title: Discovery of (-)-7-methyl-2-exo-[3'-(6-[18F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (alpha4beta2-nAChR) with optimal positron emission tomography imaging properties.
abstract: Several isomers of 7-methyl-2-exo-([(18)F]fluoropyridinyl-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane have been developed as radioligands with optimized brain kinetics for PET imaging of nAChR. The binding assay demonstrated that all isomers are beta-nAChR selective ligands with Ki = 0.02-0.3 nM. The experimental lipophilicity values of all isomers were in the optimal range for the cerebral radioligands (log D7.4= 0.67-0.99). The isomers with higher binding affinity manifested slow baboon brain kinetics, whereas the isomer with the lowest binding affinity (Ki = 0.3 nM) ((-)-7-methyl-2- exo-[3'-(6-[(18)F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane, [(18)F](-)-6c) and greatest lipophilicity (log D 7.4 = 0.99) exhibited optimal brain kinetics. [(18)F](-)-6c manifests a unique combination of the optimally rapid brain kinetics, high BP and brain uptake, and favorable metabolic profile. Pharmacological studies showed that (-)-6c is an alpha4beta2-nAChR antagonist with low side effects in mice. This combination of imaging properties suggests that [(18)F]-(-)- 6c is a potentially superior replacement for 2-[(18)F]fluoro-A-85380 and 6-[(18)F]fluoro-A-85380, the only available nAChR PET radioligands for humans.
authors.affiliation: Department of Radiology, Division of Nuclear Medicine, The Johns Hopkins UniVersity School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287-0816, USA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Gao
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kuwabara
authors.forename: Charles E
authors.initials: CE
authors.lastname: Spivak
authors.forename: Yingxian
authors.initials: Y
authors.lastname: Xiao
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kellar
authors.forename: Hayden T
authors.initials: HT
authors.lastname: Ravert
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Mohab
authors.initials: M
authors.lastname: Alexander
authors.forename: John
authors.initials: J
authors.lastname: Hilton
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: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002460:Cell Line; D006536:Heptanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010215:Papio; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D006536:Heptanes; D008055:Lipids; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D014326:Tropanes; C403531:nicotinic receptor alpha4beta2; D015082:2,2'-Dipyridyl