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Title: Radiofluorination of squalenoylated drug analogues
Author: Cremosnik, Gregor Sascha
ISNI:       0000 0004 7430 658X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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The conjugation of drugs with squalene derivatives has found wide spread application due to the ability of the conjugates to form nanoparticles in aqueous solutions. The conjugated drugs exhibit increased bioavailability and effectiveness against the targeted disease. Although in vitro experiments revealed the mechanism of action at a cellular level, in vivo whole-body distribution studies have not been performed yet. The aim of this work was to develop a radioactive analogue of a squalenoylated drug to determine its pharmacokinetic and -dynamic properties through Positron Emission Tomography (PET). In Chapter 1, a general introduction about the physical and biological properties of squalenoylated drugs is given alongside introductions to PET and previously employed strategies to radiolabel nanoparticles with [18F]fluoride. The chapter will conclude in a proposed radiolabelling strategy for squalenoylated drugs on the example of squalenoyl gemcitabine. Chapter 2 discusses the successful synthesis of a fluorinated analogue of squalenoyl gemcitabine (F-Sq-Gem). The nanoparticles of the novel conjugate were characterised with Dynamic Light Scattering (DLS) and exhibit similar properties to squalenoyl gemcitabine nanoparticles. The modification in the squalenoyl chain was well tolerated and the radiolabelled compound can be expected to behave similar to the native compound in vivo. In the third chapter, different radiofluorination methods are reviewed and analysed for their potential to radiolabel vinyl boronic esters. The copper-mediated radiofluorination of aryl boronic esters offered the potential to be applied to vinylic substrates and therefore for the radiolabelling of squalenoylated drugs. Finally, the synthesis of a terpenoid based vinyl boronic ester precursor is presented. In Chapter 4, the radiofluorination of vinyl boronic esters is discussed. The reaction required a Lewis basic moiety in proximity of the vinyl boronic ester to afford the desired products, which was not present in the envisaged precursors for squalenoylated drugs. Several attempts to adapt the target synthesis for this requirement are described. The most promising results were obtained using an allylic ether, which can be removed post-labelling.
Supervisor: Gouverneur, Veronique E. B. M. Sponsor: Marie-Curie ITN RADIOMI
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available