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Effective microPET imaging of brain 5-HT(1A) receptors in rats with [(18) F]MeFWAY by suppression of radioligand defluorination

 Jae Yong Choi  ;  Chul Hoon Kim  ;  Tae Joo Jeon  ;  Byoung Soo Kim  ;  Chi Hoon Yi  ;  Kwang Sun Woo  ;  Young Beom Seo  ;  Sang Jin Han  ;  Kyeong Min Kim  ;  Dae Ik Yi  ;  Minkyung Lee  ;  Dong Goo Kim  ;  Jung Young Kim  ;  Kyo Chul Lee  ;  Tae Hyun Choi  ;  Gwangil An  ;  Young Hoon Ryu 
 SYNAPSE, Vol.66(12) : 1015-1023, 2012 
Journal Title
Issue Date
Animals ; Brain/diagnostic imaging ; Brain Chemistry* ; Drug Stability ; Fluconazole/pharmacology ; Fluorine Radioisotopes/pharmacokinetics ; Ligands ; Male ; Miconazole/pharmacology ; Piperazines/chemical synthesis ; Piperazines/pharmacokinetics* ; Positron-Emission Tomography* ; Pyridines/chemical synthesis ; Pyridines/pharmacokinetics* ; Radiopharmaceuticals/chemical synthesis ; Radiopharmaceuticals/pharmacokinetics* ; Rats ; Rats, Sprague-Dawley ; Receptors, Serotonin, 5-HT1/analysis*
[18F]MeFWAY ; 5-HT1Areceptors ; microPET ; defluorination ; fluconazole
INTRODUCTION: [(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. CONCLUSION: In the rat brain, [(18) F]MeFWAY microPET showed skull uptake due to defluorination in vivo. We can effectively overcome this drawback with fluconazole.
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1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Dong Goo(김동구)
Kim, Chul Hoon(김철훈) ORCID logo https://orcid.org/0000-0002-7360-429X
Ryu, Young Hoon(유영훈) ORCID logo https://orcid.org/0000-0002-9000-5563
Lee, Min Kyung(이민경)
Jeon, Tae Joo(전태주) ORCID logo https://orcid.org/0000-0002-7574-6734
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