title: Preclinical evaluation of 3-18F-fluoro-2,2-dimethylpropionic acid as an imaging agent for tumor detection.
abstract: Deregulated cellular metabolism is a hallmark of many cancers. In addition to increased glycolytic flux, exploited for cancer imaging with (18)F-FDG, tumor cells display aberrant lipid metabolism. Pivalic acid is a short-chain, branched carboxylic acid used to increase oral bioavailability of prodrugs. After prodrug hydrolysis, pivalic acid undergoes intracellular metabolism via the fatty acid oxidation pathway. We have designed a new probe, 3-(18)F-fluoro-2,2-dimethylpropionic acid, also called (18)F-fluoro-pivalic acid ((18)F-FPIA), for the imaging of aberrant lipid metabolism and cancer detection.
  
  
  METHODS
  Cell intrinsic uptake of (18)F-FPIA was measured in murine EMT6 breast adenocarcinoma cells. In vivo dynamic imaging, time course biodistribution, and radiotracer stability testing were performed. (18)F-FPIA tumor retention was further compared in vivo to (18)F-FDG uptake in several xenograft models and inflammatory tissue.
  
  
  RESULTS
  (18)F-FPIA rapidly accumulated in EMT6 breast cancer cells, with retention of intracellular radioactivity predicted to occur via a putative (18)F-FPIA carnitine-ester. The radiotracer was metabolically stable to degradation in mice. In vivo imaging of implanted EMT6 murine and BT474 human breast adenocarcinoma cells by (18)F-FPIA PET showed rapid and extensive tumor localization, reaching 9.1% ± 0.5% and 7.6% ± 1.2% injected dose/g, respectively, at 60 min after injection. Substantial uptake in the cortex of the kidney was seen, with clearance primarily via urinary excretion. Regarding diagnostic utility, uptake of (18)F-FPIA was comparable to that of (18)F-FDG in EMT6 tumors but superior in the DU145 human prostate cancer model (54% higher uptake; P = 0.002). Furthermore, compared with (18)F-FDG, (18)F-FPIA had lower normal-brain uptake resulting in a superior tumor-to-brain ratio (2.5 vs. 1.3 in subcutaneously implanted U87 human glioma tumors; P = 0.001), predicting higher contrast for brain cancer imaging. Both radiotracers showed increased localization in inflammatory tissue.
  
  
  CONCLUSIONS
  (18)F-FPIA shows promise as an imaging agent for cancer detection and warrants further investigation.
authors.affiliation: Comprehensive Cancer Imaging Centre, Division of Cancer, Department of Surgery and Cancer, Imperial College London Faculty of Medicine, London, United Kingdom; and.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Witney
authors.affiliation: Comprehensive Cancer Imaging Centre, Division of Cancer, Department of Surgery and Cancer, Imperial College London Faculty of Medicine, London, United Kingdom; and.
authors.forename: Federica
authors.initials: F
authors.lastname: Pisaneschi
authors.affiliation: Comprehensive Cancer Imaging Centre, Division of Cancer, Department of Surgery and Cancer, Imperial College London Faculty of Medicine, London, United Kingdom; and.
authors.forename: Israt S
authors.initials: IS
authors.lastname: Alam
authors.affiliation: Comprehensive Cancer Imaging Centre, Division of Cancer, Department of Surgery and Cancer, Imperial College London Faculty of Medicine, London, United Kingdom; and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Trousil
authors.affiliation: Comprehensive Cancer Imaging Centre, Division of Cancer, Department of Surgery and Cancer, Imperial College London Faculty of Medicine, London, United Kingdom; and.
authors.forename: Maciej
authors.initials: M
authors.lastname: Kaliszczak
authors.affiliation: Comprehensive Cancer Imaging Centre, Division of Cancer, Department of Surgery and Cancer, Imperial College London Faculty of Medicine, London, United Kingdom; and.
authors.forename: Frazer
authors.initials: F
authors.lastname: Twyman
authors.affiliation: Comprehensive Cancer Imaging Centre, Division of Cancer, Department of Surgery and Cancer, Imperial College London Faculty of Medicine, London, United Kingdom; and.
authors.forename: Diana
authors.initials: D
authors.lastname: Brickute
authors.affiliation: Comprehensive Cancer Imaging Centre, Division of Cancer, Department of Surgery and Cancer, Imperial College London Faculty of Medicine, London, United Kingdom; and.
authors.forename: Quang-Dé
authors.initials: QD
authors.lastname: Nguyen
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, United Kingdom.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Schug
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, United Kingdom.
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
authors.affiliation: Comprehensive Cancer Imaging Centre, Division of Cancer, Department of Surgery and Cancer, Imperial College London Faculty of Medicine, London, United Kingdom; and eric.aboagye@imperial.ac.uk.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging*; D010421:Pentanoic Acids; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals
chemical_list: D005462:Fluorine Radioisotopes; D010421:Pentanoic Acids; D019275:Radiopharmaceuticals; C005566:pivalic acid
keywords: FDG; FPIA; PET; lipid metabolism; tumor detection