title: 18F-Fluorosulfate for PET Imaging of the Sodium-Iodide Symporter: Synthesis and Biologic Evaluation In Vitro and In Vivo.
abstract: Anion transport by the human sodium-iodide symporter (hNIS) is an established target for molecular imaging and radionuclide therapy. Current radiotracers for PET of hNIS expression are limited to124I-and18F-BF4-We sought new18F-labeled hNIS substrates offering higher specific activity, higher affinity, and simpler radiochemical synthesis than18F-BF4-METHODS: The ability of a range of anions, some containing fluorine, to block99mTcO4-uptake in hNIS-expressing cells was measured. SO3F-emerged as a promising candidate.18F-SO3F-was synthesized by reaction of18F-with SO3-pyridine complex in MeCN and purified using alumina and quaternary methyl ammonium solid-phase extraction cartridges. Chemical and radiochemical purity and serum stability were determined by radiochromatography. Radiotracer uptake and efflux in hNIS-transduced HCT116-C19 cells and the hNIS-negative parent cell line were evaluated in vitro in the presence and absence of a known competitive inhibitor (NaClO4). PET/CT imaging and ex vivo biodistribution measurement were conducted on BALB/c mice, with and without NaClO4inhibition.
  
  
  RESULTS
  Fluorosulfate was identified as a potent inhibitor of99mTcO4-uptake via hNIS in vitro (half-maximal inhibitory concentration, 0.55-0.56 μM (in comparison with 0.29-4.5 μM for BF4-, 0.07 μM for TcO4-, and 2.7-4.7 μM for I-). Radiolabeling to produce18F-SO3F-was simple and afforded high radiochemical purity suitable for biologic evaluation (radiochemical purity > 95%, decay-corrected radiochemical yield = 31.6%, specific activity ≥ 48.5 GBq/μmol). Specific, blockable hNIS-mediated uptake in HCT116-C19 cells was observed in vitro, and PET/CT imaging of normal mice showed uptake in thyroid, salivary glands (percentage injected dose/g at 30 min, 563 ± 140 and 32 ± 9, respectively), and stomach (percentage injected dose/g at 90 min, 68 ± 21).
  
  
  CONCLUSIONS
  Fluorosulfate is a high-affinity hNIS substrate.18F-SO3F-is easily synthesized in high yield and very high specific activity and is a promising candidate for preclinical and clinical PET imaging of hNIS expression and thyroid-related disease; it is the first example of in vivo PET imaging with a tracer containing an S-18F bond.
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, St. Thomas' Hospital, King's College London, London, United Kingdom; and.
authors.forename: Alex
authors.initials: A
authors.lastname: Khoshnevisan
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, St. Thomas' Hospital, King's College London, London, United Kingdom; and.
authors.forename: Krisanat
authors.initials: K
authors.lastname: Chuamsaamarkkee
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, St. Thomas' Hospital, King's College London, London, United Kingdom; and.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Boudjemeline
authors.affiliation: GE Healthcare, Amersham, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Jackson
authors.affiliation: GE Healthcare, Amersham, United Kingdom.
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Smith
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, St. Thomas' Hospital, King's College London, London, United Kingdom; and.
authors.forename: Antony D
authors.initials: AD
authors.lastname: Gee
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, St. Thomas' Hospital, King's College London, London, United Kingdom; and.
authors.forename: Gilbert O
authors.initials: GO
authors.lastname: Fruhwirth
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, St. Thomas' Hospital, King's College London, London, United Kingdom; and philip.blower@kcl.ac.uk.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Blower
mesh_terms: D000818:Animals; D005260:Female; D005459:Fluorides / Q000493:pharmacokinetics*; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D057054:Molecular Imaging / Q000379:methods*; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013464:Sulfuric Acids / Q000493:pharmacokinetics*; D027981:Symporters / Q000378:metabolism*; D013961:Thyroid Gland / Q000000981:diagnostic imaging / Q000378:metabolism*; D014018:Tissue Distribution; D000099209:Sodium-Iodide Symporters
chemical_list: D005459:Fluorides; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D013464:Sulfuric Acids; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C046106:fluorosulfonic acid
keywords: 18F; PET; fluorosulfate; human sodium/iodide symporter (SC5A5); thyroid