title: Sulfonium salts as leaving groups for aromatic labelling of drug-like small molecules with fluorine-18.
abstract: Positron emission tomography (PET) is unique in that it allows quantification of biochemical processes in vivo, but difficulties with preparing suitably labelled radiotracers limit its scientific and diagnostic applications. Aromatic [(18)F]fluorination of drug-like small molecules is particularly challenging as their functional group compositions often impair the labelling efficiency. Herein, we report a new strategy for incorporation of (18)F into highly functionalized aromatic compounds using sulfonium salts as leaving groups. The method is compatible with pharmacologically relevant functional groups, including aliphatic amines and basic heterocycles. Activated substrates react with [(18)F]fluoride at room temperature, and with heating the reaction proceeds in the presence of hydrogen bond donors. Furthermore, the use of electron rich spectator ligands allows efficient and regioselective [(18)F]fluorination of non-activated aromatic moieties. The method provides a broadly applicable route for (18)F labelling of biologically active small molecules, and offers immediate practical benefits for drug discovery and imaging with PET.
authors.affiliation: Institute of Nuclear Medicine - Radiochemistry, University College London, 235 Euston Road (T-5), London NW1 2BU, UK.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Sander
authors.affiliation: Institute of Nuclear Medicine - Radiochemistry, University College London, 235 Euston Road (T-5), London NW1 2BU, UK.
authors.forename: Thibault
authors.initials: T
authors.lastname: Gendron
authors.affiliation: Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Yiannaki
authors.affiliation: Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Cybulska
authors.affiliation: Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Kalber
authors.affiliation: Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.affiliation: 1] Institute of Nuclear Medicine - Radiochemistry, University College London, 235 Euston Road (T-5), London NW1 2BU, UK [2] Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK.
authors.forename: Erik
authors.initials: E
authors.lastname: Årstad
mesh_terms: D000818:Animals; D005462:Fluorine Radioisotopes; D007553:Isotope Labeling; D051379:Mice; D023421:Models, Animal; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals; D012492:Salts; D013452:Sulfonium Compounds / Q000138:chemical synthesis; D014057:Tomography, X-Ray Computed
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D012492:Salts; D013452:Sulfonium Compounds