Imaging of cholinergic terminals using the radiotracer [18F](+)-4-fluorobenzyltrozamicol: In vitro binding studies and positron emission tomography studies in nonhuman primates

• Published in: Synapse (New York, N.Y.) N.Y.), 1997-04, Vol.25 (4), p.368-380
• Main Authors: Mach, Robert H., Voytko, Mary Lou, Ehrenkaufer, Richard L.E., Nader, Michael A., Tobin, Joseph R., Efange, Simon M.N., Parsons, Stanley M., Gage, H. Donald, Smith, Cynthia R., Morton, Thomas E.
• Format: Article
• Language: English
• Subjects: Animals; Basal Ganglia - metabolism; Brain - diagnostic imaging; Brain - metabolism; Carrier Proteins - analysis; Carrier Proteins - metabolism; Cerebellum - metabolism; cholinergic terminals; Fluorine Radioisotopes - pharmacokinetics; Fluorobenzenes; Frontal Lobe - metabolism; Macaca mulatta; Magnetic Resonance Imaging; Male; Membrane Transport Proteins; Neuromuscular Depolarizing Agents - metabolism; Occipital Lobe - metabolism; Organ Specificity; Piperidines - chemical synthesis; Piperidines - metabolism; Piperidines - pharmacokinetics; positron emission tomography; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, sigma - analysis; Receptors, sigma - metabolism; rhesus monkey; Stereoisomerism; Synaptic Vesicles - metabolism; Temporal Lobe - metabolism; Tomography, Emission-Computed - methods; vesamicol receptor; Vesicular Acetylcholine Transport Proteins; Vesicular Transport Proteins
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/(SICI)1098-2396(199704)25:4<368::AID-SYN8>3.0.CO;2-8

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 (σ2 and σ2) receptors. (+)‐FBT was found to have a high affinity (Ki = 0.22 nM) for the VAcChT and lower affinities for σ1 (21.6 nM) and σ2 (35.9 nM) receptors, whereas (−)‐FBT had similar affinities for the VAcChT and σ1 receptors (∼20 nM) and a lower affinity for σ2 (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. Synapse 25:368–380, 1997. © 1997 Wiley‐Liss, Inc.