Invivoimaging of the vesicular acetylcholine transporter and the vesicular monoamine transporter

Abstract

Validation of the vesicular acetylcholine transporter (VAChT) and the neuronal vesicular monoamine transporter (VMAT2) as important molecular targets in the cholinergic and dopamine neurons, respectively, has sparked interest in the development of radiotracers for studying these markers in vitro and in vivo. Currently, a number of selective high-affinity radiotracers are available for studying these targets in vivo with positron emission tomography (PET) or single photon emission computed tomography (SPECT). PET studies of VMAT2 in neuropathology reveal changes in the density of this marker that can be verified independently. Similarly, in vivo studies with VAChT ligands suggest that the latter are potentially useful in detecting cholinergic lesions in vivo; however, additional development is required to fully realize the potential of these radioligands.

The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine

“…These drugs block amine uptake by VAChT and VMATs, respectively, and have pharmacological effects consistent with abrogation of amine storage and neurotransmission. Importantly, labeled vesamicol and tetrabenazine analogs exist that have been used successfully in brain imaging of vesicular transporter protein density in diseases such as Parkinson's, schizophrenia, and Alzheimer's disease (see [5] for review and references). The human isoforms of VMAT1 (SLC18A1) and VMAT2 (SLC18A2) transport catecholamines and serotonin, and are inhibited by reserpine, equally well, but hVMAT2 transports histamine, and is blocked by tetrabenazine, much better than hVMAT1, and rodent VMAT isoforms (slc18a1 and slc18a2) also exhibit these differences [14,15,25].…”

“…hVAChT/SLC18A3 was cloned from a human cDNA library [13] following homology cloning of rodent VAChT/slc18a3 [13] using a Caenorhabditis elegans putative vesicular acetylcholine transporter (unc-17) cDNA as probe [1], coupled with functional demonstration of proton-and ATP-dependent, and vesamicol-sensitive, acetylcholine transport in CV-1 fibroblasts expressing the heterologous VAChT cDNA. The structure, function, and role in neuronal and endocrine cell function of the VATs/SLC18 s have been recently and comprehensively reviewed [5,7,12,29,33,42,44]. Recently, VMAT expression in non-neuroendo-…”

Assessment of Islet Specificity of Dihydrotetrabenazine Radiotracer Binding in Rat Pancreas and Human Pancreas

“…Neurons and pancreatic b-cells accumulate monoamines by using VMAT2 (8)(9)(10), the pharmacology of which has been extensively characterized with bovine adrenal medulla chromaffin granules (11). The VMAT2 antagonist 11 C-dihydrotetrabenazine ( 11 C-DTBZ) is an established tracer for PET imaging of the dopaminergic system of the brain (12). High uptake of 11 C-DTBZ radioactivity is evident in the pancreas of nondiabetic rodents.…”

Dual Radiotracer Analysis of Cholinergic Neuronal Changes in Prediabetic Mouse Pancreas

“…[4][5][6][7][8][9] However, few have applied neurofunctional radiotracers to the study of the peripheral nervous system, which includes autonomic control of the richly innervated pancreas. [10][11][12][13] The goal of this project is to adapt the use of tracers used primarily in the central nervous system to develop a strategy that will ultimately allow an in vivo, radiotracer-based method of imaging cholinergic function by PET to identify type 1 diabetes mellitus in its earliest stages, when therapeutic interventions may be most effective.…”

“…The PET radiotracer (ϩ)- 5,8,9 The VAChT is responsible for loading presynaptic vesicles with the neurotransmitter ACh and has been shown to be a reliable marker of acetylcholine activity in vivo. 16 We have previously reported that [ 18 F]FBT localizes in the pancreas.…”