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Southcott, Lily Diana

University of British Columbia

Advances in nuclear medicine include new chelating ligands that form highly stable and kinetically inert complexes with relevant radiometal ions for use in diagnosis or therapy. Designing new compounds for radiopharmaceuticals usually considers four components including a radionuclide, a bifunctional chelator, a targeting vector, and a linker. Taking the small, bidentate molecule 8-hydroxyquinoline from its historic use in nuclear medicine as [¹¹¹In][In(oxine)₃], new high denticity ligands were synthesized including H₅decaox, H₄neunox, H₂pyhox, H₂amidohox and H₂amidoC3hox. These chelators and their various metal complexes were assessed through nuclear magnetic resonance spectroscopy, X-ray crystallography, and combined UV-vis and potentiometry titrations. The extensive radiolabeling of H5decaox with ¹¹¹In and ⁸⁹Zr showed a promising new ligand, and further progressions with modifications to synthesize H₄neunox, incorporating a primary amine to allow for additional conjugation chemistry. A maleimide group was installed and was able to conjugate to the monoclonal antibody Trastuzumab to produce a new immuno-Positron Emission Tomography tracer with ⁸⁹Zr and assess its preliminary in vivo mice imaging and biodistribution. Studies with H₂pyhox proved it a robust chelator, forming stable complexes with ¹¹¹In, ⁶⁴Cu and ²²⁵Ac, while the metal complexes with In³⁺, Cu²⁺ and La³⁺ were solved with X-ray crystallography. H₂amidohox and H₂amidoC3hox were compared through their solution studies with In³⁺, Cu²⁺ and Pb²⁺ and the radiolabeling and challenge experiments with ¹¹¹In, ⁶⁴Cu and ²⁰³Pb confirmed the superiority of H₂amidohox. Combined, studying this range of 8-hydroxyquinoline containing chelators has broadened our understanding of the capabilities of this ligand family, and developed a new bifunction chelator platform with H₄neunox, which can be pursued with different targeting vectors and radiometals.

Text

2022-08-03

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/82244

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/