Lone pair activity, versatility, and charge : lessons from chelators designed for radiopharmaceuticals
department or school: Science, Faculty of
department or school: Chemistry, Department of
data provider: DSpace
degree campus: UBCV
creator: Ingham, Aidan
issued: 2022-04-13T18:44:34Z
issued: 2022
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Metal-based radiopharmaceuticals provide a vital option to treat patients suffering from metastatic cancers. This class of drugs can both diagnose and destroy widely disseminated tumour cells in a targeted manner, including tumours that demonstrate a resistance to other forms of treatments such as chemotherapy. To selectively seek out tumour cells, most metal-based radiopharmaceuticals are designed to involve four components: a radiometal, a bifunctional chelator, a linker, and a targeting vector. The bifunctional chelator coordinates the metal and keeps it attached to the drug whilst in the body. There are many different types of diagnostic and therapeutic radiometals. Thus, to save time and resources, a non-bifunctional version of the chelator is tested with the selected radiometal to ensure they are a strong match before a bifunctional version is constructed. This thesis focuses on the design, synthesis, and evaluation of (non-bifunctional) open-chain chelators, which have been paired with large (radio)metal ions. Amide-based chelators EGTAm and ampam were matched with [ⁿᵃᵗᐟ²⁰³Pb]Pb²⁺ ions, and their respective complexes were studied via NMR spectroscopy, X-ray diffraction, potentiometric titrations, and radiolabeling studies. Neither chelator was found to be a suitable match, likely due to their large scaffolds and amide donor groups being mismatched with one another for Pb²⁺ ion chelation. A diprotic analogue of ampam, known as H₂ampa, was then tested with [ⁿᵃᵗᐟ²⁰³Pb]Pb²⁺, [²²⁵Ac]Ac³⁺ and [ⁿᵃᵗᐟ²¹³Bi]Bi³⁺ ions. To evaluate these complexes, NMR spectroscopy, X-ray diffraction, thermodynamic solution studies, and radiolabeling studies were carried out. From these preliminary studies, H₂ampa was found to be a versatile chelator demonstrating a high affinity for all three radiometals. Finally, H₅decapa and H₄noonpa were tested with [²²⁵Ac]Ac³⁺ ions via radiolabeling and serum stability studies. Both chelators demonstrated a high affinity for [²²⁵Ac]Ac³⁺ ions and for…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/81179
note: LONE PAIR ACTIVITY, VERSATILITY, AND CHARGE: LESSONS FROM CHELATORS DESIGNED FOR RADIOPHARMACEUTICALS by Aidan Ingham MSci, University of Bristol, 2016 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) April 2022 © Aidan Ingham, 2022 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Lone Pair Activity, Versatility, and Charge: Lessons from Chelators Designed for Radiopharmaceuticals submitted by Aidan Ingham in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry Examining Committee: Dr. Chris Orvig, Chemistry, UBC Supervisor Dr. Glenn Sammis, Chemistry, UBC Supervisory Committee Member Dr. Parisa Mehrkhodavandi, Chemistry, UBC University Examiner Dr. Marcel Bally, Experimental Therapeutics, BC Cancer University Examiner Additional Supervisory Committee Members: Dr. Jay Kizhakkedathu, Pathology, UBC Supervisory Committee Member Dr. Zachary Hudson, Chemistry, UBC Supervisory Committee Member iii Abstract Metal-based radiopharmaceuticals provide a vital option to treat patients suffering from metastatic cancers. This class of drugs can both diagnose and destroy widely disseminated tumour cells in a targeted manner, including tumours that demonstrate a resistance to other forms of treatments such as chemotherapy. To selectively seek out tumour cells, most metal-based radiopharmaceuticals are designed to involve four components: a radiometal, a bifunctional chelator, a linker, and a targeting vector. The bifunctional chelator coordinates the metal and keeps it attached to the drug whilst in the body. There are many different types of diagnostic and therapeutic radiometals. Thus, to save time and resources, a non-bifunctional version of the chelator is tested…
has type: Thesis/Dissertation
date issued: 2022-05
is shown at: 10.14288/1.0412791
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
contributor: Orvig, Chris
type: Text
identifier URI: http://hdl.handle.net/2429/81179