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

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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.