Coordination Chemistry of (Radio)metal Ions

本提案涉及金属离子的基本潜在配位化学，用于两种生物医学应用：配体设计，合成和表征，金属复合物的合成和表征，以及物理研究，以最佳地匹配配体与金属离子。建议是基本的配位化学，始终考虑到应用。核医学中金属同位素的配位化学-我们的团队与TRIUMF， BC癌症机构和加拿大主要同位素供应商Nordion合作，以扩大核医学放射性金属的潜力。正电子发射断层扫描（PET）和单光子发射断层扫描（SPECT）是两种早期发现疾病的成像方式，特别是在肿瘤学领域。新的有前途的放射性药物，更具体的疾病过程，正在发现PET和SPECT使用我们现在建立的“pa”家族配体，加上新的氧和羟酸配体家族。为了实现这一目标，人们正在探索新的配体设计策略、合成方法、用于金属配体载体的金属配体组合、放射性标记方法和化学方法。这一进步很大程度上是通过与具有特异性和高亲和力的癌症生物标志物的生物分子（如肽、脂质、寡糖、寡核苷酸和抗体）的配体的合成偶联而实现的。这些配体作为可行的显像剂正在通过发现新的强大的、可重复的、高产的和快速的方法来实现，这些方法可以将放射性同位素选择引入这些生物分子中，以获得化学稳定的实体，特别关注68Ga或111In作为潜在的显像剂或治疗剂。该方案研究了各种各样的放射性金属（许多镧系元素）。* * * 2。镧系化合物治疗骨吸收障碍——已知许多影响骨疾病发病机制的因素，其中最突出的是钙摄取不足。一类新的骨质疏松药物，包括口服雷奈酸锶，刺激成骨细胞增殖和抑制破骨细胞活性；然而，关于慢性锶在骨内积累的潜在毒性的不确定性可能会限制该产品的使用。低剂量的镧系元素（Ln），特别是镧，已经被证明具有与雷奈酸锶相似的作用，我们正在与萨斯喀彻温大学的Dean K. Wasan和UBC材料工程系的R. Wang教授合作，开发新的配体，将这些离子输送到体内骨骼。***这两个项目都可能产生用于人类治疗和诊断的新药物，从而对加拿大人有重大好处。

This proposal concerns the basic underlying coordination chemistry of metal ions for two biomedical applications: ligand design, synthesis and characterization, metal complex synthesis and characterization, and physical studies, to best match ligands with metal ions. The proposal is basic coordination chemistry, always with the applications in mind.***1. Coordination Chemistry of Metallic Isotopes in Nuclear Medicine - Our group works together with TRIUMF, the BC Cancer Agency, and Canada's major isotope supplier Nordion to grow the potential of Nuclear Medicine radiometals. Positron Emission Tomography (PET) and Single Photon Emission Tomography (SPECT) are two imaging modalities that inform the early detection of disease, particularly in the area of oncology. New promising radiopharmaceuticals, more specific for disease processes, are being discovered for both PET and SPECT using our now established "pa" family of ligands, plus new oxinate and hydroxamate ligand families. In order to achieve this goal new ligand design strategies, syntheses, metal-ligand combinations for application to metal-ligand-vector, radiolabelling methods and chemistry are being discovered. Much of this advancement is made possible by the synthetic conjugation to coordinating ligands of biomolecules (e.g. peptides, lipids, oligosaccharides, oligonucleotides and antibodies) with specific and high affinity for cancer biomarkers. These ligands as viable imaging agents are being realized through the discovery of new robust, reproducible, high-yielding and rapid methods for introducing the radioisotope of choice into these biomolecules to give chemically stable entities, with a particular focus on 68Ga or 111In as potential imaging or therapy agents. A wide variety of radiometals (many lanthanides) are studied in the programme. ***2. Lanthanide Compounds for Bone Resorption Disorders - Many contributing factors are known to influence the pathogenesis of bone disease with the most prominent being inadequate calcium uptake. A new class of osteoporosis drugs, including oral strontium ranelate, stimulate osteoblast proliferation and inhibit osteoclast activity; however, uncertainty regarding the potential toxicity of chronic strontium accumulation in bone may limit the utility of this product. Low doses of lanthanides (Ln), particularly lanthanum La, have been shown to act similarly to strontium ranelate and we are developing new ligands to deliver these ions to bone in vivo, in collaboration with Dean K. Wasan of the University of Saskatchewan and Prof. R. Wang of UBC's Department of Materials Engineering.***Both projects could possibly lead to new medicinal agents for human treatment and diagnosis thereby being of significant benefit to Canadians.