Non-Benzenoid Fluorophores to Enable New Imaging Modalities

The development of new medicines has been central to realising the increases in life expectancy and quality of life enjoyed by modern civilization. Whereas traditional folk remedies were discovered by trial and error, modern drug development relies on having a deep understanding of the biological processes that occur for any given disease. This knowledge allows new medicines to be specifically designed with an understanding of how they actually work.

In order to gain this understanding of the complex and interrelated cellular processes that can occur in either diseased or healthy cells, scientists have made extensive use of so-called "bio-imaging" techniques. The most straightforward way to acquire an image of a biological sample is to use an optical microscope of the type you might find in a biology classroom. However, It is not possible to identify the various substances that may be present in a cell just by looking at such an image. Instead, scientists make use of "fluorescent probes" - molecules that will glow a particular colour, but only in the presence of a particular substance they have been designed to detect. Using such fluorescent probes allows us to determine whether or not a substance is present, how much of it is present, where exactly within cells it occurs, and for how long it may be present. For example, fluorescent probes that allow the imaging of a protein called amyloid-beta have shown it plays a crucial role in Alzheimer's disease; other fluorescent probes have revealed the key role played by various proteins in cancer.

Fluorescent probe molecules consist of a "receptor" part (whose purpose is to detect a particular substance), joined to a "fluorophore" (whose job is to emit the coloured light the microscope will detect). Currently a great number of different receptors have been developed to detect many different substances. On the other hand, when it comes to choosing a fluorophore, there are actually not that many to choose from. Specifically there are about a dozen well-known fluorophores, each with its own advantages and disadvantages. As such, there is a pressing need to discover and develop new fluorophores with different characteristics to the ones we already have, as this will allow many current limitations in bio-imaging to be overcome.

We propose to develop new fluorophores based on a molecule called "azulene". The name comes from the Spanish word "azul" (="blue"), as it is highly coloured and is also fluorescent. Some azulenes occur in nature and are responsible for the blue colour of certain mushrooms and corals. The fluorescence properties of azulene will enable us to develop fluorophores that work in new ways (e.g. by emitting more than one colour of light simultaneously) and so will be able to give us valuable new information through imaging substances that have been difficult to study up to now. Longer term, it is our aspiration that these new tools we are developing will allow greater insights into disease mechanisms, hence enabling the development of new medicines for the benefit of society.