title: Radiosynthesis and pre-clinical evaluation of [(18)F]fluoro-[1,2-(2)H(4)]choline.
abstract: BACKGROUND
  Choline radiotracers are widely used for clinical PET diagnosis in oncology. [(11)C]Choline finds particular utility in the imaging of brain and prostate tumor metabolic status, where 2-[(18)F]fluoro-2-deoxy-D-glucose ('FDG') shows high background uptake. More recently we have extended the clinical utility of [(11)C]choline to breast cancer where radiotracer uptake correlates with tumor aggressiveness (grade). In the present study, a new choline analog, [(18)F]fluoro-[1,2-(2)H(4)]choline, was synthesized and evaluated as a potential PET imaging probe.
  
  
  METHODS
  [(18)F]Fluorocholine, [(18)F]fluoro-[1-(2)H(2)]choline and [(18)F]fluoro-[1,2-(2)H(4)]choline were synthesized by alkylation of the relevant precursor with [(18)F]fluorobromomethane or [(18)F]fluoromethyl tosylate. Radiosynthesis of [(18)F]fluoromethyl tosylate required extensive modification of the existing method. [(18)F]Fluorocholine and [(18)F]fluoro-[1,2-(2)H(4)]choline were then subjected to in vitro oxidative stability analysis in a chemical oxidation model using potassium permanganate and an enzymatic model using choline oxidase. The two radiotracers, together with the corresponding di-deuterated compound, [(18)F]fluoro-[1-(2)H(2)]choline, were then evaluated in vivo in a time-course biodistribution study in HCT-116 tumor-bearing mice.
  
  
  RESULTS
  Alkylation with [(18)F]fluoromethyl tosylate proved to be the most reliable radiosynthetic route. Stability models indicate that [(18)F]fluoro-[1,2-(2)H(4)]choline possesses increased chemical and enzymatic (choline oxidase) oxidative stability relative to [(18)F]fluorocholine. The distribution of the three radiotracers, [(18)F]fluorocholine, [(18)F]fluoro-[1-(2)H(2)]choline and [(18)F]fluoro-[1,2-(2)H(4)]choline, showed a similar uptake profile in most organs. Crucially, tumor uptake of [(18)F]fluoro-[1,2-(2)H(4)]choline was significantly increased at late time points compared to [(18)F]fluorocholine and [(18)F]fluoro-[1-(2)H(2)]choline.
  
  
  CONCLUSIONS
  Stability analysis and biodistribution suggest that [(18)F]fluoro-[1,2-(2)H(4)]choline warrants further in vivo investigation as a PET probe of choline metabolism.
authors.affiliation: Comprehensive Cancer Imaging Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Smith
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Julius
authors.initials: J
authors.lastname: Leyton
authors.forename: Bo
authors.initials: B
authors.lastname: Shan
authors.forename: Quang-de
authors.initials: QD
authors.lastname: Nguyen
authors.forename: Meg
authors.initials: M
authors.lastname: Perumal
authors.forename: David
authors.initials: D
authors.lastname: Turton
authors.forename: Erik
authors.initials: E
authors.lastname: Årstad
authors.forename: Sajinder K
authors.initials: SK
authors.lastname: Luthra
authors.forename: Edward G
authors.initials: EG
authors.lastname: Robins
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
mesh_terms: D000818:Animals; D002794:Choline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D003903:Deuterium / Q000737:chemistry; D004355:Drug Stability; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D011854:Radiochemistry
chemical_list: C514960:fluorocholine; D003903:Deuterium; D002794:Choline