The synthesis of novel PET and SPECT imaging agents and the development of new radioiododeboronation procedures

O'Rourke, Kerry M. (2018) The synthesis of novel PET and SPECT imaging agents and the development of new radioiododeboronation procedures. PhD thesis, University of Glasgow.

Abstract

During the course of this PhD, a number of potential PET and SPECT imaging agents were synthesised for particular in vivo targets. The first targets were monocarboxylate transporters 1 and 2 (MCT 1 and 2) which are responsible for the transport of moncarboxylates such as lactate and pyruvate across plasma membranes. The generation of imaging agents which bind to these MCTs could lead to the effective molecular imaging of epileptogenic regions of the brain. A potent and selective inhibitor of MCT 1 and 2 was previously synthesised by AstraZeneca (AR-C155858). In this project, a library of analogues of this compound was synthesised, containing potential sites for radiolabelling. A group of these compounds underwent preliminary biological evaluation to determine the inhibitory effect on lactate uptake against MCT 1, 2 and 4 (the most active being thienopyrimidine 73). The second target was poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme used in the repair of DNA. Targeting PARP-1 with radiotracers could aid the diagnosis and monitoring of various tumours. A small library of potential PET imaging agents, which have the potential to undergo facile radiofluorination, were synthesised based on the PARP-1 inhibitor olaparib. This series of compounds were subject to a PARP-1 immunofluorescence assay and the most potent compound in the series was found to be phthalazinone 147.
The second part of this thesis describes the development of novel radioiododeboronation methods using both gold(I) and potassium acetate catalysis. These methods were used in the radiosynthesis of a number of aromatic iodides, giving the radiolabelled products in high radiochemical yields. SPECT imaging agents [125I]MIBG and a PARP-1 tracer were also generated under these conditions.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Funder's Name: Engineering and Physical Sciences Research Council (EPSRC), Engineering and Physical Sciences Research Council (EPSRC)
• Supervisor's Name: Sutherland, Dr. Andrew
• Date of Award: 2018
• Depositing User: Miss Kerry O'Rourke
• Unique ID: glathesis:2018-39012
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 18 Dec 2018 16:21
• Last Modified: 08 Feb 2019 13:26
• URI: https://theses.gla.ac.uk/id/eprint/39012

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