Chemical Exchange Saturation Transfer MRI
Recently, Chemical Exchange Saturation Transfer (CEST) MRI is emerging as an attractive approach with the capability of directly using low concentration, exchangeable protons-containing agents for generating quantitative MRI contrast. The ability to utilize diamagnetic compounds has been extensively exploited to detect many clinical compounds, such as FDA approved drugs, X-ray/CT contrast agents, nutrients, supplements, and biopolymers. The ability to directly off-label use clinical compounds permits CEST MRI to be rapidly translated to clinical settings.
In 2000, Balaban and his colleagues demonstrated a new type of MRI contrast could be obtained by a few diamagnetic metabolites containing exchangeable protons and named it as “chemical exchange saturation transfer” (CEST) . To date, CEST MRI has been exploited to detect a broad spectrum of compounds, both endogenously and exogenously. In an endogenous CEST MRI study, no contrast agent injection is required. Rather, it detects the CEST contrast stemming from endogenous molecules, which may change substantially as a result of the changes in the concentrations of biological molecules, intra- or extra- cellular pH, or cell function and metabolism, associated with pathological abnormalities. Indeed, many early CEST MRI studies have been focused on detecting the altered metabolites, protein concentration, and pH in cancer . Very often, the exchangeable protons in endogenous molecules, such as proteins, are abundant, hence providing sufficient sensitivity for CEST MRI detection. As such, CEST MRI has become an appealing non-invasive technology to detect and monitor the progression of many diseases, including cancers , stroke , neurodegenerative diseases , musculoskeletal diseases , and kidney diseases . Interested readers are referred to several recent reviews covering the development and applications of endogenous CEST MRI .
On the other hand, exogenous-agent-based CEST MRI can be designated to target specific molecular targets and biomarkers, thereby potentially providing higher specificity than the endogenous counterparts. By the name, the agent-based approach requires administering contrast agents, which is often referred to as a minimally invasive approach to differentiate from the imaging approaches that are completely non-invasive. Over the last two decades, hundreds of exogenous CEST MRI agents have been reported, which, based on the agent’s magnetic properties, can be categorized into diaCEST, for those use diamagnetic agents , paraCEST, for those use paramagnetic metal complexes , and hyperCEST, for those use compounds containing hyperpolarized atoms . Among them, diaCEST agents have the highest biocompatibility and versatility. Mounting evidence shows that diaCEST agents, including both natural compounds and synthetic agents, can be used for a broad spectrum of biomedical applications. More importantly, many clinical compounds can be directly used as diaCEST MRI agents, providing a practical way to pursue highly translatable MR molecular imaging.
2. Basics of CEST MRI
The phenomenon of intermolecular saturation transfer through proton exchange was known as early as 1960s . In 1990s, in the context with development of metabolic MR spectroscopy and imaging, chemical exchange saturation transfer NMR and MRI gained a renewed interest because of the ability to detect small concentrations of molecules indirectly by the change in water MR signal , which later was named chemical exchange saturation transfer (CEST) by Ward et al. .
In a CEST MRI study, the magnetization of exchangeable protons are first manipulated (i.e., saturation in most of the CEST studies) using radiofrequency (RF) pulses irradiated at the specific frequency offset corresponding to the chemical shift difference between the exchangeable protons and water. For instance, the frequency offsets (∆ω) are around 1.2 and 3.5 ppm (with respect to the water resonance) for hydroxyl protons on glucose and amide protons on peptide and proteins, respectively. As exchangeable protons constantly exchange between the CEST agents and water molecules, the saturated magnetization is transferred continuously from CEST agents to water, resulting in a decrease in water signal (MR image intensity). Although a single exchange-transfer process only produces a water signal decease equivalent to the number of exchangeable protons in the CEST agent pool (i.e., mM here), continuous irradiating at the frequency offsets of the exchangeable protons will pump more and more saturated protons from the CEST pool to bulky water pool (where proton concentration [H]~110 M), resulting in a substantial MR signal change, namely CEST contrast. The CEST technology thus provides a detection amplification strategy allowing detecting a small amount of exchangeable protons through a relatively large change in water MR signal. Especially for protons with relatively fast exchange rate (kex > hundreds sec−1) but within the slow to intermediate regime, this strategy can provide a nearly 1000-time signal amplification .
