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UBC Theses and Dissertations

Development of metal-based (radio)pharmaceuticals for imaging and therapy Kostelnik, Thomas Isaac N.

Abstract

Contemporary metalloradiopharmaceuticals are usually comprised of four components; radionuclide, bifunctional chelator, linker and targeting vector. Physical decay of the radionuclide is responsible for the diagnostic or therapeutic effect of the drug, and the bifunctional chelator simultaneously binds the radiometal ion to prevent release in vivo and provides a handle for covalent linkage to the other component of the molecule. Optimal performance of these components is essential for effective radiopharmaceuticals, and have been the focus of this thesis. Antimony-119 is considered one of the most promising radionuclides for Auger electron therapy; however, few studies exploring separation and radiolabeling of radioantimony exist in the literature. Bombardment of natSn with 12.8 MeV protons achieved production of primarily ¹²⁰mSb, as well as ¹¹⁷mSn. These species were then used to monitor separation radiochemistry and the purified ¹²⁰mSb was successfully radiolabeled. Non-bifunctional chelators H₆phospa, H₆dipedpa, and H₆eppy were synthesized and studied with In³⁺, Lu³⁺, Y³⁺, Sc³⁺, and La³⁺ via NMR and thermodynamic solution studies. Results showed that H₆phospa formed the most thermodynamically stable complexes. As a result, H₆dappa was synthesized as a bifunctional analogue. While thermodynamic results were encouraging, serum stability studies revealed complex lability, which was further supported by DFT calculations. Inspired by interest in [²⁰³/²¹²Pb]Pb²⁺, DTPAm was synthesized and studied. NMR spectra and preliminary radiolabeling studies with [²⁰³Pb]Pb²⁺ were encouraging; however, thermodynamic parameters and serum stability studies (with ²⁰³Pb) pointed towards complex lability, likely as a result of the lack of ionisable protons of DTPAm. Lastly, interest in phosphonate-bearing ligands resulted in studies exploring their use in delivering oral La³⁺ for bone-resorption disorders. Working closely with Dr. David Weekes, large scale batches of La(XT) were synthesized. Following animal studies, the lanthanum content of animal tissue (healthy Sprague Dawley rats) was analyzed by ICP-MS. Short-term studies (4 weeks) pointed towards dose-dependent lanthanum concentrations in bone (femur) and no observable toxicity. Long-term studies (3 months) showed no kidney or liver toxicity, however minimal mechanical advantage of La³⁺ incorporation into bone was noted. Synthesis and NMR studies were also carried out on dppa and DEDA-(PO) to investigate their stability with La³⁺, among other metal ions.

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