title: Synthesis, fluorine-18 radiolabeling, and biological evaluation of N-((E)-4-fluorobut-2-en-1-yl)-2beta-carbomethoxy-3beta-(4'-halophenyl)nortropanes: candidate radioligands for in vivo imaging of the brain dopamine transporter with positron emission tomography.
abstract: The N-(E)-fluorobutenyl-3beta-(para-halo-phenyl)nortropanes 9-12 were synthesized as ligands of the dopamine transporter (DAT) for use as (18)F-labeled positron emission tomography (PET) imaging agents. In vitro competition binding assays demonstrated that compounds 9-12 have a high affinity for the DAT and are selective for the DAT compared to the serotonin and norepinephrine transporters. MicroPET imaging with [(18)F]9-[(18)F]11 in anesthetized cynomolgus monkeys showed high uptake in the putamen with lesser uptake in the caudate, but significant washout of the radiotracer was only observed for [(18)F]9. PET imaging with [(18)F]9 in an awake rhesus monkey showed high and nearly equal uptake in both the putamen and caudate with peak uptake achieved after 20 min followed by a leveling-off for about 10 min and then a steady washout and attainment of a quasi-equilibrium. During the time period 40-80 min postinjection of [(18)F]9, the ratio of uptake in the putamen and caudate vs cerebellum uptake was > or = 4.
authors.affiliation: Department of Radiology, Emory University, Atlanta, Georgia, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Stehouwer
authors.forename: Lauryn M
authors.initials: LM
authors.lastname: Daniel
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Voll
authors.forename: Larry
authors.initials: L
authors.lastname: Williams
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Plott
authors.forename: John R
authors.initials: JR
authors.lastname: Votaw
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owens
authors.forename: Leonard
authors.initials: L
authors.lastname: Howell
authors.forename: Mark M
authors.initials: MM
authors.lastname: Goodman
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002421:Caudate Nucleus / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D006801:Humans; D008024:Ligands; D008252:Macaca fascicularis; D009662:Nortropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011699:Putamen / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D005462:Fluorine Radioisotopes; D008024:Ligands; C551944:N-(4-fluorobut-2-en-1-yl)-2-carbomethoxy-3-(4'-fluorophenyl)nortropane; D009662:Nortropanes; D019275:Radiopharmaceuticals