The pulse sequence for CEST labeling is similar to traditional magnetization transfer contrast (MTC) labeling in that a frequency-selective RF saturation pulse (power = B1, offset = ∆ω) is applied for a period of time (Tsat), followed by subsequent MR images acquisition. For a full spectral assessment, a range of offsets are intermittently irradiated, and one image is acquired per offset. Typically, an image without saturation pulses is also acquired as the reference image. The CEST MRI signal is often depicted using Z-spectrum, in which the normalized MR signal (SΔω)/S0 is plotted with respect to the frequency offset of the saturation pulses (∆ω), where SΔω is the MRI signal with RF irradiated at Δω, and S0 is the reference signal acquired without RF saturation. The CEST contrast is commonly quantified using magnetization transfer ratio asymmetry (MTRasym), defined by MTRasym = (S−Δω − S+Δω)/S0, where −Δω is the frequency offsets on the opposite side with respect to the water frequency offset (set to 0). While bearing several limitations, the MTRasym approach can effectively separate the CEST effect from other effects such as water direct saturation and MTC co-existing in the Z-spectrum and still is the most widely used metric in CEST MRI studies. It should be noted that the CEST contrast (MTRasym) is strongly affected by acquisition parameters such as field strength (B0) , tissue intrinsic T1/T2 relaxation times , the shape, B1, and length of the saturation RF pulses . Importantly, it is suggested that B1 should be adjusted with respect to the exchange rate of a CEST agent, i.e., optimal B1~kex/2π . As a result, different exchangeable protons may have different CEST-B1 dependences. Hence, caution has to be taken when correlating the measured CEST contrast with physically meaningful parameters such as agent concentration and exchange rate. Interested readers are referred to several excellent review papers  for more details about the CEST MRI technology.
Compared to conventional MRI contrast agents, CEST MRI agents have a number of unbeatable advantages. CEST MRI has the ability to exploit non-metallic, bioorganic, biocompatible, diamagnetic compounds. As endogenous and exogenous biologically relevant molecules and compounds contain hydroxyl (–OH, 0.8–2 ppm from water), amino (–NH2, 1.8–2.4 ppm), or amide (–NH, 3.5–6.3 ppm) groups, they inherently are good candidate CEST agents . To date, a wide range of diamagnetic compounds (Table 1) have been investigated , and many of them, for example, X-ray and CT contrast agents , drugs , nutrients and supplements , and drug carriers , are clinically available agents. The advantage to use these compounds as CEST MRI agents is unprecedented: they can be used directly in humans, which is one of the most formidable challenges for the clinical use of most newly synthesized contrast agents. Besides the excellent potential of translatability, CEST MRI also has a number of technical advantages. First, unlike metallic agents that can strongly affect the inherent tissue T1 and T2 properties, CEST agents may be used in conjugation with other MRI methods simultaneously as exchangeable protons only slightly affect tissue T2 times and have a negligible effect on tissue T1 times. Moreover, CEST MRI contrast can be turned on and off at will by turning RF pulses on and off . Hence, it is possible to simultaneously acquire other (inherent) MRI contrast and CEST MRI contrast , allowing combined detection of CEST agents with other morphologic, functional, and molecular assessments. Finally, simultaneous detection of multiple CEST agents is also possible as long as the agents have distinctive CEST offsets, which sometimes is referred to as multi-colored MRI detection .
Table 1. DIACEST library (Reprinted with permission from Ref ).
|Exchangeable Proton||Signal Frequency Offset Δω (ppm)||Examples|
|Hydroxyl (–OH)||0.8–2, 4.8||Glucose ; 3-OMG 
2DG ; dextran ; sucralose ; sucrose ; glucosamine ; phenols 
|Amide (–NH)||3.5, 4.2, 5.6||Poly-L-lysine ; iopamidol ; iopromide ; mobile proteins |
|Amino (–NH2)||1.8–2.4||L-arginine ; protamine ; cytosine/5-FC ; proteins 
folate acids 
|Heterocyclic ring amide (–NH)||5–6.3||Barbituric acid ; thymidine ; uridin70e |
|Hydrogen bonds||6–12||Salicylic acids ; imidazoles ; H2O2 |
|Aliphatic protons (rNOE)||−1.6, −3.5||Mobile proteins |
CEST MRI is a rapidly developing technology with the unprecedented ability to directly use a broad spectrum of clinical agents and even drugs as MRI contrast agents, providing a practical way to realize “label-free” theranostics. The inventory of CEST agents keeps expanding. It is anticipated that many CEST agents may be advanced to the clinic in the near future to help diagnosis or treatment monitoring in a personalized manner.
The entry is from 10.3390/ph14010011
- Ward, K.M.; Aletras, A.H.; Balaban, R.S. A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). J. Magn. Reson. 2000, 143, 79–87.
