title: Synthesis and in vivo studies of the stereoisomers of N-[11C]methyl-homoepibatidine.
abstract: The carbon-11 labeled enantiomers of nicotinic acetylcholine receptor (nAChR) ligand N-[11C]methyl-homoepibatidine have been synthesized to study the neuronal nicotinic acetylcholine receptors (nAChRs). In vivo evaluations were performed in mice and pig using positron emission tomography (PET). The radioligands displayed a strong enantioselectivity. The (-)-enantiomer showed high uptake in the brain while the (+)-enantiomer was rapidly washed out. In metabolite studies in mice >65% unchanged ligand was found in the blood after 60 minutes. No metabolites were found in the brain. After intravenous application of N-[11C]methyl-(-)-homoepibatidine in the pig specific accumulation in the thalamus was seen. Blocking experiments with cytisine showed specific binding consistent with labeling of the alpha4beta2-nAChR-subtype in the brain. Quantitative kinetic modeling of radiotracers in the pig brain was performed using the arterial input function. The brain uptake of the (-)-isomer was best fitted by a three-compartment model. High distribution volumes were found in the thalamus (DV(TOT) = 66.617, DV(S) = 59.910) versus a low uptake in the cerebellum (DV(TOT) = 8.605m, DV(S) = 1.898). The binding characteristics suggest N-[11C]methyl-(-)-homoepibatidine to be suited for PET imaging studies, but high toxicity prevents routine use in humans.
authors.affiliation: Center for Radiopharmaceutical Science, Swiss Federal Institute of Technology Zürich, Paul Scherrer Institute Villigen, University Hospital Zürich, CH-8091, Zürich, Switzerland.
authors.forename: J T
authors.initials: JT
authors.lastname: Patt
authors.forename: J E
authors.initials: JE
authors.lastname: Spang
authors.forename: A
authors.initials: A
authors.lastname: Buck
authors.forename: H
authors.initials: H
authors.lastname: Cristina
authors.forename: M
authors.initials: M
authors.lastname: Arras
authors.forename: P A
authors.initials: PA
authors.lastname: Schubiger
authors.forename: G
authors.initials: G
authors.lastname: Westera
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D005260:Female; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism; D013552:Swine; D014055:Tomography, Emission-Computed
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C440009:N-methylhomoepibatidine; D018722:Nicotinic Agonists; D011725:Pyridines; C082748:epibatidine