Molecular probes for understanding disease using PET and fluorescence imaging

Morgan, Timaeus Edmund Francis (2019) Molecular probes for understanding disease using PET and fluorescence imaging. PhD thesis, University of Glasgow.

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Abstract

During the course of this PhD, several libraries of potential PET imaging agents were synthesised for testing their affinity and selectivity for sphingosine-1-phosphate 5 receptors (S1P5). These receptors are located within oligodendrocytes and are proposed to have a major role in the re-myelination of neurons. Imaging of these receptors could lead to new treatments and diagnostic tools for the management of demyelinating disorders, such as multiple sclerosis (MS). The libraries of compounds were subject to biological evaluation and two lead compounds, fluorobenzamides 89 and 94, were identified as being the most potent and selective for S1P5 receptors. The synthesis of a further compound that was described in the literature as having high affinity for S1P5 was adapted to allow for the preparation of precursor 124 for 11C-labelling. The radiosynthesis of compound [11C]33 was then optimised.

An improved synthesis of AB5186, an imaging agent for the translocator protein (TSPO),was developed. TSPO has been shown to be involved in inflammatory processes and is a biomarker for many inflammatory diseases. Evaluation of AB5186 led to the synthesis of a higher affinity compound LW223 (155), which was not sensitive to the single nucleotide polymorphism present in TSPO. A synthesis of LW223 (155) was developed that allowed for the production of two potential precursors for radiofluorination. Investigation of the radiochemistry showed a chloro-precursor was the most efficient for 18F-labelling.

Finally, an investigation into a polymer-supported nitrite reagent approach for the synthesis of benzotriazole derived α-amino acids allowed the preparation of a variety of functionalised compounds in relatively few steps. Further derivatisation of these compounds led to the discovery of a benzotriazole derived α-amino acid 212 with strong fluorescence in the visible region.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry, radiochemistry, positron emission tomography.
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Sutherland, Dr. Andrew
Date of Award: 2019
Depositing User: Mr Timaeus E. F. Morgan
Unique ID: glathesis:2019-76760
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 12 Dec 2019 11:49
Last Modified: 05 Mar 2020 21:39
Thesis DOI: 10.5525/gla.thesis.76760
URI: http://theses.gla.ac.uk/id/eprint/76760
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