Development of metal-based (radio)pharmaceuticals for imaging and therapy
department or school: Science, Faculty of
department or school: Chemistry, Department of
data provider: DSpace
degree campus: UBCV
creator: Kostelnik, Thomas Isaac N.
issued: 2020-12-16T21:03:00Z
issued: 2020
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: 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 synthes…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/76827
note: DEVELOPMENT OF METAL-BASED (RADIO)PHARMACEUTICALS FOR IMAGING AND THERAPY by Thomas Isaac N. Kostelnik B.Sc (Hons.), Mount Allison University, 2015 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) December 2020 © Thomas Isaac N. Kostelnik, 2020 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Development of Metal-Based (Radio)pharmaceuticals for Imaging and Therapy submitted by Thomas Kostelnik in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Chemistry Examining Committee: Chris Orvig, Professor, Department of Chemistry, UBC Supervisor Michael O Wolf, Professor, Department of Chemistry, UBC Supervisory Committee Member Harry Brumer, Professor, Department of Chemistry, UBC University Examiner Thomas Chang, Professor, Department of Pharmaceutical Sciences, UBC University Examiner Additional Supervisory Committee Members: Pierre Kennepohl, Associate Professor, Department of Chemistry, University of Calgary Supervisory Committee Member Lawrence McIntosh, Professor, Department of Biochemistry and Molecular Biology, UBC Supervisory Committee Member iii 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 promis…
has type: Thesis/Dissertation
date issued: 2021-05
is shown at: 10.14288/1.0395325
language: eng
degree discipline: Chemistry
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/76827