The development of novel PET imaging agents for the poly(ADP-ribose) polymerase 1 and synaptic vesicle 2A proteins

McErlain, Holly (2022) The development of novel PET imaging agents for the poly(ADP-ribose) polymerase 1 and synaptic vesicle 2A proteins. PhD thesis, University of Glasgow.

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The primary focus of this PhD research was the development and synthesis of several potential PET imaging agents for the PARP-1 and SV2A proteins. The first section of this thesis details the synthesis of a small library of novel PARP-1 inhibitors (HM library) with capacity for application as PET imaging agents. The core structure of these compounds was that of established PARP-1 inhibitor olaparib and was modified with a novel linker to allow incorporation of aromatic units that could undergo late-stage radiolabelling. The physicochemical properties of this library were determined via HPLC methodology and subsequently, four candidates were submitted to in vitro biological testing of PARP-1 inhibition. Finally, an initial optimisation study for the radiosynthesis of a novel fluorine-18 PET imaging agent for PARP-1 was conducted.

The second section describes a new six-step racemic synthesis of [18F]MNI-1038 an established PET imaging agent for the SV2A protein via an organotin precursor, and the fluorine-19 equivalent. Modification of this route and utilisation of asymmetric iminium organocatalysis facilitated the first enantioselective synthesis of the important PET radiotracer [18F]SynVesT-1 in eight steps, and the corresponding fluorine-19 analogue.

The final section describes the exploration of two novel transition metal catalysed methods for the transformation of ubiquitous phenols via aryl nonafluorobutanesulfonates. Firstly, a new ruthenium-catalysed reaction for the iodination of arenes was examined. This study produced some promising results and demonstrated the potential for application of this methodology in the synthesis of SPECT imaging agents.

Subsequently, a novel sodium iodide-accelerated, palladium-catalysed reaction was developed for the construction of aryl C‒P bonds. The synthetic utility of this methodology was then exemplified through the synthesis of various organophosphorus compounds including triarylphosphine oxides, dialkyl arylphosphine oxides, aryl phosphonates and an aryl phosphinate. Furthermore, this reaction was employed for the synthesis of an organic light emitting diode (OLED) material and a phosphonophenylalanine mimic with applications in medicinal chemistry.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Supported by funding from Ian Sword and the University of Glasgow.
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Sutherland, Professor Andrew
Date of Award: 2022
Depositing User: Theses Team
Unique ID: glathesis:2022-83218
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 21 Oct 2022 13:35
Last Modified: 21 Oct 2022 13:37
Thesis DOI: 10.5525/gla.thesis.83218
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