title: Radiolabelling and evaluation of novel haloethylsulfoxides as PET imaging agents for tumor hypoxia.
abstract: The significance of imaging hypoxia with the PET 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. Labelled 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 two novel sulfoxides which we synthesised from a single precursor molecule via either 2-[(18)F]fluoroethyl azide click chemistry or conventional nucleophilic displacement of a chloride leaving group. The yields of the click chemistry approach were 90±5% of [(18)F]2 based on 2-[(18)F]fluoroethyl azide, and the yields for the S(N) reaction were 15±5% of [(18)F]1 based on K[(18)F]F. Both radiotracers underwent metabolism in an in vitro assay using S9 liver fractions with biological half-lives of 32.39 and 43.32 min, respectively. Imaging studies using an SK-RC-52 tumor model in BALB/c nude mice have revealed that only [(18)F]1 is retained in hypoxic tumors, whereas [(18)F]2 is cleared from those tumors at a rate similar to that of muscle tissue. [(18)F]1 has emerged as a promising new lead structure for further development of sulfoxide-based hypoxia imaging agents. In particular, the mechanism of uptake needs to be elucidated and changes to the chemical structure need to be made in order to reduce metabolism and improve radiotracer kinetics.
authors.affiliation: School of Chemistry and Bio21 Institute, The University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Laurens
authors.forename: Shinn Dee
authors.initials: SD
authors.lastname: Yeoh
authors.forename: Angela
authors.initials: A
authors.lastname: Rigopoulos
authors.forename: Diana
authors.initials: D
authors.lastname: Cao
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Cartwright
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: O'Keefe
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Tochon-Danguy
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: White
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.forename: Uwe
authors.initials: U
authors.lastname: Ackermann
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007553:Isotope Labeling; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D051381:Rats; D013454:Sulfoxides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D013454:Sulfoxides