Cybulska, Klaudia Aleksandra; (2018) Sulfonium Salts for the Synthesis of PET Tracers. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Positron Emission Tomography (PET) is a non-invasive medical imaging technique, which allows for quantification of biochemical processes in vivo by employing positron emitting radiopharmaceuticals. Fluorine-18 is the most widely used radionuclide due to its favourable physical properties. Despite impressive technological advancements and large investments in PET instrumentation, its full medical potential has not been realised. The lack of broadly applicable, versatile and robust 18F-labelling strategies hampers development of PET tracers. This work describes development and optimisation of dibenzothiophene sulfonium salts as leaving groups for efficient [18F]fluorination of aromatic molecules. A novel ring-closing reaction for sulfonium salt formation is described, which allows access to structurally diverse N-heterocyclic scaffolds, such as indoles, imidazoles and pyridines. Insights into the cyclisation mechanism and factors which orchestrate reactivity of the system are provided. A scope of common pharmacological motifs was selected to demonstrate the potential of dibenzothiophene sulfonium salts for accessing drug-like molecules. The presented strategy was exploited to simplify and enhance radiosynthesis of a tracer for the imaging for the mGluR5 receptor, [18F]FPEB. A concise and practical approach is presented, which afforded the radiolabelled product in a high radiochemical yield, offering evident advantages over existing strategies. Synthesis of a sulfonium salt precursor to a novel tracer for the imaging of aldosterone-producing adenomas is described. Radiolabelling proceeded in an excellent RCY, allowing biological evaluation in vivo. The results of this work constitute a major advancement in the field of PET chemistry, rendering dibenzothiophene sulfonium salt as one of the most attractive strategies for 18F-labelling in the multitude of novel approaches. The research has the potential to provide tools for early preclinical imaging and ultimately, might lead to development of new tracers for improving patient care.

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