Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491536
Title: Hypoxia-Selective Copper Radiopharmaceuticals
Author: Holland, Jason P.
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2008
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Abstract:
This thesis presents detailed experimental and computational investigations into the chemistry of copper(II) and zinc(II) bis(thiosemicarbazonato) complexes as potential' radiopharmaceutical agents for imaging and therapy. Chapter 1 provides an introduction to the field of molecular imaging in medicine with particular emphasis on the role of positron emission tomography in oncology. Key aspects of tumour physiology are discussed, and the effects of tumour hypoxia on radiotherapy and chemotherapy are considered. A range of hypoxia-selective radiopharmaceuticals are also introduced including a review of the chemistry and biochemistry of copper(II) complexes of bis(thiosemicarbazonato) ligands. Finally, the aims of this thesis are described. Chapter 2 is divided into two sections. The first section provides a general introduction to computational chemistry and density functional theory. The second section describes computational studies on a range of copper(II) bis(thiosemicarbazonato) complexes with the specific aim of understanding the molecular origins of hypoxia-selectivity and facilitating the design of new complexes with greater hypoxia-selectivity. Chapter 3 reports detailed electrochemical, spectroscopic and computational studies aimed at elucidating the mechanism of hypoxia-selectivity of copper(II) bis(thiosemicarbazonato) complexes. Spectroelectrochemistry experiments have been used to characterise several new species. The delicate equilibria between reduction, reoxidation, protonation and ligand dissociation are also considered and a new mechanistic scheme is proposed. Chapter 4 describes the design and optimisation of a new synthetic route which facilitates rapid functionalisation of the copper(II) bis(thiosemicarbazonato) ligands with biologically active molecules. The methodology has been used to synthesise zinc(II) and copper(II) bis(thiosemicarbazonato) complexes functionalised with a diverse range of saccharides. Transmetallation from the zinc(II) analogues using copper(II) salts is described as a fast and efficient route for radiolabelling and copper64 radiolabelled complexes have been prepared and characterised by a range of in vitro and in vivo experiments. Chapter 5 describes the results obtained for several projects designed at increasing the scope of copper-based radiopharmaceuticals. Preliminary synthetic studies towards the development of complexes for imaging Parkinsonian-type diseases and strategies for dual radiolabelling are presented. Chapter 6 gives general conclusions and future prospects for the development of copper-based radiopharmaceuticals. Chapter 7 reports all experimental details.
Supervisor: Not available Sponsor: Not available
Qualification Name: University of Oxford, 2008 Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.491536  DOI: Not available
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