title: Derivatives of (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane are potential ligands for positron emission tomography imaging of extrathalamic nicotinic acetylcholine receptors.
abstract: A series of novel racemic 7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane derivatives with picomolar in vitro binding affinity at nicotinic acetylcholine receptors (nAChRs) were synthesized and their enantiomers were resolved by semipreparative chiral HPLC. The (-)-enantiomers showed substantially greater in vitro inhibition binding affinity than the corresponding (+)-enantiomers. The compounds with best binding affinities have been radiolabeled with positron emitting isotopes 11C and 18F as potential radioligands for positron emission tomography imaging of the nAChR. In vivo enantioselectivity of the radiolabeled (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane derivatives was observed in biodistribution studies in rodents and baboon. One of the radiolabeled compounds, (-)-7-methyl-2-exo-[3'-(2-[18F]fluoropyridin-5-yl))-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane, exhibited good properties as a first practical PET radioligand for imaging of extrathalamic nAChR in baboon brain and holds promise for further investigation for human studies.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287-0816, USA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Gao
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Horti
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kuwabara
authors.forename: Hayden T
authors.initials: HT
authors.lastname: Ravert
authors.forename: John
authors.initials: J
authors.lastname: Hilton
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Holt
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Mohab
authors.initials: M
authors.lastname: Alexander
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Endres
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D051379:Mice; D048530:Papio anubis; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C524105:7-methyl-2-(3'-(6-fluoropyridin-3-yl)-5'-pyridinyl)-7-azabicyclo(2.2.1)heptane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D008024:Ligands; D011725:Pyridines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic