Investigations into the Radiochemistry of Gallium- and Fluorine-Containing Compounds for Molecular Imaging Applications

Abstract

Hypoxia is the condition characterised by lack of oxygen supplied to the body or a region of the body. It has been strongly related to cancer since the 1950’s and it is still considered responsible for the malignant progression of tumours, therapy resistance and weak prognosis. Thus, tumour hypoxia has been widely investigated in the last decades as a potential target in oncology. However, despite years of research and a variety of information collected, yet there are still many unanswered questions on hypoxia mechanisms that haven’t yet been addressed. The inhibition of hypoxia-inducible factor (HIF) has attracted the interest in drug developments. However, in recent years, inhibition of carbonic anhydrase IX (CAIX), which is also related to HIF, has attracted the attention of many research groups working on hypoxia worldwide.
It was hypothesised that targeting HIF and CAIX together by a small molecule attached to an imaging agent for positron emission tomography (PET) or single photon emission tomography (SPECT) would allow one to detect and inhibit hypoxia. The new family of compounds discussed through this thesis aimed to shed further light on these aspects, by inclusion of an unsymmetrical thiosemicarbazonate complex, a glycosyl coumarin unit and a fluorine-18 unit in the tracer design. Bis(thiosemicarbazonate) metal complexes have been extensively used as PET and SPECT imaging agents and they have also shown some in vivo hypoxia uptake while glycosyl coumarin has shown good CAIX inhibition. Several new compounds have been synthesised and fully characterised through different techniques such as 1D and 2D NMR and mass spectrometry. Labelling with gallium-68 has been also performed in order to evaluate the potential application of such complexes as PET imaging agents additionally to optical imaging agents. Significant progress has been made in the direction of the synthesis of these compounds, and further cellular uptake and behaviour.
Specifically, Chapter 1 includes a literature review, where medical imaging is introduced along with some basic background on cancer and hypoxia. Examples are cited on how thiosemicarbazonato complexes have been related and used through the years as antitumour and potential imaging agents. In addition, the potential of glucosyl coumarin as hypoxia target molecule are quoted. The review concludes with the upcoming field of nanomedicine and the possibility of graphene oxides as nanocarriers of targeting molecules or imaging tracers.
In Chapters 2,3 and 4 are discussed the results obtained through the thesis. Chapter 2 describes and analyses the synthesis of three new mono(substituted) precursors and of a number of new non-radioactive and radioactive metal complexes that are relied on two identical mono(substituted) ligands. Moreover, Chapter 3 describes the synthesis and characterisation of asymmetric acenaphthenoquinone bis(thiosemicarbazonate) metal complexes originated by the mono(substituted) ligands described in Chapter 2. The radiolabelling of these complexes with gallium-68 and fluorine-18 is also presented. In both chapters, it is examined the investigations of the behaviour of those compounds in the cellular environment through in vitro fluorescence imaging, cell viability and radioactive uptake assays. Moreover, in Chapter 3 the attempted attachment of a CAIX selective inhibitor to these metal complexes is outlined. Specifically, the characterisation and functionalisation of a glucosyl coumarin derivative is described. On the other side, Chapter 4 communicates the potentials of graphene oxides as nanocarriers of thiosemicarbazonate complexes and/or glucosyl coumarin. The non-covalent radiolabelling of the new nanohybrids with gallium-68 is presented in this chapter for the first time along with the cellular investigation of their toxicity and uptaking features.
An overview of this work and the conclusions drawn are discussed in Chapter 5. Certain possible future exploitations related to the results discussed are suggested in this chapter to fully optimise the potentials of those complexes in a hypoxic environment.
Lastly, Chapter 6 contains the experimental procedures and protocols that were developed through this thesis. Additional supporting crystallographic data, figures and tables are presented in the supplementary information.

Date of Award	1 May 2019
Original language	English
Awarding Institution	University of Bath University of Bath
Supervisor	Sofia Pascu (Supervisor) & Ian Eggleston (Supervisor)