The Design of Novel Chelating Ligands for Unconventional Radiometals

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Metallic radioisotopes (aka radiometals) possess vast chemical diversity and range of radioactive emission properties (e.g.; decay emissions, half-lives), making them extremely amenable for incorporation into radiopharmaceuticals for molecular imaging or targeted radionuclide therapy. Despite this potential utility, the use of radiometals is hindered by isotope availability issues, and identification of appropriate chelating ligands. Chelating ligands in radiopharmaceutical design are molecules that bind tightly to radiometals. The ligand holds the metal in a specific environment but does not deliver the radiometal to a specific target. Thus, covalent attachment to a targeting vector (e.g.; peptide, antibody) is required. To manipulate a radiometal in radiopharmaceutical design, a concrete understanding of the metal's coordination chemistry is required. Many radiometals with favourable radioactive emissions are underdeveloped and lack this fundamental understanding; my research program aims to address this gap in knowledge. The short-term objectives of this inorganic radiochemistry research program are to design, synthesize, characterize, and study novel chelating ligands that possess superior stability and specificity compared to commercial standards, for cutting-edge radiometals such as actinium-225, mercury-197m, and antimony-119. We will also investigate methods to attach these novel ligands to biomolecules (e.g.; peptides, DNA intercalators, antibodies) and study how these systems can be efficiently delivered to in vitro molecular targets. My joint appointment with TRIUMF - Canada's particle accelerator centre, will give my team complete access to these underdeveloped but promising radiometals. TRIUMF is one of only a few world institutions where this research is possible, placing us at the forefront of this field. This research intersects the fields of organic/inorganic chemistry, molecular biology, and radiochemistry.******Novelty & Significance: The work proposed here is fundamental to elucidate coordination chemistry of underdeveloped radiometals, by investigating new chelating ligands. The novel ligand architectures that will be studied will help the inorganic chemistry research community to intimately understand and exploit the effects of metal-chelate complex choice in radiopharmaceutical design. A long-term outcome of this research will be to improve imaging and treatment options in nuclear medicine applications to the benefit of many Canadians.*****