transporter used in radioligand-binding studies to measure the in vitro concentration of VMAT2 in mammalian brain (Scherman et al, 1988;Darchen et al, 1989;Vander Borght et al, 1995;Wilson et al, 1996). Positron emission tomography (PET) imaging of [ 11 C]DTBZ binding has now been developed as a noninvasive tool to estimate brain levels of VMAT2 in vivo (Kilbourn et al, 1993;Frey et al, 1996;Chan et al, 1999;Koeppe et al, 1999), in particular in the striatum (caudate and putamen) in which most of VMAT2 (90% to 95%) is considered to be localized to the dopamine nerve terminals (cf. Boileau et al, 2008).…”

Whole-Body Biodistribution and Radiation Dosimetry of 18F-FP-(+)-DTBZ (18F-AV-133): A Novel Vesicular Monoamine Transporter 2 Imaging Agent

“…One study (3) pointed out the deficiencies in imaging PD based on dopamine transporter tracers, which highlighted the need for additional new imaging agents to reliably diagnose and predict the progress of this neurodegenerative disease. Imaging of the VMAT2 has thus been proposed as an alternative for following degeneration of monoaminergic neurons in PD (8). 11 C-tetrabenazine and derivatives targeting VMAT2 have been successfully developed and tested in humans (9).…”

“…Thus, 11 C-(1)-DTBZ could be a potentially useful marker for VMAT2 reduction. The reduction of VMAT2 directly reflects the loss of monoamine neurons; therefore, it is applicable as a tool in the diagnosis of PD (8).…”