- Guivel-Scharen, V.; Sinnwell, T.; Wolff, S.D.; Balaban, R.S. Detection of proton chemical exchange between metabolites and water in biological tissues. J. Magn. Reson. 1998, 133, 36–45.
- Mori, S.; Abeygunawardana, C.; van Zijl, P.C.; Berg, J.M. Water exchange filter with improved sensitivity (WEX II) to study solvent-exchangeable protons. Application to the consensus zinc finger peptide CP-1. J. Magn. Reson. B 1996, 110, 96–101.
- Mori, S.; Johnson, M.O.N.; Berg, J.M.; van Zijl, P.C.M. Water Exchange Filter (WEX Filter) for Nuclear Magnetic Resonance Studies of Macromolecules. J. Am. Chem. Soc. 1994, 116, 11982–11984.
- Zhou, J.; Payen, J.F.; Wilson, D.A.; Traystman, R.J.; van Zijl, P.C. Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Nat. Med. 2003, 9, 1085–1090.
- Zhou, J.; Yan, K.; Zhu, H. A simple model for understanding the origin of the amide proton transfer MRI signal in tissue. Appl. Magn. Reson. 2012, 42, 393–402.
- van Zijl, P.C.; Zhou, J.; Mori, N.; Payen, J.F.; Wilson, D.; Mori, S. Mechanism of magnetization transfer during on-resonance water saturation. A new approach to detect mobile proteins, peptides, and lipids. Magn. Reson. Med. 2003, 49, 440–449.
- Schure, J.R.; Shrestha, M.; Breuer, S.; Deichmann, R.; Hattingen, E.; Wagner, M.; Pilatus, U. The pH sensitivity of APT-CEST using phosphorus spectroscopy as a reference method. NMR Biomed. 2019, 32, e4125.
- Zhou, J.; Wilson, D.A.; Sun, P.Z.; Klaus, J.A.; Van Zijl, P.C. Quantitative description of proton exchange processes between water and endogenous and exogenous agents for WEX, CEST, and APT experiments. Magn. Reson. Med. 2004, 51, 945–952.
- Sun, P.Z.; Zhou, J.; Sun, W.; Huang, J.; van Zijl, P.C. Detection of the ischemic penumbra using pH-weighted MRI. J. Cereb. Blood Flow Metab. 2007, 27, 1129–1136.
- Leigh, R.; Knutsson, L.; Zhou, J.; van Zijl, P.C. Imaging the physiological evolution of the ischemic penumbra in acute ischemic stroke. J. Cereb. Blood Flow Metab. 2018, 38, 1500–1516.
- McVicar, N.; Li, A.X.; Goncalves, D.F.; Bellyou, M.; Meakin, S.O.; Prado, M.A.; Bartha, R. Quantitative tissue pH measurement during cerebral ischemia using amine and amide concentration-independent detection (AACID) with MRI. J. Cereb. Blood Flow Metab. 2014, 34, 690–698.
- Tietze, A.; Blicher, J.; Mikkelsen, I.K.; Ostergaard, L.; Strother, M.K.; Smith, S.A.; Donahue, M.J. Assessment of ischemic penumbra in patients with hyperacute stroke using amide proton transfer (APT) chemical exchange saturation transfer (CEST) MRI. NMR Biomed. 2014, 27, 163–174.
- Wang, E.; Wu, Y.; Cheung, J.S.; Zhou, I.Y.; Igarashi, T.; Zhang, X.; Sun, P.Z. pH imaging reveals worsened tissue acidification in diffusion kurtosis lesion than the kurtosis/diffusion lesion mismatch in an animal model of acute stroke. J. Cereb. Blood Flow Metab. 2017, 37, 3325–3333.
- Zhou, J.; van Zijl, P.C. Defining an Acidosis-Based Ischemic Penumbra from pH-Weighted MRI. Transl. Stroke Res. 2011, 3, 76–83.
- Cai, K.; Haris, M.; Singh, A.; Kogan, F.; Greenberg, J.H.; Hariharan, H.; Detre, J.A.; Reddy, R. Magnetic resonance imaging of glutamate. Nat. Med. 2012, 18, 302–306.
- Haris, M.; Nath, K.; Cai, K.; Singh, A.; Crescenzi, R.; Kogan, F.; Verma, G.; Reddy, S.; Hariharan, H.; Melhem, E.R.; et al. Imaging of glutamate neurotransmitter alterations in Alzheimer’s disease. NMR Biomed. 2013, 26, 386–391.
