Desmond, Antonia Louisa; (2013) Fluorine-18 labelling of novel voltage-gated sodium channel ligands for applications in positron emission tomography (PET) imaging and oncology. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Voltage-gated sodium channels (VGSCs) are essential for the initiation and propagation of neuronal impulses. Specifically, these channels initiate the rising phase of action potentials in electrically excitable cells, allowing the conduction of electrical information. There are 9 different sub-types of VGSCs, each found in different tissues, with a minimum 50% identical genetic code.1 Recently, it has been reported that some VGSC sub-types are over-expressed in highly metastatic tumours.2 Their presence allows the up-regulation of some key biochemical processes. In fact, the metastatic potential of the tumours has a positive correlation with the expression of sodium channels.2-6 This thesis focussed on developing a novel positron emission tomography (PET) tracer to target VGSCs. We hypothesised that a PET scan using a VGSC ligand may be able to highlight tumours with high metastatic potential, and assist in the selection of the most appropriate clinical treatment. At present, there is no known clinical PET tracer for imaging VGSCs. Our project involved the adaptation of the 3-(4-substituted-phenoxyphenyl) pyrazoles,7 a known group of VGSC modulators, into novel fluorine-18 labelled PET imaging agents. These were chosen due to their strong affinity for VGSCs and their structural characteristics, which allowed multiple approches to introduce a fluorine-18 label. Several compounds of interest were successfully synthesised. Optimal radiolabelling strategies were identified and methodologies developed, to produce PET agents in good synthesis time, yield and purity. The fluorine-19 standards for these compounds underwent a full VGSC isoform selectivity screen to identify the most potent and selective compounds. The fluorine-18 PET agents were also put through a series of in vitro and in vivo studies including automated and manual electrophysiology, biodistribution, metabolism and autoradiography. Ultimately, we aimed to target specific VGSC sub-types that were highly expressed by specific aggressive tumour types. Following this study, an interesting VGSC PET agent was revealed that warrants further investigation.

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