The Design of Novel Chelating Ligands for Unconventional Radiometals

金属放射性同位素（又称放射性金属）具有广泛的化学多样性和放射性发射特性（例如;衰变发射，半衰期），使得它们非常适合掺入用于分子成像或靶向放射性核素治疗的放射性药物中。尽管有这种潜在的效用，放射性金属的使用受到同位素可用性问题和适当螯合配体的鉴定的阻碍。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，但不将放射性金属递送到特定的目标。因此，共价连接到靶向载体（例如;肽、抗体）是必需的。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理解。许多具有良好放射性排放的放射性金属都不发达，缺乏这种基本的理解;我的研究计划旨在解决这一知识差距。这个无机放射化学研究计划的短期目标是设计，合成，表征和研究新型螯合配体，与商业标准相比，具有上级稳定性和特异性，用于尖端放射性金属，如锕-225，汞-197 m和锑-119。我们还将研究将这些新的配体连接到生物分子上的方法（例如;肽，DNA嵌入剂，抗体），并研究如何将这些系统有效地传递到体外分子靶点。我与加拿大TRIUMF粒子加速器中心的联合任命将使我的团队完全获得这些尚未开发但有前途的放射性金属。TRIUMF是世界上为数不多的可以进行这项研究的机构之一，使我们处于该领域的最前沿。这项研究与有机/无机化学，分子生物学和放射化学领域交叉。 新奇和意义：通过研究新的螯合配体，本文提出的工作对阐明不发达放射性金属的配位化学具有重要意义。将研究的新型配体结构将有助于无机化学研究界密切了解和利用金属螯合物选择在放射性药物设计中的作用。这项研究的长期成果将是改善核医学应用中的成像和治疗选择，使许多加拿大人受益。

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.