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Wharton, Luke Alexander

University of British Columbia

Radiometal-based pharmaceuticals have emerged as powerful clinical tools which can achieve both diagnostic imaging and targeted therapy of disease and have become crucial for accurate staging of progression and treatment of tumours. Such radiopharmaceuticals are comprised of four-components: the radionuclide, bifunctional chelator, covalent linker, and the biological targeting vector. This thesis has focused on the development of bifunctional chelators for large radiometal ions, with an emphasis towards the alpha emitters ²²⁵Ac and ²¹³Bi for targeted alpha therapy and other suitable imaging companions (¹⁵⁵Tb, ¹¹¹In, ⁴⁴Sc) for diagnostics. H₄neunpa-NH₂ was pursued as high-denticity ligand for [²¹³Bi]Bi³⁺. A comprehensive assessment of the complexation properties of H₄neunpa-NH₂ was undertaken with Bi³⁺ using NMR, DFT and X-ray diffraction studies, revealing an ideal match for the ligand binding cavity. Radiochemistry studies showed highly impressive results compared to well established ligands such as DOTA, with H₄neunpa-NH₂ achieving quantitative radiolabeling of [²¹³Bi]Bi³⁺ within 5 min at 10⁻⁸ M ligand concentration, which was accompanied by the formation of a kinetically inert complex. Further in vivo studies of the CycMSHhex bioconjugates showed promising results for targeting melanoma tumours. Two structurally related high denticity chelators – H₄picoopa and H₃TPAN-triazole-Bn-NH₂ – were investigated for [²²⁵Ac]Ac³⁺ and [¹¹¹In]In³⁺ chelation. Both ligands demonstrated highly effective radiolabeling of each radionuclide, achieving high molar activities under mild conditions (10 min, RT) with the formation of kinetically inert complexes. Bifunctional derivatives of both chelators were prepared and coupled to CycMSHhex for in vivo SPECT/CT studies in mice using [¹¹¹In]In³⁺. Overall H₃TPAN-triazole-Bn-NH₂ showed superior results, being considerably easier to synthesise and characterise in solution, and showed promise for further development as an ²²⁵Ac/¹¹¹In theranostic. Lastly, a fundamental aspect of chelate design was challenged through the synthesis of H₄noneunpaX, a ligand with an inverted donor group arrangement, and the complexation chemistry studied through NMR, DFT, solution thermodynamics and radiolabeling experiments. H₄noneunpaX exhibited highly favourable complexation with Ln³⁺ ions and was further developed into a bifunctional derivative for in vivo SPECT/CT studies of two [¹⁵⁵Tb]Tb³⁺-radiolabeled Tyr³-octreotate based bioconjugates which showed excellent results, with high tumour uptake (11.0±2.62 %ID/g at 4 h) and no evidence of degradation in vivo.

Text

2022-08-03

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/82238

Chemistry

University of British Columbia

UBCV

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