Metal-organic compounds as scaffolds and libraries, for the exploration of biologically relevant chemical space.

为蛋白质靶标创造具有亲和力的配体的能力取决于三维空间中特定位置的功能的呈现。金属配体通常不被用于受体靶向，然而金属配合物由于其较高的配位数和增加的结构多样性而在寻址化学空间方面具有独特的能力。此外，金属-有机配体可以设计成具有对组合文库筛选特别有价值的特征，并且可以被创建为具有荧光特性。 这项研究计划旨在探索金属有机化合物作为能够靶向细胞表面受体的新实体。这些化合物是独一无二的，因此它们以集成的金属-有机结构存在，其中金属络合物本身对受体结合和/或独特的功能性质至关重要。以下建议侧重于以非常稳定的Re和作为支架的三羰基氚核为基础的金属络合物；这是一个被公认为生物惰性系统的核心。出于诊断目的，短寿命的伽马发射体Tc-99m(T1/2=6小时)是SPECT成像中使用最广泛的同位素，并继续在分子成像中发挥重要作用，而Re同位素则被建议用于癌症治疗。该提案还调查了镓与能够进行双模式成像的新型络合物的使用，使用Ga-68(T1/2=68min)进行PET成像，使用天然Ga-69/71进行荧光显微镜成像。拟议的研究计划将在金属-有机支架和文库的主题下开发以下子项目：β-Sheet有机金属、金属环肽、OBOC有机金属文库、用于多模式成像的镓螯合物以及作为成像纳米平台的植物病毒。

The ability to create ligands with affinity for a protein target depends upon the presentation of functionality in specific locations of three dimensional space. Metal-based ligands have typically not been utilized for receptor targeting, and yet metal complexes have unique abilities in terms of addressing chemical space due to their higher coordination number and increased structural diversity. In addition, metal-organic ligands can be designed with features that are particularly valuable for combinatorial library screening and may be created to have fluorescent properties. This research proposal seeks to explore metal-organic compounds as novel entities capable of targeting cell surface receptors. These compounds are uniquely created such that they exist as integrated metal-organic constructs, where the metal complex itself is critical for receptor binding and/or for unique functional properties. The following proposal focuses on metal complexes based on the very stable rhenium and technetium tricarbonyl core as the scaffold; a core that is well established as a biologically inert system. For diagnostic purposes, the short lived gamma emitter Tc-99m (t1/2 = 6 hr) is the most widely used isotope for SPECT imaging and continues to play an important role in molecular imaging, while Re isotopes are proposed for cancer therapy. The proposal also investigates the use of gallium, with novel complexes that are capable of dual modality imaging, using Ga-68 (t1/2 = 68 min) for PET imaging and natural Ga-69/71 for fluorescence microscopy. The proposed research program will develop the following sub-projects within the theme of metal-organic scaffolds and libraries: beta-sheet organometallics, metal-cyclic peptides, OBOC organometallic libraries, Ga chelates for multi-modality imaging, and plant viruses as a nanoplatform for imaging.