Diabetes Mellitus is a widely recognised yet still poorly understood disease which afflicts hundreds of millions around the globe. The disease is characterised by a decline in both mass and functionality of pancreatic β-cells, which are responsible for insulin production. Currently, type 2 diabetes is diagnosed at a late stage of progression, limiting clinical opportunities for treatment. There is a clear unmet need for improved early detection of diabetes, which can come in the form of molecular imaging probes designed to image pancreatic β-cell loss.
The work described within this thesis is primarily focussed on the development of imaging probes targeted directly to these cells. This is through the incorporation of agonists for the receptors GLP-1R and GPR40 which are enriched by pancreatic β-cells. A significant body of work involved the peptide exendin-4, a potent agonist of GLP-1R which is utilised in the clinic for the treatment of diabetes. Exendin-4 was conjugated to a gadolinium(III) complex to generate the MRI contrast agent GdEx, which was shown to exhibit pancreas-specific contrast enhancement in both wild-type and disease-model mice. An additional family of optical imaging agents based on terbium(III)- and rhodamine-exendin-4 conjugates of exendin-4 were also generated. These were shown to provide receptor-level information about GLP-1R in vitro.
An alternative targeting method was employed in the development of the ligand GPR-L1. This ligand was designed to bind to the receptor GPR40. The ligand was found to be reasonably versatile, with chelation to a number of lanthanide(III) centres successfully carried out. During characterisation of these complexes, it was found that the aromatic nature of the GPR40 targeting moiety could sensitise both Eu(III) and Tb(III) luminescence. Additionally, the fluorescence of the indole was utilised to verify the GPR40 targeting ability of the ligand through in vitro analysis.
Zinc(II) ions play a critical role in the stabilisation of insulin storage and a final avenue of this body of work explored cyanine dyes capable of responding to the presence of Zn2+. These compounds were found to exhibit some versatility, with a series of alternative zinc-sensing moieties examined. Some steps were taken towards the development of dual-modal imaging probes based on these cyanine frameworks as well as targeted fluorescent optical agents.