Coordination Chemistry of (Radio)metal Ions

这一建议涉及金属离子在两个生物医学应用中的基本配位化学：配体设计、合成和表征、金属络合物的合成和表征以及物理研究，以使配体与金属离子最佳匹配。我们的建议是基础配位化学，始终考虑到应用。*1.核医学中金属同位素的配位化学-我们的团队与TRIUMF、不列颠哥伦比亚省癌症机构和加拿大主要同位素供应商Nordion合作，以提高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)是两种有助于疾病早期发现的成像方式，特别是在肿瘤学领域。新的有希望的放射性药物，更专用于疾病过程，正在被发现，用于PET和SPECT，使用我们现在建立的“pa”配体家族，加上新的草酸盐和异羟甲酸酯配体家族。为了实现这一目标，人们正在发现新的配体设计策略、合成方法、应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。这一进展在很大程度上是由于合成了与癌症生物标记物具有特异性和高亲和力的生物分子(如肽、脂类、寡糖、寡核苷酸和抗体)的配位配体。这些配体作为可行的显像剂正在通过发现新的健壮、可重复、高产量和快速的方法来实现，以便将所选择的放射性同位素引入到这些生物分子中以获得化学稳定的实体，特别是68Ga或111In作为潜在的成像或治疗试剂。该方案研究了多种放射性金属(许多稀土元素)。*2.稀土化合物治疗骨吸收障碍-已知有许多因素影响骨骼疾病的发病机制，其中最突出的是钙吸收不足。一种新型的骨质疏松药物，包括口服雷奈酸锶，可以刺激成骨细胞的增殖并抑制破骨细胞的活性；然而，关于锶在骨中慢性蓄积的潜在毒性的不确定性可能会限制该产品的应用。低剂量的镧(Ln)，特别是镧，已被证明与雷奈酸锶的作用相似，我们正在与萨斯喀彻温大学的迪恩·K·瓦桑和UBC材料工程系的R·王教授合作，开发新的配体，将这些离子运送到体内的骨骼中。*这两个项目可能会导致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.