Development of Imaging Agents to Target Tumour Hypoxia
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Tumour hypoxia contributes to resistance to conventional chemo- and radiotherapy. The identification of hypoxic tumours is key to therapy planning to implement a hypoxia- guided clinical management strategy. There are no established methods in routine clinical use to detect hypoxia that are non-invasive and can be routinely prepared. Hypoxic tumours may be indirectly identified by detection of carbonic anhydrase IX (CA IX) expression, an enzyme upregulated to stabilize the pH of hypoxic tumours. This thesis describes the design, synthesis and evaluation of small molecules for imaging CA IX expressing tumours with Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI). Molecular imaging provides a repeatable, non- invasive, in vivo measurement of several critical parameters of which PET imaging has shown superior sensitivity and MRI exquisite soft tissue contrast. Imaging agents were designed that comprise of: (i) a CA IX targeting group, a sulfonamide moiety (-SO2NH2) for CA IX targeting in vivo; (ii) a variable linking chain to allow fine tuning of pharmacokinetic properties, and (iii) a reporter group to chelate a range of metals for MRI/PET applications. Three generations of imaging agent were designed. Generation I single modal imaging agents could be utilized for MRI or PET imaging, as they incorporate a DOTA reporter group. Generation II single modal imaging agents were designed exclusively for 68Ga PET imaging, they boast a NOPO reporter group, an underexplored macrocyclic chelator in medical imaging that has remarkable selectivity for gallium chelation. Generation III bimodal imaging agents incorporate either two DOTA reporter groups or a mix of DOTA/NOPO reporter groups for MRI/PET dual modality imaging.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
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Detection of carbonic anhydrase IX (CA IX) expression
Positron Emission Tomography (PET)
Magnetic Resonance Imaging (MRI)