This thesis is concerned with designing and synthesising novel chemosensors for use as multi-functional imaging agents for both MRI and optical imaging towards Zn2+ sensing.
The divalent zinc ion (Zn2+) is an essential biological element for living organisms and partakes in a number of biological mechanisms. As a result, any Zn2+ change in its homeostasis can lead to implications to a broad range of pathologies, both physical and neurological. This has made imaging Zn2+ ions crucial towards the elucidation of its distribution and function in cells and tissues. For this project, we have been designing novel multi - modal molecular imaging agents that will target Zn2+ in cells, and hopefully in the presence of possible competing cations.
It is the synergistic combination of MRI and optical imaging that has led to the design and synthesis of a first generation of compounds. The aims have been to synthesise chemical probes based on MRI agents with the ability to sense Zn2+ levels via optical - MRI methods. In order to synthesise these probes, both a Gd3+ based MRI contrast agent and chromophore have been used for MRI and fluorescence visualization respectively. A Zn2+ sensor has also been attached, which upon binding should cause a molecular or electronic change which would be detected primarily via the chromophore.
Three probes were designed and their synthesis towards them explained throughout the thesis.
The first section of the thesis describes the preparation of a quinoline-based DO3A derivative for eventual complexation to a Gd3+ centre. The synthesis and purification methods are discussed, followed by some preliminary studies of the probe‟s behaviour towards Zn2+ ions.
The second part of the thesis explains the various building blocks required to subsequently synthesise the final two probes, by discussing various synthetic approaches, in particular efforts to derivatise new fluorophores and Zn2+ sensing groups.
The final part of the thesis discusses approaches towards a 1,7 - bi-substituted DOTA - based Gd3+ complex and a DOTA - based tetraamide Gd3+ complex. The successful probes that were developed were fully characterised and have undergone preliminary MRI and biological tests. They have been found to be MRI active with the ability to enter and be non - toxic towards cells with an ability to sense Zn2+ ions selectively. Fluorescence tests have also exhibited a change in fluorescence by the probe when perturbed by Zn2+ ions.