title: Fluorine-18 radiolabeling of a nitrophenyl sulfoxide and its evaluation in an SK-RC-52 model of tumor hypoxia.
abstract: The significance of imaging hypoxia with the positron emission tomography ligand [(18) F]FMISO has been demonstrated in a variety of cancers. However, the slow kinetics of [(18) F]FMISO require a 2-h delay between tracer administration and patient scanning. Labeled chloroethyl sulfoxides have shown faster kinetics and higher contrast than [(18) F]FMISO in a rat model of ischemic stroke. However, these nitrogen mustard analogues are unsuitable for routine production and use in humans. Here, we report on the synthesis and in vitro and in vivo evaluation of a novel sulfoxide, which contains an ester moiety for hydrolysis and subsequent trapping in hypoxic cells. Non-decay corrected yields of radioactivity were 1.18 ± 0.24% (n = 27, 2.5 ± 0.5% decay corrected radiochemical yield) based on K[(18) F]F. The radiotracer did not show any defluorination and did not undergo metabolism in an in vitro assay using S9 liver fractions. Imaging studies using an SK-RC-52 tumor model in BALB/c nude mice have revealed that [(18) F]1 is retained in hypoxic tumors and has similar hypoxia selectivity to [(18) F]FMISO. Because of a three times faster clearance rate than [(18) F]FMISO from normoxic tissue, [(18) F]1 has emerged as a promising new radiotracer for hypoxia imaging.
authors.affiliation: School of Chemistry, The University of Melbourne, Melbourne, Australia.|Bio21 Institute, The University of Melbourne, Melbourne, Australia.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Laurens
authors.affiliation: Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.
authors.forename: Shinn Dee
authors.initials: SD
authors.lastname: Yeoh
authors.affiliation: Olivia Newton-John Cancer Research Institute, Melbourne, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Rigopoulos
authors.affiliation: Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: O'Keefe
authors.affiliation: Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.|Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia.
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Tochon-Danguy
authors.affiliation: School of Chemistry, The University of Melbourne, Melbourne, Australia.|Bio21 Institute, The University of Melbourne, Melbourne, Australia.
authors.forename: Lee Wenn
authors.initials: LW
authors.lastname: Chong
authors.affiliation: School of Chemistry, The University of Melbourne, Melbourne, Australia.|Bio21 Institute, The University of Melbourne, Melbourne, Australia.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: White
authors.affiliation: Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.|Olivia Newton-John Cancer Research Institute, Melbourne, Australia.|Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia.|School of Cancer Medicine, La Trobe University, Melbourne, Australia.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.affiliation: Bio21 Institute, The University of Melbourne, Melbourne, Australia.|Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.|Olivia Newton-John Cancer Research Institute, Melbourne, Australia.|Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia.
authors.forename: Uwe
authors.initials: U
authors.lastname: Ackermann
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007553:Isotope Labeling; D051379:Mice; D057054:Molecular Imaging; D011854:Radiochemistry; D013454:Sulfoxides / Q000737:chemistry; D000072258:Tumor Hypoxia
chemical_list: D005462:Fluorine Radioisotopes; D013454:Sulfoxides; C000624968:ethyl 2-((2-fluoroethyl)(4-(4-nitrophenylsulfinyl)phenyl)amino)acetate; D005998:Glycine
keywords: SK-RC-52 tumor model; hypoxia; radiolabeling; small animal imaging