Molecular imaging of cancer by glucosamine chemical exchange saturation transfer MRI: A preclinical study

Abstract

Glucosamine (GlcN) was recently proposed as an agent with an excellent safety profile to detect cancer with the chemical exchange saturation transfer (CEST) MRI technique. Translation of the GlcN CEST method to the clinical application requires evaluation of its sensitivity to the different frequency regions of irradiation. Hence, imaging of the GlcN signal was established for the full Z spectra recorded following GlcN administration to mice bearing implanted 4T1 breast tumors. Significant CEST effects were observed at around 1.5, 3.6 and −3.4 ppm, corresponding to the hydroxyl, amine/amide exchangeable protons and for the Nuclear Overhauser Enhancement (NOE), respectively. The sources of the observed CEST effects were investigated by identifying the GlcN metabolic products as observed by 13 C NMR spectroscopy studies of extracts from the same tumor model following treatment with [UL-13 C]-GlcNÁHCl. The CEST contribution can be attributed to several phosphorylated products of GlcN, including uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc), which is a substrate for the O-linked and N-linked glycosylated proteins that may be associated with the increase of the NOE signal. The observation of a significant amount of lactate among the metabolic products hints at acidification as one of the sources of the enhanced CEST effect of GlcN. The proposed method may offer a new approach for clinical molecular imaging that enables the detection of metabolically active tumors and may play a role in other diseases.

What do we know about dynamic glucose-enhanced (DGE) MRI and how close is it to the clinics? Horizon 2020 GLINT consortium report

“…Preliminary animal data demonstrated a pattern of DGE signal increase using either D-glucose (Glc) [8,9] (hereafter referred to as "DGE") or glucose analogs, e.g., 3-O-methyl-D-glucose (3OMG) (hereafter referred to as analog-based DGE, e.g., 3OMG-based DGE) in various tumor models [11,12] (Table 1). In addition, recent work by several groups showed the possibility of detecting other metabolites based on the CEST effect from hydroxyl protons, such as sucrose, glucosamine (2-amino-2-deoxy-d-glucose, GlcN), and N-acetyl-glucosamine (GlcNAc) [13][14][15]. Thus, developing new MRI techniques with increased sensitivity to substrate levels of non-radioactive glucose analogs holds promise as a potential replacement for the ubiquitous FDG-PET [16], with the caveat of course that FDG is used in tracer quantities, while any MRI contrast agent requires orders of magnitude larger concentrations for it to be detectable (usually in the mM range).…”

“…Both can also be used as CEST contrast agents as they enter and accumulate in tumor cells via members of the GLUT family. The ability to image tumors by GlcN or Glc-NAc CEST MRI has been demonstrated in several tumors of murine model [9,14,15]. The CEST detection of GlcN and GlcNAc allows the differentiation of tumors according to their aggressiveness.…”

“…The contribution of GlcN to CEST contrast can be attributed to GlcN itself and to its phosphorylated products. It can also be explained by tissue acidosis associated with lactate buildup [13,15]. The NOE effect indicates that the CEST arises from intracellular GlcN and its metabolites, since free GlcN molecules do not elicit such effects [13,15].…”

“…It can also be explained by tissue acidosis associated with lactate buildup [13,15]. The NOE effect indicates that the CEST arises from intracellular GlcN and its metabolites, since free GlcN molecules do not elicit such effects [13,15]. Another advantage of using GlcN or GlcNAc is that they can be detected for their amine/amide peaks around ~ 2-3 ppm, unlike other glucose analogs whose hydroxyl protons have a small chemical shift relative to the water signal (around 1-1.5 ppm).…”

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

“…Not surprisingly, the first sugars studied as contrast agents in vivo were D-Glc, 29,30,[41][42][43][44][45][46][47][48][49][50][51][52][53][54] and other single-ring hexoses, such as 2-deoxy-D-glucose (2-DG), 55,56 3-O-methyl-D-glucose (3-OMG), [57][58][59][60] and D-glucosamine (D-GlcN). 61,62 Some artificial sweeteners (sucralose, Slc, and maltitol, Mlt) and glucose dimers (maltose, Mls) F I G U R E 1 A, Structures of sugars studied as potential contrast agents using exchange-based MRI. B, Overview of compartmental location of sugars (S), their metabolic products (if any) in tumors, and the rate constants (k) for transport or metabolism.…”