Potential of [(18)F]beta-CFT-FE (2beta-carbomethoxy-3beta-(4-fluorophenyl)-8-(2-[(18)F]fluoroethyl)nortropane) as a dopamine transporter ligand: A PET study in the conscious monkey brain.
A dopamine transporter (DAT) ligand 2beta-carbomethoxy-3beta-(4-fluoro-phenyl)-8-(2-[(18)F]fluoroethyl)nortropane ([(18)F]beta-CFT-FE) was synthesized and evaluated in comparison with [(11)C]beta-CFT in monkey brain using animal positron emission tomography (PET). [(18)F]beta-CFT-FE and [(11)C]beta-CFT were injected intravenously to conscious monkeys for a 91-min PET scan with arterial blood sampling for metabolite analysis. In the conscious state, [(18)F]beta-CFT-FE provided a peak about 20 min after the injection and declined thereafter in the striatum of monkey brain, while [(11)C]beta-CFT continuously increased with time up to 91 min after injection. Metabolite analysis revealed that [(18)F]beta-CFT-FE was more rapidly metabolized in plasma than [(11)C]beta-CFT. The striatal binding of both ligands was dose-dependently displaced by preadministration of a specific DAT inhibitor, GBR12909, at doses of 0.5 and 5 mg/kg; however, the displacement degree of [(11)C]beta-CFT-FE was higher than that of [(18)F]beta-CFT. The effects of the anesthetics, ketamine and isoflurane, on binding were more prominent in [(11)C]beta-CFT than [(18)F]beta-CFT-FE. Specificity and affinity of beta-CFT-FE to DAT were evaluated in an in vitro assay using cloned human DAT, serotonin transporter, and norepinephrine transporter in comparison with other conventional DAT ligands, showing that beta-CFT-FE had lower affinity and higher specificity to DAT than beta-CFT and beta-CIT. These results suggested that [(18)F]beta-CFT-FE could be a potential imaging agent for DAT, providing excellent selectivity and tracer kinetics for quantitative PET imaging.
Harada
Norihiro
N
Central Research Laboratory, Hamamatsu Photonics K.K., Hamakita, Shizuoka 434-8601, Japan.
Ohba
Hiroyuki
H
Fukumoto
Dai
D
Kakiuchi
Takeharu
T
Tsukada
Hideo
H
D000777:Anesthetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000097:blood / Q000493:pharmacokinetics; D003243:Consciousness; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008024:Ligands; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009662:Nortropanes / Q000097:blood / Q000493:pharmacokinetics*; D010879:Piperazines / Q000494:pharmacology; D012680:Sensitivity and Specificity; D014055:Tomography, Emission-Computed
D000777:Anesthetics; D002250:Carbon Radioisotopes; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D005462:Fluorine Radioisotopes; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009662:Nortropanes; D010879:Piperazines; C493214:SLC6A3 protein, human; D007649:Ketamine; C043425:vanoxerine; D007530:Isoflurane