UBC Theses and Dissertations

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UBC Theses and Dissertations

Radiolabelled carbohydrate conjugates : studies of Alzheimer's disease therapeutics and tumor imaging Bowen, Meryn Louisa


This thesis is split into two distinct parts, with the common theme being the radiolabeling of carbohydrate-conjugates. Chapter 2 discusses radioiodinating 3 -hydroxy-4-pyridinones, of interest in treating Alzheimer’s disease. Chapters 3 - 5 describe glucosamine conjugates of ⁹⁹mTc investigated as potential carbohydrate-based SPECT imaging agents. Alzheimer’s disease (AD) sufferers develop characteristic beta-amyloid plaques in their brains, made up of beta-amyloid protein with high concentrations of zinc and copper. The redox active copper ion can form reactive oxygen species (ROS) which damage surrounding tissue and lead to cell death. 3-Hydroxy-4-pyridinones are of interest in the treatment of AD because they are antioxidants and metal chelators, targeting both the plaques and ROS. Functionalisation of these pyridinones with a glucose moiety masks the chelating portion of the molecule, and may facilitate blood brain barrier (BBB) crossing via the GLUT glucose transporters. To determine this BBB permeability, two compounds were labelled with ¹²⁵1 and then assessed using a rat brain perfusion procedure. They were observed to cross the BBB, a crucial finding in the decision to pursue this line of research for AD therapy. A⁹⁹mTc..based SPECT tumor imaging agent would increase worldwide access to the important diagnostic tools of nuclear medicine. Chapters 3 - 5 discuss the synthesis, characterization and assay results of several monoanionic glucosamine-appended tridentate ligands and their complexes with the ⁹⁹mTc and Re tricarbonyl cores. The length of the linker between the glucosamine and the metal binding portion of the molecule range between two and eleven carbons. The binding moiety was also varied to give a library of molecules with different binding groups and linker lengths; useful for structure-activity relationship determination in a range of assays. The interaction of the compounds with hexokinase was assessed, and none of the compounds were found to be substrates for hexokinase. Transport of the compounds into cells by the GLUT transporters was also assayed, and found to be insignificant for all compounds tested. Valuable information on the tolerances of these proteins was discovered and Chapter 6 includes ideas for improvements in future compounds.

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