- Pepin, J.; Francelle, L.; Carrillo-de Sauvage, M.A.; de Longprez, L.; Gipchtein, P.; Cambon, K.; Valette, J.; Brouillet, E.; Flament, J. In vivo imaging of brain glutamate defects in a knock-in mouse model of Huntington’s disease. Neuroimage 2016, 139, 53–64.
- Bagga, P.; Crescenzi, R.; Krishnamoorthy, G.; Verma, G.; Nanga, R.P.; Reddy, D.; Greenberg, J.; Detre, J.A.; Hariharan, H.; Reddy, R. Mapping the alterations in glutamate with GluCEST MRI in a mouse model of dopamine deficiency. J. Neurochem. 2016, 139, 432–439.
- Ling, W.; Regatte, R.R.; Navon, G.; Jerschow, A. Assessment of glycosaminoglycan concentration in vivo by chemical exchange-dependent saturation transfer (gagCEST). Proc. Natl. Acad. Sci. USA 2008, 105, 2266–2270.
- Singh, A.; Haris, M.; Cai, K.; Kassey, V.B.; Kogan, F.; Reddy, D.; Hariharan, H.; Reddy, R. Chemical exchange saturation transfer magnetic resonance imaging of human knee cartilage at 3 T and 7 T. Magn. Reson. Med. 2012, 68, 588–594.
- Juras, V.; Winhofer, Y.; Szomolanyi, P.; Vosshenrich, J.; Hager, B.; Wolf, P.; Weber, M.; Luger, A.; Trattnig, S. Multiparametric MR Imaging Depicts Glycosaminoglycan Change in the Achilles Tendon during Ciprofloxacin Administration in Healthy Men: Initial Observation. Radiology 2015, 275, 763–771.
- Deng, M.; Yuan, J.; Chen, W.T.; Chan, Q.; Griffith, J.F.; Wang, Y.X. Evaluation of Glycosaminoglycan in the Lumbar Disc Using Chemical Exchange Saturation Transfer MR at 3.0 Tesla: Reproducibility and Correlation with Disc Degeneration. Biomed. Environ. Sci. 2016, 29, 47–55.
- Liu, J.; Han, Z.; Chen, G.; Li, Y.; Zhang, J.; Xu, J.; van Zijl, P.C.M.; Zhang, S.; Liu, G. CEST MRI of sepsis-induced acute kidney injury. NMR Biomed. 2018, 31, e3942.
- Wang, F.; Takahashi, K.; Li, H.; Zu, Z.; Li, K.; Xu, J.; Harris, R.C.; Takahashi, T.; Gore, J.C. Assessment of unilateral ureter obstruction with multi-parametric MRI. Magn. Reson. Med. 2018, 79, 2216–2227.
- Wang, F.; Kopylov, D.; Zu, Z.; Takahashi, K.; Wang, S.; Quarles, C.C.; Gore, J.C.; Harris, R.C.; Takahashi, T. Mapping murine diabetic kidney disease using chemical exchange saturation transfer MRI. Magn. Reson. Med. 2016, 76, 1531–1541.
- Zhou, J.; Heo, H.Y.; Knutsson, L.; van Zijl, P.C.M.; Jiang, S. APT-weighted MRI: Techniques, current neuro applications, and challenging issues. J. Magn. Reson. Imaging 2019, 50, 347–364.
- Goldenberg, J.M.; Pagel, M.D. Assessments of tumor metabolism with CEST MRI. NMR Biomed. 2019, 32, e3943.
- van Zijl, P.C.; Yadav, N.N. Chemical exchange saturation transfer (CEST): What is in a name and what isn’t? Magn. Reson. Med. 2011, 65, 927–948.
- Kogan, F.; Hariharan, H.; Reddy, R. Chemical Exchange Saturation Transfer (CEST) Imaging: Description of Technique and Potential Clinical Applications. Curr. Radiol. Rep. 2013, 1, 102–114.
- Goffeney, N.; Bulte, J.W.; Duyn, J.; Bryant, L.H., Jr.; van Zijl, P.C. Sensitive NMR detection of cationic-polymer-based gene delivery systems using saturation transfer via proton exchange. J. Am. Chem. Soc. 2001, 123, 8628–8629.
- Dorazio, S.J.; Olatunde, A.O.; Tsitovich, P.B.; Morrow, J.R. Comparison of divalent transition metal ion paraCEST MRI contrast agents. J. Biol. Inorg. Chem. 2014, 19, 191–205.
