School of Chemistry - Theses
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ItemThe Evaluation of Oxorhenium(V) and Oxotechnetium(V) Complexes for the Diagnosis of Alzheimer’s Disease( 2020)Alzheimer’s disease (AD) is the most common neurodegenerative condition and is characterised by the presence of insoluble deposits within the brain that primarily consist of aggregated forms of the amyloid-beta (AB) peptide. The role that AB plays in the development and progression of AD remains uncertain. Accurate diagnostic information for suspected AD patients is imperative for the development of patient care plans, potential therapeutics and may aid in further understanding of AD pathology. The development of radiotracers that can bind to AB is of great interest as they can allow estimation of the plaque burden in patients that may have AD. Such compounds must bind specifically to AB plaques and be able to cross the blood brain barrier (BBB). Technetium-99m is the most commonly utilised radionuclide for single-photon-emission computed tomography (SPECT) imaging. This is attributed to its widely applicable half-life of six hours and its availability from benchtop generators. Lipophilic, charge-neutral technetium complexes have been shown to cross the BBB and this sets a precedent for the development of diagnostic amyloid-targeting complexes using the technetium-99m radionuclide. As there are no stable isotopes of technetium, its group seven congener rhenium is utilised for exploratory synthesis and characterisation. Ligands of a pyridyl-N3S donor set and their corresponding oxorhenium(V) complexes have been synthesised and characterised as models for the potential to incorporate amyloid-targeting groups directly into rhenium and technetium complexes. The small, charge-neutral complexes [ReOL30] and [ReOL31] were analysed by X-ray crystallography and the ligand H2L30-Trt was successfully radiolabelled with technetium-99m under mild conditions using a kit-based approach. A series of tetradentate N3S ligands that directly incorporate a styrylpyridyl amyloid-targeting group have been characterised and the corresponding oxorhenium(V) complexes show excellent binding to AB plaques on human brain tissue. The ligands H2L34-Trt and H2L35-Trt were both radiolabelled with technetium-99m under mild conditions and were shown to be suitably lipophilic for BBB permeability. The biological properties of the two technetium-99m complexes were examined by biodistribution experiments in wild-type mice. The styrylpyridyl complexes [ReOL34-36] confirm that the direct incorporation of amyloid targeting groups to metal complexes is a viable strategy in the design of radiotracers for assisting in the diagnosis of Alzheimer’s disease. Further work is required to improve the BBB permeability of this class of compounds. The design of technetium complexes with very high specificity for diagnostic targets is of great interest in the diagnosis of AD as well as other diseases. A bidentate pyridyl thiosemicarbazide ligand that includes a 1,2,4,5-tetrazine group was synthesised to form 2:1 complexes with the oxorhenium(V) and oxotechnetium(V) cores. The tetrazine groups of the rhenium complex [ReO(HL38)2]+ were shown to rapidly react with a simple transcyclooctene by an inverse electron demand Diels-Alder reaction under mild conditions. The corresponding technetium 99m complex [99mTc][TcO(HL38)2]+ was also synthesised. There exist many diagnostic and therapeutic applications for the tetrazine-containing complex [ReO(HL38)2]+ in bioorthogonal reactions for excellent pathological selectivity.