Near-IR and MRI probes towards multi-modal imaging and ion sensing

Abstract

Associated with the development of all types of diabetes is the loss of pancreatic β-cell mass. It is known that Zn2+ ions are concentrated within β-cells of the pancreas and that Zn2+ is co-released with insulin from the β-cells in response to high glucose levels. Thus, determination of Zn2+ concentrations in the insulin granules allows β-cell mass quantification, and has potential for monitoring the onset and status of diabetes. However, there are few chemical probes that are capable of this function. Medical imaging has become universal in the diagnosis and monitoring of disease, and many imaging modalities are available for this purpose. However, any imaging technique, such as magnetic resonance imaging (MRI) and optical imaging are not without their own inherent limitations. The principle of dual-modal imaging is that by combining two or more of these techniques, by the means of a single contrast agent with two functionalities, the limitations associated with each technique can be synergistically overcome. For this reason, this thesis aims to develop a dual-modal MR/near-infrared (NIR) imaging agent that selectively binds to Zn2+ ions within the pancreas, to ultimately achieve a more profound understanding of the role that zinc plays in diabetes. This thesis firstly describes the synthesis and properties of functionalisable NIR fluorophores which offer several advantages over conventional visible fluorophores, such as better tissue depth penetration and reduced damage to biological samples. These fluorophores were then successfully conjugated to different Zn2+ ion sensing moieties and their ability to detect cellular Zn2+ concentrations by optical imaging determined. Next these probes were conjugated to gadolinium chelates to generate novel dual-modal MR/NIR optical zinc sensors whose efficacy were proven through fluorescence titrations or in vitro. Finally, MRI chelates were conjugated with targeting peptides with one of the probes demonstrating excellent enhancement of the signal within the pancreas.