Imaging of sugar-based contrast agents using their hydroxyl proton exchange properties

The ability of CEST MRI to detect the presence of millimolar concentrations of non-metallic contrast agents has made it possible to study, non-invasively, important biological molecules such as proteins and sugars, as well as drugs already approved for clinical use. Here, we review efforts to use sugar and sugar polymers as exogenous contrast agents, which is possible based on the exchange of their hydroxyl protons with water protons. While this capability has raised early enthusiasm, for instance about the possibility of imaging D-glucose metabolism with MRI in a way analogous to PET, experience over the past decade has shown that this is not trivial. On the other hand, many studies have confirmed the possibility of imaging a large variety of sugar analogues, each with potentially interesting applications to assess tissue physiology. Some promising applications are the study of (i) sugar delivery and transport to assess blood-brain barrier integrity and (ii) sugar uptake by cells for their characterization (e.g., cancer versus healthy), as well as (iii) clearance of sugars to assess tissue drainage-for instance, through the glymphatic system. To judge these opportunities and their challenges, especially in the clinic, it is necessary to understand the technical aspects of detecting the presence of rapidly exchanging protons through the water signal in MRI, especially as a function of magnetic field strength. We expect that novel approaches in terms of MRI detection (both saturation transfer and relaxation based), MRI data analysis, and sugar design will push this young field forward in the next decade.