title: Synthesis and biological evaluation of novel carbon-11 labeled pyridyl ethers: candidate ligands for in vivo imaging of alpha4beta2 nicotinic acetylcholine receptors (alpha4beta2-nAChRs) in the brain with positron emission tomography.
abstract: The most abundant subtype of cerebral nicotinic acetylcholine receptors (nAChR), alpha4beta2, plays a critical role in various brain functions and pathological states. Imaging agents suitable for visualization and quantification of alpha4beta2 nAChRs by positron emission tomography (PET) would present unique opportunities to define the function and pharmacology of the nAChRs in the living human brain. In this study, we report the synthesis, nAChR binding affinity, and pharmacological properties of several novel 3-pyridyl ether compounds. Most of these derivatives displayed a high affinity to the nAChR and a high subtype selectivity for alpha4beta2-nAChR. Three of these novel nAChR ligands were radiolabeled with the positron-emitting isotope (11)C and evaluated in animal studies as potential PET radiotracers for imaging of cerebral nAChRs with improved brain kinetics.
authors.affiliation: Department of Radiology, Division of Nuclear Medicine, PET Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-0816, USA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Gao
authors.forename: Hayden T
authors.initials: HT
authors.lastname: Ravert
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kuwabara
authors.forename: Yingxian
authors.initials: Y
authors.lastname: Xiao
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Endres
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: Dean F
authors.initials: DF
authors.lastname: Wong
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Horti
mesh_terms: D000818:Animals; D001923:Brain Chemistry; D002250:Carbon Radioisotopes; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000032:analysis* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002250:Carbon Radioisotopes; D008055:Lipids; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2