Synthesis and in vivo studies of the stereoisomers of N-[C-11]methyl-homoepibatidine

The carbon-11 labeled enantiomers of nicotinic acetylcholine receptor (nACh R) ligand N-[C-11]methyl-homoepibatidine have been synthesized to study the neuronal nicotinic acetylcholine receptors (nAChRs). In vivo evaluations were per-formed 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 ligan d was found in the blood after 60 minutes. No metabolites were found in the brain. After intravenous application of N-[C-11]methyl-(-)-homoepibatidine in the pig specific accumulation in the thalamus was seen. Blocking experi ments with cytisine showed specific binding consistent with labeling of the alpha4 beta2-nAChR-subtype in the brain. Quantitative kinetic modeling of radiotracers in the pig brain was performed using the arterial input functi on. The brain uptake of the (-)-isomer was best fitted by a three-compartme nt model. High distribution volumes were found in the thalamus (DVTOT = 66. 617, DVs = 59.910) versus a low uptake in the cerebellum (DVTOT = 8.605m, D VS = 1.898). The binding characteristics suggest N-[C-11]methyl-(-)-homoepi batidine to be suited for PET imaging studies, but high toxicity prevents r outine use in humans. (C) 2001 Elsevier Science Inc. All rights reserved.