UBC Theses and Dissertations

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UBC Theses and Dissertations

Hydroxamate-based non-macrocyclic chelators for zirconium-89 and other isotopes of hard metal ions Jang, Jefferey Andrew


The development of radiopharmaceuticals for imaging and therapy has become a major focus in the field of cancer treatment. Bifunctional chelators (BFCs) attach to bioconjugates that allow for targeted radiation. This thesis examines the hydroxamate-based (hydroxamic acid) ligands for hard radiometal ions, such as zirconium-89. The current gold standard for ⁸⁹Zr⁴⁺ complexation is the chelating siderophore, desferrioxamine, a hexadentate ligand that has been shown to have stability issues for complexation with ⁸⁹Zr⁴⁺. New hydroxamate ligands have shown that flexibility is an issue for having four arms bind to ⁸⁹Zr⁴⁺. The potentially octadentate, hydroxamate-based ligand, H₄octaha (1), was designed to overcome the flexibility issue. The synthesis of H₄octaha (1) encountered issues with the formation of a side reaction when synthesizing a protected arm and the selectivity of amines when alkylating the dien backbone. These issues led to the development of a new ligand, H₅decaha (2). H₅decaha (2) is a potentially decadentate, hydroxamate-based ligand that was designed to solve the issues with the synthesis of H₄octaha (1). The synthesis of the ligand was completed; however, the yield was too low for analysis by ¹H NMR and ¹³C NMR. Initial complexation test for H₅decaha (2) with Ga³⁺ suggest that the ligand was synthesized and H₅decaha (2) complexes with a Ga³⁺ ion and two Na⁺ ions. The ligand H₄noonha (3) is a potentially octadentate, hydroxamate-based ligand that uses 1,2-bis(aminoethoxylethane) as a backbone replacing dien. The ligand was synthesized and analyzed by ¹H NMR spectroscopy; however, due to a contaminant, additional analyses could not be completed. Additional synthesis attempts were made; however, not enough product was obtained to continue the analysis for characterization. The functionalized dien (4) was synthesized to make H₄octaha (1) and H₅decaha (2) into bifunctional chelators. Purification by reduced pressure and column chromatography were not successful. The backbone was precipitated out as an HCl salt, which suffers from insolubility issues making analysis difficult.

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