GlycoCEST, GlucoCEST, pH Agents, Translation to Humans
Xavier Golay1, Moritz Zaiss2, Steffi Thust3, and Mina Kim1

1Institute of Neurology, University College London, London, United Kingdom, 2Max Planck Institute for Biological Cybernetics, Tuebingen, Germany, 3Radiology, National Hospital for Neurology and Neurosurgery, London, United Kingdom

Synopsis

CEST is a powerful technique to measure metabolites and other molecules in small concentration through indirect exchange of its labile protons by saturation transfer. In this presentation, a review of its use to indirectly assess metabolic processes is presented, based on amide proton transfer imaging, as well as GlucoCEST and GlycoCEST.

Introduction

Chemical exchange saturation transfer (CEST) has recently emerged as an alternative contrast mechanism for MRI (1-3). In CEST-MRI, molecules in solution are saturated by selective RF irradiation. The saturation is transferred to the water pool via labile protons of the solute, such as amide (NH) and hydroxyl (OH) (3), as first demonstrated by Wolff and Balaban (1). Through chemical exchange or dipolar interactions, saturated labile protons exchange with non-saturated water protons, leading to an accumulation of saturated protons in the water pool. After a few seconds of RF irradiation, this gives rise to an observable signal reduction in the water pool. Highest sensitivity to proton transfer is achieved if the exchange rate from solute to water is large enough and the solute has a high concentration of exchangeable protons.

Contrast agents of interest

Endogenous and exogenous CEST agents are usually classified in two main groups: diamagnetic (diaCEST) and paramagnetic (paraCEST) CEST agents (4). The members of each class can be further divided into sub-groups depending on other criteria such as molecular size, endogenous occurrence and type of molecular construct. In particular, there are a few groups involving specific labile protons, molecules, or mechanisms, and therefore those groups are categorized into sub-groups. In this lecture, we will focus on amide proton transfer CEST (APT-CEST) as a means to detect pH changes (3), and hydroxyl-based exchange glucoCEST for glucose (5, 6) and glycoCEST for glycogen (7).

Detection of pH

The CEST exchange rate depends on its milieu, and in particular on its direct chemical environment. It can be demonstrated that the exchange rate constant k in aqueous solution can be divided into an acid- and base-catalyzed proton exchange ka and kb respectively, and a constant k0 depending on the environment (pH buffer and other solutes):

k = ka[H3O+] + kb[OH-]+k0

As such, CEST imaging found an ideal application in the identification of tissue ischemia based on its dependency on pH. Numerous studies have shown that pH changes can be visualized through CEST contrast (3, 8-11), and furthermore that CEST imaging has the potential to spatially map pH (12). With a mostly based-catalyzed saturation transfer in vivo, reduced saturation transfer as a sign of acidosis can be observed in areas of brain ischemia within 2 hours (13). In animal models, a consistent correlation of APT signal with ADC maps has been demonstrated in hyperacute stroke (14), but pH changes can occur earlier without ADC evidence of cellular depolarization (15). A localised pH reduction may precede ADC changes and extend beyond the boundaries of final infarction, indicating that APT-CEST can depict viable ischaemic tissue (16).

Translation onto clinical MRI systems, despite their limitations on RF pulse duration and duty cycle, appears feasible to achieve an overall contrast similar to that of continuous wave saturation used in preclinical systems (17). In human studies, some success has been achieved in generating quantitative pH maps for hyperacute stroke studies within a clinically justifiable time frame, with a demonstration of sufficient overlap with the final infarct core in patients (18, 19).

Gluco- and GlycoCEST

The native CEST contrast can reflect on a number of metabolites specifically. In this context, glycogen or glucose might be interesting DiaCEST agents. Glycogen first, as an energy storage agent, plays a central role in glucose homeostasis. It is regulated through complex metabolic pathways and is produced by the liver shortly after food intake. Detection of production of glucose in the liver has been shown in perfused liver studies upon stimulation through glucagon (7). Early indication of GlycoCEST being used as a marker of Glycogen production has recently been demonstrated at 3T in both rats and humans (20, 21).

In addition, GlucoCEST can be useful for imaging tumour cells, as they preferentially use anaerobic glucose breakdown, even in the presence of abundant oxygen (‘Warburg effect’). In animal experiments, the difference in GlucoCEST signal before and after injection of glucose has shown remarkable spatial overlap with Fluorodeoxyglucose (FDG) maps, supporting its validity (5).

In patients, dynamic injection of glucose has been shown to provide similar early-phase contrast to dynamic Gadolinium enhanced T1 weighted MRI (DCE), therefore most likely reflecting local blood flow, vascular permeability and volume of the extracellular space. Whether or not dynamic GlucoCEST can also reflect on glucose metabolism, and especially in brain tumours, remains a point of controversy. The first translation of dynamic glucose enhanced MRI into human glioma observed variations in GlucoCEST contrast across glioma components over time (22).

Conclusion

Here we demonstrated the usefulness of some of the CEST effects to assess some of the most basic aspects of metabolism. These effects remain difficult to quantify due to their reliance on assumptions, however allow to open a window into a part of the physiology until now only accessible through spectroscopic methods or molecular imaging involving the use of radiolabelled tracers.

