title: Evaluation of deuterated 18F- and 11C-labeled choline analogs for cancer detection by positron emission tomography.
abstract: OBJECTIVE
  (11)C-Choline-positron emission tomography (PET) has been exploited to detect the aberrant choline metabolism in tumors. Radiolabeled choline uptake within the imaging time is primarily a function of transport, phosphorylation, and oxidation. Rapid choline oxidation, however, complicates interpretation of PET data. In this study, we investigated the biologic basis of the oxidation of deuterated choline analogs and assessed their specificity in human tumor xenografts.
  
  
  METHODS
  (11)C-Choline, (11)C-methyl-[1,2-(2)H(4)]-choline ((11)C-D4-choline), and (18)F-D4-choline were synthesized to permit comparison. Biodistribution, metabolism, small-animal PET studies, and kinetic analysis of tracer uptake were carried out in human colon HCT116 xenograft-bearing mice.
  
  
  RESULTS
  Oxidation of choline analogs to betaine was highest with (11)C-choline, with reduced oxidation observed with (11)C-D4-choline and substantially reduced with (18)F-D4-choline, suggesting that both fluorination and deuteration were important for tracer metabolism. Although all tracers were converted intracellularly to labeled phosphocholine (specific signal), the higher rate constants for intracellular retention (K(i) and k(3)) of (11)C-choline and (11)C-D4-choline, compared with (18)F-D4-choline, were explained by the rapid conversion of the nonfluorinated tracers to betaine within HCT116 tumors. Imaging studies showed that the uptake of (18)F-D4-choline in three tumors with similar radiotracer delivery (K(1)) and choline kinase α expression-HCT116, A375, and PC3-M-were the same, suggesting that (18)F-D4-choline has utility for cancer detection irrespective of histologic type.
  
  
  CONCLUSIONS
  We have shown here that both deuteration and fluorination combine to provide protection against choline oxidation in vivo. (18)F-D4-choline showed the highest selectivity for phosphorylation and warrants clinical evaluation.
authors.affiliation: Comprehensive Cancer Imaging Centre at Imperial College, Faculty of Medicine, Imperial College London, United Kingdom.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Witney
authors.forename: Israt S
authors.initials: IS
authors.lastname: Alam
authors.forename: David R
authors.initials: DR
authors.lastname: Turton
authors.forename: Graham
authors.initials: G
authors.lastname: Smith
authors.forename: Laurence
authors.initials: L
authors.lastname: Carroll
authors.forename: Diana
authors.initials: D
authors.lastname: Brickute
authors.forename: Frazer J
authors.initials: FJ
authors.lastname: Twyman
authors.forename: Quang-Dé
authors.initials: QD
authors.lastname: Nguyen
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tomasi
authors.forename: Ramla O
authors.initials: RO
authors.lastname: Awais
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D045744:Cell Line, Tumor; D002794:Choline / Q000031:analogs & derivatives / Q000378:metabolism; D003903:Deuterium; D004195:Disease Models, Animal; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008545:Melanoma / Q000000981:diagnostic imaging / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D010084:Oxidation-Reduction; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D011849:Radioactive Tracers
chemical_list: D002250:Carbon Radioisotopes; D011849:Radioactive Tracers; D019788:Fluorodeoxyglucose F18; D003903:Deuterium; D002794:Choline