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UBC Theses and Dissertations

Lone pair activity, versatility, and charge : lessons from chelators designed for radiopharmaceuticals Ingham, Aidan


Metal-based radiopharmaceuticals provide a vital option to treat patients suffering from metastatic cancers. This class of drugs can both diagnose and destroy widely disseminated tumour cells in a targeted manner, including tumours that demonstrate a resistance to other forms of treatments such as chemotherapy. To selectively seek out tumour cells, most metal-based radiopharmaceuticals are designed to involve four components: a radiometal, a bifunctional chelator, a linker, and a targeting vector. The bifunctional chelator coordinates the metal and keeps it attached to the drug whilst in the body. There are many different types of diagnostic and therapeutic radiometals. Thus, to save time and resources, a non-bifunctional version of the chelator is tested with the selected radiometal to ensure they are a strong match before a bifunctional version is constructed. This thesis focuses on the design, synthesis, and evaluation of (non-bifunctional) open-chain chelators, which have been paired with large (radio)metal ions. Amide-based chelators EGTAm and ampam were matched with [ⁿᵃᵗᐟ²⁰³Pb]Pb²⁺ ions, and their respective complexes were studied via NMR spectroscopy, X-ray diffraction, potentiometric titrations, and radiolabeling studies. Neither chelator was found to be a suitable match, likely due to their large scaffolds and amide donor groups being mismatched with one another for Pb²⁺ ion chelation. A diprotic analogue of ampam, known as H₂ampa, was then tested with [ⁿᵃᵗᐟ²⁰³Pb]Pb²⁺, [²²⁵Ac]Ac³⁺ and [ⁿᵃᵗᐟ²¹³Bi]Bi³⁺ ions. To evaluate these complexes, NMR spectroscopy, X-ray diffraction, thermodynamic solution studies, and radiolabeling studies were carried out. From these preliminary studies, H₂ampa was found to be a versatile chelator demonstrating a high affinity for all three radiometals. Finally, H₅decapa and H₄noonpa were tested with [²²⁵Ac]Ac³⁺ ions via radiolabeling and serum stability studies. Both chelators demonstrated a high affinity for [²²⁵Ac]Ac³⁺ ions and formed kinetically inert complexes; however, H₄noonpa was deemed more favourable due to the simpler and more reliable radiochemistry methodologies that could be applied to study its monoanionic complex compared to the dianionic complex H₅decapa formed.

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