Copper is an essential trace micronutrient that plays roles in biology ranging from enzymatic catalysis to cellular respiration. However, if not properly regulated, it’s redox activity has the potential to cause oxidative stress through the production of reactive oxygen species. The dysregulation of copper has been associated with a variety of disease states including diabetes and multiple cancers. While increasing tools are being developed for monitoring intracellular copper pools significantly less attention has been given to the extracellular labile pool. To address this gap, we have developed a bioluminescent  imaging probe, picolinic ester caged-diphenylterazine (pic-DTZ) for monitoring labile, extracellular copper using a coelenterazine-like imidazopyrazinone and the genetically-engineered, marine-based luciferase, nanoluciferase. Unlike the more commonly-used firefly luciferase, nanoluciferase does not require ATP making it amenable to extracellular applications. Here we show that pic-DTZ demonstrates high metal and oxidation state selectivity for Cu(II) in aqueous buffer as well as selectivity for labile pools over coordinatively inaccessible, protein-bound Cu(II). We demonstrate the potential of pic-DTZ as a diagnostic tool in human serum and plasma for copper-associated diseases. Additionally, we apply pic-DTZ towards extracellular copper dynamic in anticancer treatments in a breast cancer cell model.

Caged imidazopyrazinone for selective bioluminescence detection of labile extracellular copper(II)

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