Purpose: Modern imaging technologies such as CT, PET, SPECT, and MRI employ contrast agents to visualize the tumor microenvironment, providing information on malignancy and response to treatment. Currently, all clinical imaging agents require chemical labeling, i.e. with iodine (CT), radioisotopes (PET/SPECT), or paramagnetic metals (MRI). The goal was to explore the possibility of using simple D‐glucose as an infusable biodegradable MRI agent for cancer detection.Methods: D‐glucose signals were detected using chemical exchange saturation transfer (glucoCEST) MRI of its hydroxyl groups. Feasibility was established in phantoms as well as in vivo using two human breast cancer cell lines, MDA‐MB‐231 and MCF‐7, implanted orthotopically in nude mice. PET and contrast‐enhanced MRI were also acquired.Results: Both tumor types exhibited significant glucoCEST signal enhancement during systemic sugar infusion (mild hyperglycemia), allowing their noninvasive visualization. GlucoCEST showed differences between types, while PET and CE‐MRI did not. Data are discussed in terms of signal contributions from the increased vascular volume in tumors and especially from the acidic extracellular extravascular space (EES), where glucoCEST signal is expected to be enhanced due to a slow down of hydroxyl proton exchange.Conclusions: This observation opens up the possibility for using simple non‐toxic sugars as contrast agents for cancer detection with MRI by employing hydroxyl protons as a natural label. Magn Reson Med, 2012.

A new high‐throughput MRI method for screening chemical exchange saturation transfer (CEST) agents is demonstrated, allowing simultaneous testing of multiple samples with minimal attention to sample configuration and shimming of the main magnetic field (B₀). This approach, which is applicable to diamagnetic, paramagnetic and liposome CEST agents, employs a set of inexpensive glass or plastic capillary tubes containing CEST agents put together in a cheap plastic tube holder, without the need for liquid between the tubes to reduce magnetic susceptibility effects. In this setup, a reference image of direct water saturation spectra is acquired in order to map the absolute water frequency for each volume element (voxel) in the sample image, followed by an image of saturation transfer spectra to determine the CEST properties. Even though the field over the total sample is very inhomogeneous due to air–tube interfaces, the shape of the direct saturation spectra is not affected, allowing removal of susceptibility shift effects from the CEST data by using the absolute water frequencies from the reference map. As a result, quantitative information such as the mean CEST intensity for each sample can be extracted for multiple CEST agents at once. As an initial application, we demonstrate rapid screening of a library of 16 polypeptides for their CEST properties, but in principle the number of tubes is limited only by the available signal‐noise‐ratio, field of view and gradient strength for imaging. Copyright © 2010 John Wiley & Sons, Ltd.

Irreversible responsive PARAmagnetic Chemical Exchange Saturation Transfer (PARACEST) MRI contrast agents constitute a new type of agent for molecular imaging. To investigate the utility of this approach, a novel PARACEST MRI contrast agent, Yb(III)‐(1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic acid)‐orthoaminoanilide (Yb‐DO3A‐oAA), was developed that detects nitric oxide (NO). The agent exhibited two CEST effects at −11 ppm and +8 ppm, which were assigned to chemical exchange from amide and amine functional groups, respectively. The effects of pH, temperature, and concentration were investigated to characterize the complex and to optimize PARACEST detection. This responsive PARACEST MRI contrast agent incurred an irreversible covalent change in the presence of NO and O₂, which caused an irreversible disappearance of both PARACEST effects from MR images. The NO‐dependent response of a relaxivity‐based MRI contrast agent, Gd‐DO3A‐oAA, was investigated for comparison. This report highlights the advantages of irreversible MRI contrast agents, demonstrates that large changes in PARACEST can be used to create a highly responsive agent, and indicates challenges that must be overcome to apply this type of contrast agent to in vivo biomedical applications in molecular imaging. Magn Reson Med, 2007.