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Title: ¹⁸F-labelling of new chemotypes for drug discovery
Author: Khotavivattana, Tanatorn
ISNI:       0000 0004 6421 4729
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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In this thesis, the 18F-labelling of new "chemotypes" will be described with the aim of application in pharmaceutically interesting targets. In Chapter 1, a general introduction to the effect of fluorine substituents on molecular properties and reactivity is provided. This includes the application of organofluorine in both medicinal chemistry and positron emission tomography. Chapter 2 describes a novel silver-mediated 18F-labelling of Ar-SCF3, Ar OCF3 and Ar-OCF2H, including [18F]Riluzole, the 18F labelled version of a drug for treatment of amyotrophic lateral sclerosis (ALS). This work demonstrates that AgOTf can induce halogen exchange nucleophilic 18F-fluorination under mild reaction conditions with a wide range of substrates. In addition, the 18F-labelled Ar-SCF3 substrate is further transformed into the [18F]Umemoto reagent in a single step. The Umemoto reagent has been extensively used for electrophilic trifluoromethylation of various functional groups. Therefore the labelling of this reagent could potentially expand the radiochemical space available for PET applications. To augment the utility of this reagent, we developed a late-stage stereoselective trifluoromethylation-thiocyclisation of alkenes using electrophilic trifluoromethylating reagents such as Umemoto reagent or Togni reagent, which will be discussed in Chapter 3. In this process, thiourea acts as both S-nucleophile and CF3 radical initiator; therefore no metal or photoredox catalyst is required. The reaction affords novel trifluoromethylated 2-amino-thiazolines and 2-amino-thiazines, important scaffolds in the development of aspartate beta-secretase enzyme (BACE-1) inhibitors, a therapeutic target for Alzheimer's disease. Chapter 4 investigates the 18F-labelling of a,a-difluoro-a-aryloxyacetic acid, a class of substrate that can serve as a versatile intermediate which can undergo various decarboxylative functionalisation reactions to afford a wide range of novel 18F labelled a fluorinated aryl ethers. Finally, Chapter 5 gives full experimental procedures and characterisation data for all compounds.
Supervisor: Gouverneur, Veronique Sponsor: Royal Thai Government ; Society of Chemical Industry (SCI) ; Royal Society for a Wolfson Research Merit Award
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available