title: Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2beta-carbo-1'-fluoro-2-propoxy-3beta-(4-chlorophenyl)tr opanes. Ligands for the imaging of dopamine transporters by positron emission tomography.
abstract: 2beta-(R)-Carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((R)-FIPCT, R-6) and 2beta-(S)-carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((S)-FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2beta-carbo-R-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (R-12) and 2beta-carbo-S-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (S-12) followed by treatment with no carrier-added potassium[(18)F]fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [(3)H]WIN 35428 and [(3)H]citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [(18)F](R)-FIPCT and [(18)F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [(18)F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [(18)F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT for DAT indicate [(18)F](R)-FIPCT and [(18)F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.
authors.affiliation: Emory Center for Positron Emission Tomography and Departments of Radiology, Psychiatry and Behavior Sciences, Neurology, and Neurosurgery, Emory University, Atlanta, Georgia 30320, USA.
authors.forename: D
authors.initials: D
authors.lastname: Xing
authors.forename: P
authors.initials: P
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Keil
authors.forename: C D
authors.initials: CD
authors.lastname: Kilts
authors.forename: B
authors.initials: B
authors.lastname: Shi
authors.forename: V M
authors.initials: VM
authors.lastname: Camp
authors.forename: G
authors.initials: G
authors.lastname: Malveaux
authors.forename: T
authors.initials: T
authors.lastname: Ely
authors.forename: M J
authors.initials: MJ
authors.lastname: Owens
authors.forename: J
authors.initials: J
authors.lastname: Votaw
authors.forename: M
authors.initials: M
authors.lastname: Davis
authors.forename: J M
authors.initials: JM
authors.lastname: Hoffman
authors.forename: R A
authors.initials: RA
authors.lastname: BaKay
authors.forename: T
authors.initials: T
authors.lastname: Subramanian
authors.forename: R L
authors.initials: RL
authors.lastname: Watts
authors.forename: M M
authors.initials: MM
authors.lastname: Goodman
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011699:Putamen / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014162:Transfection; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D014562:Caudata / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C405042:N-methyl-2-carbo-1-fluoro-2-isopropanoxy-3-(4-chlorophenyl)tropane; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; C493214:SLC6A3 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493216:Slc6a3 protein, rat; C493232:Slc6a4 protein, rat; D014326:Tropanes; D012701:Serotonin; D004298:Dopamine