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各种放射性发射性质(例如衰变发射、半衰期)，因此极易被纳入用于分子成像或靶向放射性核素治疗的放射性药物。尽管有这种潜在的用途，放射性金属的使用受到同位素可获得性问题和合适的螯合配体识别的阻碍。在放射性药物设计中，螯合配体是与放射性金属紧密结合的分子。配体在特定的环境中持有金属，但不将放射性金属传递到特定的靶子。因此，需要共价连接到靶向载体(例如，肽、抗体)。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发射的放射性金属是不发达的，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。这一无机放射化学研究计划的短期目标是设计、合成、表征和研究新型的螯合配体，与商业标准相比，具有更好的稳定性和专一性，用于尖端放射性金属，如Ac-225、汞-197m和Sb-119。我们还将研究将这些新型配体连接到生物分子(例如多肽、DNA嵌入剂、抗体)的方法，并研究如何将这些系统有效地传递到体外分子靶标。我与TRIUMF-加拿大粒子加速器中心的联合任命，将使我的团队完全能够接触到这些不发达但有希望的放射性金属。TRIUMF是少数几个可以进行这项研究的世界机构之一，使我们走在了这一领域的前沿。这项研究涉及有机/无机化学、分子生物学和放射化学等领域。 新颖性和意义：本文提出的工作是通过研究新的螯合配体来阐明不发达的放射性金属的配位化学的基础。将研究的新型配体结构将有助于无机化学研究界深入了解和开发金属络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.