title: Imaging of cholinergic terminals using the radiotracer [18F](+)-4-fluorobenzyltrozamicol: in vitro binding studies and positron emission tomography studies in nonhuman primates.
abstract: The goal of the present set of studies was to characterize the in vitro binding properties and in vivo tissue kinetics for the vesicular acetylcholine transporter (VAcChT) radiotracer, [18F](+)-4-fluorobenzyltrozamicol ([18F](+)-FBT). In vitro binding studies were conducted in order to determine the affinity of the (+)- and (-)-stereoisomers of FBT for the VAcChT as well as sigma (sigma 1 and sigma 2) receptors. (+)-FBT was found to have a high affinity (Ki = 0.22 nM) for the VAcChT and lower affinities for sigma 1 (21.6 nM) and sigma 2 (35.9 nM) receptors, whereas (-)-FBT had similar affinities for the VAcChT and sigma 1 receptors (approximately 20 nM) and a lower affinity for sigma 2 (110 nM) receptors. PET imaging studies were conducted in rhesus monkeys (n = 3) with [18F](+)-FBT. [18F](+)-FBT was found to have a high accumulation and slow rate of washout from the basal ganglia, which is consistent with the labeling of cholinergic interneurons in this brain region. [18F](+)-FBT also displayed reversible binding kinetics during the 3 h time course of PET and produced radiolabeled metabolites that did not cross the blood-brain barrier. The results from the current in vitro and in vivo studies indicate that [18F](+)-FBT is a promising ligand for studying cholinergic terminal density, with PET, via the VAcChT.
authors.affiliation: Department of Radiology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Mach
authors.forename: M L
authors.initials: ML
authors.lastname: Voytko
authors.forename: R L
authors.initials: RL
authors.lastname: Ehrenkaufer
authors.forename: M A
authors.initials: MA
authors.lastname: Nader
authors.forename: J R
authors.initials: JR
authors.lastname: Tobin
authors.forename: S M
authors.initials: SM
authors.lastname: Efange
authors.forename: S M
authors.initials: SM
authors.lastname: Parsons
authors.forename: H D
authors.initials: HD
authors.lastname: Gage
authors.forename: C R
authors.initials: CR
authors.lastname: Smith
authors.forename: T E
authors.initials: TE
authors.lastname: Morton
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D005464:Fluorobenzenes; D005625:Frontal Lobe / Q000378:metabolism; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D026901:Membrane Transport Proteins; D009467:Neuromuscular Depolarizing Agents / Q000378:metabolism; D009778:Occipital Lobe / Q000378:metabolism; D009928:Organ Specificity; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000032:analysis / Q000378:metabolism; D013237:Stereoisomerism; D013572:Synaptic Vesicles / Q000378:metabolism*; D013702:Temporal Lobe / Q000378:metabolism; D014055:Tomography, Emission-Computed / Q000379:methods*; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D005462:Fluorine Radioisotopes; D005464:Fluorobenzenes; D026901:Membrane Transport Proteins; D009467:Neuromuscular Depolarizing Agents; D010880:Piperidines; D017480:Receptors, sigma; C493461:Slc18a3 protein, rat; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; C087277:4-fluorobenzyltrozamicol; C006189:vesamicol