title: Effective microPET imaging of brain 5-HT(1A) receptors in rats with [(18) F]MeFWAY by suppression of radioligand defluorination.
abstract: BACKGROUND
  [(18) F]MeFWAY has been developed for imaging the serotonin 1A receptors in the brain. The purpose of this study were to verify the metabolic stability of [(18) F]MeFWAY, to measure the degree of defluorination of [(18) F]MeFWAY in vivo, to investigate methods of inhibition of defluorination of [(18) F]MeFWAY, and to assess the efficacy of [(18) F]MeFWAY in rat brains in vivo.
  
  
  METHODS
  MicroPET experiments in rats were conducted to confirm the distribution of radioactivity in the brain. Nondisplaceable binding potential (BP(ND) ) in the hippocampus and frontal cortex were also analyzed. Miconazole and fluconazole were tested for the ability to suppress defluorination of [(18) F]MeFWAY. We conducted a blockade and displacement experiment by treating with WAY-100635.
  
  
  RESULTS
  In vitro stability tests showed that MeFWAY was very stable in serum for 6 h, but PET revealed that authentic [(18) F]MeFWAY underwent significant defluorination in vivo. In vitro inhibition study against decreasing parent activity in liver microsomes, miconazole and fluconazole suppressed metabolic elimination of MeFWAY. However, in the PET study, fluconazole showed more potent inhibitory activity than miconazole. In the suppression of metabolizing enzymes using fluconazole, radioactivity in skull was dramatically decreased by 81% (compared with 69% with miconazole) and it was coupled with an increase in brain uptake. Moreover, BP(ND) in hippocampus was 5.53 and 2.66 in frontal cortex. The blockade and displacement study showed the specificity of [(18) F]MeFWAY to 5-HT(1A) receptors.
  
  
  CONCLUSIONS
  In the rat brain, [(18) F]MeFWAY microPET showed skull uptake due to defluorination in vivo. We can effectively overcome this drawback with fluconazole.
authors.affiliation: Department of Pharmacology, Brain Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jae Yong
authors.initials: JY
authors.lastname: Choi
authors.forename: Chul Hoon
authors.initials: CH
authors.lastname: Kim
authors.forename: Tae Joo
authors.initials: TJ
authors.lastname: Jeon
authors.forename: Byoung Soo
authors.initials: BS
authors.lastname: Kim
authors.forename: Chi Hoon
authors.initials: CH
authors.lastname: Yi
authors.forename: Kwang Sun
authors.initials: KS
authors.lastname: Woo
authors.forename: Young Beom
authors.initials: YB
authors.lastname: Seo
authors.forename: Sang Jin
authors.initials: SJ
authors.lastname: Han
authors.forename: Kyeong Min
authors.initials: KM
authors.lastname: Kim
authors.forename: Dae Ik
authors.initials: DI
authors.lastname: Yi
authors.forename: Minkyung
authors.initials: M
authors.lastname: Lee
authors.forename: Dong Goo
authors.initials: DG
authors.lastname: Kim
authors.forename: Jung Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Kyo Chul
authors.initials: KC
authors.lastname: Lee
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Choi
authors.forename: Gwangil
authors.initials: G
authors.lastname: An
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Ryu
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D001923:Brain Chemistry; D004355:Drug Stability; D015725:Fluconazole / Q000494:pharmacology; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D008024:Ligands; D008297:Male; D008825:Miconazole / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044263:Receptors, Serotonin, 5-HT1 / Q000032:analysis*
chemical_list: D005462:Fluorine Radioisotopes; D008024:Ligands; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D044263:Receptors, Serotonin, 5-HT1; C515664:mefway; D008825:Miconazole; D015725:Fluconazole