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

Abstract

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.

Tissue response curve‐shape analysis of dynamic glucose‐enhanced and dynamic contrast‐enhanced magnetic resonance imaging in patients with brain tumor

“…The technique enables the use of biodegradable compounds as MRI contrast agents. Dynamic glucose-enhanced (DGE) [1][2][3][4][5][6] MRI targets the exchangeable hydroxyl (OH) protons in glucose and employs dynamic image acquisition before, during, and after intravenous administration of D-glucose. DGE MRI can be based on chemical exchange saturation transfer (glucoCEST), [7][8][9] chemical exchange sensitive spin-lock (glucoCESL), 10,11 or T 2 relaxivity of glucose.…”

“…It should be emphasized that the tissue uptake kinetics of D-glucose differ from those of gadolinium. 1,[5][6][7] The challenge in kinetic modeling of DGE MRI is to include the intracellular uptake and metabolism of D-glucose to lactate or other metabolites. This leads to faster disappearance of the CEST signal over time [5][6][7] compared with, for instance, fluorodeoxyglucose in positron emission tomography (PET), where the phosphorylated product remains.…”

“…1,[5][6][7] The challenge in kinetic modeling of DGE MRI is to include the intracellular uptake and metabolism of D-glucose to lactate or other metabolites. This leads to faster disappearance of the CEST signal over time [5][6][7] compared with, for instance, fluorodeoxyglucose in positron emission tomography (PET), where the phosphorylated product remains. D-glucose is transported over the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier and thus can cause signal enhancement in normal tissue and CSF.…”

“…D-glucose is transported over the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier and thus can cause signal enhancement in normal tissue and CSF. 2,6,17 Another challenge is the conversion from DGE signal change to concentration, which is complicated by different influencing factors such as pH, magnetization transfer effects other than CEST, as well as contributions from changes in the transverse relaxivity of D-glucose caused by OH proton exchange. 12,13 The other differences to DCE MRI are the nonzero baseline concentration of D-glucose, and the fact that the injected D-glucose amount is higher than for a true tracer and may affect the physiology.…”

A numerical human brain phantom for dynamic glucose‐enhanced (DGE) MRI: On the influence of head motion at 3T

“…Dynamic glucose-enhanced (DGE) MRI employs chemical exchange saturation transfer (CEST) or exchange-enhanced relaxation to study tissue uptake of glucose analogues, which, for D-glucose, is determined by tissue perfusion, transport and metabolism. [12][13][14][15][16][17][18][19][20][21] DGE MRI explores the change in signal intensity of several sugar hydroxyl protons, located approximately between 0.6 and 3.0 ppm relative to the proton resonance of free water in the water saturation spectrum (Z-spectrum). The inherently slow (minute time scale) infusion and uptake of D-glucose requires long scan times of around 10-20 min.…”