Acknowledgements

MK, MZ and ST are partly supported by a grant (GLINT) from the European Union‘s Horizon 2020 research and innovation programme under grant agreement No 667510

References

  1. Ward KM, Aletras AH, Balaban RS. A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). J Magn Reson. 2000;143(1):79-87.
  2. Goffeney N, Bulte JW, Duyn J, Bryant LH, Jr., van Zijl PC. Sensitive NMR detection of cationic-polymer-based gene delivery systems using saturation transfer via proton exchange. J Am Chem Soc. 2001;123(35):8628-9.
  3. Zhou J, Payen JF, Wilson DA, Traystman RJ, van Zijl PC. Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Nature medicine. 2003;9(8):1085-90.
  4. Hancu I, Dixon WT, Woods M, Vinogradov E, Sherry AD, Lenkinski RE. CEST and PARACEST MR contrast agents. Acta radiologica. 2010;51(8):910-23.
  5. Walker-Samuel S, Ramasawmy R, Torrealdea F, Rega M, Rajkumar V, Johnson SP, et al. In vivo imaging of glucose uptake and metabolism in tumors. Nature medicine. 2013;19(8):1067-72.
  6. Chan KW, McMahon MT, Kato Y, Liu G, Bulte JW, Bhujwalla ZM, et al. Natural D-glucose as a biodegradable MRI contrast agent for detecting cancer. Magn Reson Med. 2012;68(6):1764-73.
  7. van Zijl PC, Jones CK, Ren J, Malloy CR, Sherry AD. MRI detection of glycogen in vivo by using chemical exchange saturation transfer imaging (glycoCEST). Proc Natl Acad Sci U S A. 2007;104(11):4359-64.
  8. Zaiss M, Xu J, Goerke S, Khan IS, Singer RJ, Gore JC, et al. Inverse Z-spectrum analysis for spillover-, MT-, and T1 -corrected steady-state pulsed CEST-MRI--application to pH-weighted MRI of acute stroke. NMR in biomedicine. 2014;27(3):240-52.
  9. Sun PZ, Wang E, Cheung JS. Imaging acute ischemic tissue acidosis with pH-sensitive endogenous amide proton transfer (APT) MRI--correction of tissue relaxation and concomitant RF irradiation effects toward mapping quantitative cerebral tissue pH. Neuroimage. 2012;60(1):1-6.
  10. Huang D, Li S, Dai Z, Shen Z, Yan G, Wu R. Novel gradient echo sequence-based amide proton transfer magnetic resonance imaging in hyperacute cerebral infarction. Molecular medicine reports. 2015;11(5):3279-84.
  11. Li H, Zu Z, Zaiss M, Khan IS, Singer RJ, Gochberg DF, et al. Imaging of amide proton transfer and nuclear Overhauser enhancement in ischemic stroke with corrections for competing effects. NMR in biomedicine. 2015;28(2):200-9.
  12. McVicar N, Li AX, Goncalves DF, Bellyou M, Meakin SO, Prado MA, et al. Quantitative tissue pH measurement during cerebral ischemia using amine and amide concentration-independent detection (AACID) with MRI. Journal of cerebral blood flow and metabolism. 2014;34(4):690-8.
  13. Dai Z, Ji J, Xiao G, Yan G, Li S, Zhang G, et al. Magnetization transfer prepared gradient echo MRI for CEST imaging. PloS one. 2014;9(11):e112219.
  14. Huang D, Li S, Dai Z, Shen Z, Yan G, Wu R. Novel gradient echo sequencebased amide proton transfer magnetic resonance imaging in hyperacute cerebral infarction. Molecular medicine reports. 2015;11(5):3279-84.
  15. Zhou J, van Zijl PC. Defining an Acidosis-Based Ischemic Penumbra from pH-Weighted MRI. Translational stroke research. 2011;3(1):76-83.
  16. Sun PZ, Zhou J, Sun W, Huang J, van Zijl PC. Detection of the ischemic penumbra using pH-weighted MRI. Journal of cerebral blood flow and metabolism. 2007;27(6):1129-36.
  17. Sun PZ, Wang E, Cheung JS, Zhang X, Benner T, Sorensen AG. Simulation and optimization of pulsed radio frequency irradiation scheme for chemical exchange saturation transfer (CEST) MRI-demonstration of pH-weighted pulsed-amide proton CEST MRI in an animal model of acute cerebral ischemia. Magnetic resonance in medicine. 2011;66(4):1042-8.
  18. Tee YK, Harston GW, Blockley N, Okell TW, Levman J, Sheerin F, et al. Comparing different analysis methods for quantifying the MRI amide proton transfer (APT) effect in hyperacute stroke patients. NMR in biomedicine. 2014;27(9):1019-29.
  19. Tietze A, Blicher J, Mikkelsen IK, Ostergaard L, Strother MK, Smith SA, et al. Assessment of ischemic penumbra in patients with hyperacute stroke using amide proton transfer (APT) chemical exchange saturation transfer (CEST) MRI. NMR in biomedicine. 2014;27(2):163-74.
  20. Chen SZ, Yuan J, Deng M, Wei J, Zhou J, Wang YX. Chemical exchange saturation transfer (CEST) MR technique for in-vivo liver imaging at 3.0 tesla. European radiology. 2016;26(6):1792-800.
  21. Deng M, Chen SZ, Yuan J, Chan Q, Zhou J, Wang YX. Chemical Exchange Saturation Transfer (CEST) MR Technique for Liver Imaging at 3.0 Tesla: an Evaluation of Different Offset Number and an After-Meal and Over-Night-Fast Comparison. Molecular imaging and biology. 2016;18(2):274-82.
  22. Xu X, Yadav NN, Knutsson L, Hua J, Kalyani R, Hall E, et al. Dynamic Glucose-Enhanced (DGE) MRI: Translation to Human Scanning and First Results in Glioma Patients. Tomography : a journal for imaging research. 2015;1(2):105-14.
Proc. Intl. Soc. Mag. Reson. Med. 25 (2017)