The Design of Novel Chelating Ligands for Unconventional Radiometals

金属放射性同位素（又名放射性金属）具有广泛的化学多样性和放射性发射特性范围（例如，衰变发射、半衰期），使其非常适合掺入放射性药物中用于分子成像或靶向放射性核素治疗。尽管有这种潜在的用途，但放射性金属的使用受到同位素可用性问题和确定合适的螯合配体的阻碍。放射性药物设计中的螯合配体是与放射性金属紧密结合的分子。配体将金属保持在特定的环境中，但不会将放射性金属运送到特定的目标。因此，需要与靶载体（如肽、抗体）的共价附着。为了在放射性药物设计中操纵放射性金属，需要对金属的配位化学有具体的了解。许多具有良好放射性排放的放射性金属不发达，缺乏这种基本认识；我的研究项目旨在解决这一知识缺口。这个无机放射化学研究项目的短期目标是设计、合成、表征和研究新型螯合配体，这些配体与商业标准相比，具有优越的稳定性和特异性，适用于前沿放射性金属，如锕-225、汞-197m和锑-119。我们还将研究将这些新型配体附着到生物分子（如肽、DNA插层器、抗体）上的方法，并研究这些系统如何有效地递送到体外分子靶标上。我与加拿大粒子加速器中心（TRIUMF）的联合任命，将使我的团队完全接触到这些尚未开发但有前途的放射性金属。TRIUMF是世界上仅有的几个可以进行这项研究的机构之一，使我们处于该领域的前沿。这项研究交叉了有机/无机化学、分子生物学和放射化学等领域。

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.