Safer Metal Based Imaging Agents

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Project Summary Metals offer a stunning array of properties that can be exploited for biomedical purposes. Metals such as platinum, ruthenium and copper are used in chemotherapy. Yttrium and indium are used in radiotherapy. Neodymium, europium and terbium are finding application in luminescent probes. Copper, gallium and whole host of other metal isotopes can be used in PET and SPECT imaging. Gadolinium is widely used in MRI, while manganese is proposed as an alternative. However, these advantageous properties come with a price: the risk of metal ion toxicity. To make metals safe for most in vivo application they must be held tightly in a coordinating ligand. The purpose of this ligand is to shield the body from the metal ion, avoiding the body’s natural metal transport and storage systems and permit the metallo-pharmaceutical to perform as intended. But most crucially this ligand allows the metal ion to be excreted. Broadly speaking, metals fall into one of two categories: 1) Those to which evolving life was exposed and took advantage: the essential minerals. And 2) those to which evolving life had no exposure and are not normally found in lifeforms: the xenobiotic metals (which includes many of the heavy metals). One might expect that these two classes of metal ion would be fundamentally different, but, they share a common feature in biology: neither can be excreted. Xenobiotic metals because these pathways never developed and essential minerals because they are too valuable to lose. Clearly metal ions escaping from the ligands in which they are administered represents a serious problem and risk to human health. Once out of the ligand they are incorporated into the body and can never leave. This means that the complexes formed between metal and ligand must be as robust as possible. Although there are some excellent ligand systems already in use in clinical medicine, concern continues to exist about the release of metal ions from these ligand structures. The aim of this small project is to investigate whether a small, and comparatively simple, modification to these ligand systems would lead to substantial improvements in the robustness of the complex. If so it will have the effect of paving the way to yet safer ligand systems for metals in biomedical applications.