title: Preparation and evaluation of ethyl [(18)F]fluoroacetate as a proradiotracer of [(18)F]fluoroacetate for the measurement of glial metabolism by PET.
abstract: BACKGROUND
  Changes in glial metabolism in brain ischemia, Alzheimer's disease, depression, schizophrenia, epilepsy and manganese neurotoxicity have been reported in recent studies. Therefore, it is very important to measure glial metabolism in vivo for the elucidation and diagnosis of these diseases. Radiolabeled acetate is a good candidate for this purpose, but acetate has little uptake in the brain due to its low lipophilicity. We have designed a new proradiotracer, ethyl [(18)F]fluoroacetate ([(18)F]EFA), which is [(18)F]fluoroacetate ([(18)F]FA) esterified with ethanol, to increase the lipophilicity of fluoroacetate (FA), allowing the measurement of glial metabolism.
  
  
  METHODS
  The synthesis of [(18)F]EFA was achieved using ethyl O-mesyl-glycolate as precursor. The blood-brain barrier permeability of ethyl [1-(14)C]fluoroacetate ([(14)C]EFA) was estimated by a brain uptake index (BUI) method. Hydrolysis of [(14)C]EFA in the brain was calculated by the fraction of radioactivity in lipophilic and water fractions of homogenized brain. Using the plasma of five animal species, the stability of [(14)C]EFA was measured. Biodistribution studies of [(18)F]EFA in ddY mice were carried out and compared with [(18)F]FA. Positron emission tomography (PET) scanning using common marmosets was performed for 90 min postadministration. At 60 min postinjection of [(18)F]EFA, metabolite studies were performed. Organs were dissected from the marmosets, and extracted metabolites were analyzed with a thin-layer chromatography method.
  
  
  RESULTS
  The synthesis of [(18)F]EFA was accomplished in a short time (29 min) and with a reproducible radiochemical yield of 28.6+/-3.6% (decay corrected) and a high radiochemical purity of more than 95%. In the brain permeability study, the BUI of [(14)C]EFA was 3.8 times higher than that of sodium [1-(14)C]fluoroacetate. [(14)C]EFA was hydrolyzed rapidly in rat brains. In stability studies using the plasma of five animal species, [(14)C]EFA was stable only in primate plasma. Biodistribution studies in mice showed that the uptake of [(18)F]EFA in selected organs was higher than that of [(18)F]FA. From nonprimate PET studies, [(18)F]EFA was initially taken into the brain after injection. Metabolites related to the tricarboxylic acid (TCA) cycle were detected in common marmoset brain.
  
  
  CONCLUSIONS
  [(18)F]EFA rapidly enters the brain and is then converted into TCA cycle metabolites in the brains of common marmosets. [(18)F]EFA shows promise as a proradiotracer for the measurement of glial metabolism.
authors.affiliation: Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mori
authors.forename: Li-Quan
authors.initials: LQ
authors.lastname: Sun
authors.forename: Masato
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kiyono
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Okazawa
authors.forename: Takako
authors.initials: T
authors.lastname: Furukawa
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Kawashima
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welch
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujibayashi
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002144:Callithrix; D002952:Citric Acid Cycle; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D005463:Fluoroacetates / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D009457:Neuroglia / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D005463:Fluoroacetates; D019275:Radiopharmaceuticals