- Hancu, I.; Dixon, W.T.; Woods, M.; Vinogradov, E.; Sherry, A.D.; Lenkinski, R.E. CEST and PARACEST MR contrast agents. Acta Radiol. 2010, 51, 910–923.
- Ferrauto, G.; Delli Castelli, D.; Di Gregorio, E.; Terreno, E.; Aime, S. LipoCEST and cellCEST imaging agents: Opportunities and challenges. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2016, 8, 602–618.
- Jayapaul, J.; Schroder, L. Nanoparticle-Based Contrast Agents for (129)Xe HyperCEST NMR and MRI Applications. Contrast Media Mol. Imaging 2019, 2019, 9498173.
- Zeng, Q.; Bie, B.; Guo, Q.; Yuan, Y.; Han, Q.; Han, X.; Chen, M.; Zhang, X.; Yang, Y.; Liu, M.; et al. Hyperpolarized Xe NMR signal advancement by metal-organic framework entrapment in aqueous solution. Proc. Natl. Acad. Sci. USA 2020, 117, 17558–17563.
- Forsén, S.; Hoffman, R.A. Study of moderately rapid chemical exchange reactions by means of nuclear magnetic double resonance. J. Chem. Phys. 1963, 39, 2892.
- Swanson, S.D. Protein mediated magnetic coupling between lactate and water protons. J. Magn. Reson. 1998, 135, 248–255.
- Mori, S.; Eleff, S.M.; Pilatus, U.; Mori, N.; van Zijl, P.C. Proton NMR spectroscopy of solvent-saturable resonances: A new approach to study pH effects in situ. Magn. Reson. Med. 1998, 40, 36–42.
- Liepinsh, E.; Otting, G. Proton exchange rates from amino acid side chains--implications for image contrast. Magn. Reson. Med. 1996, 35, 30–42.
- Ryoo, D.; Xu, X.; Li, Y.; Tang, J.A.; Zhang, J.; van Zijl, P.C.M.; Liu, G. Detection and Quantification of Hydrogen Peroxide in Aqueous Solutions Using Chemical Exchange Saturation Transfer. Anal. Chem. 2017, 89, 7758–7764.
- Zaiss, M.; Anemone, A.; Goerke, S.; Longo, D.L.; Herz, K.; Pohmann, R.; Aime, S.; Rivlin, M.; Navon, G.; Golay, X.; et al. Quantification of hydroxyl exchange of D-Glucose at physiological conditions for optimization of glucoCEST MRI at 3, 7 and 9.4 Tesla. NMR Biomed. 2019, 32, e4113.
- van Zijl, P.C.M.; Lam, W.W.; Xu, J.; Knutsson, L.; Stanisz, G.J. Magnetization Transfer Contrast and Chemical Exchange Saturation Transfer MRI. Features and analysis of the field-dependent saturation spectrum. Neuroimage 2018, 168, 222–241.
- Khlebnikov, V.; van der Kemp, W.J.M.; Hoogduin, H.; Klomp, D.W.J.; Prompers, J.J. Analysis of chemical exchange saturation transfer contributions from brain metabolites to the Z-spectra at various field strengths and pH. Sci. Rep. 2019, 9, 1089.
- Zaiss, M.; Xu, J.; Goerke, S.; Khan, I.S.; Singer, R.J.; Gore, J.C.; Gochberg, D.F.; Bachert, P. Inverse Z-spectrum analysis for spillover-, MT-, and T1 -corrected steady-state pulsed CEST-MRI--application to pH-weighted MRI of acute stroke. NMR Biomed. 2014, 27, 240–252.
- Sun, P.Z.; Murata, Y.; Lu, J.; Wang, X.; Lo, E.H.; Sorensen, A.G. Relaxation-compensated fast multislice amide proton transfer (APT) imaging of acute ischemic stroke. Magn. Reson. Med. 2008, 59, 1175–1182.
- Sun, P.Z.; van Zijl, P.C.; Zhou, J. Optimization of the irradiation power in chemical exchange dependent saturation transfer experiments. J. Magn. Reson. 2005, 175, 193–200.
- Liu, G.; Song, X.; Chan, K.W.; McMahon, M.T. Nuts and bolts of chemical exchange saturation transfer MRI. NMR Biomed. 2013, 26, 810–828.
- Woessner, D.E.; Zhang, S.; Merritt, M.E.; Sherry, A.D. Numerical solution of the Bloch equations provides insights into the optimum design of PARACEST agents for MRI. Magn. Reson. Med. 2005, 53, 790–799.
- Zaiss, M.; Bachert, P. Chemical exchange saturation transfer (CEST) and MR Z-spectroscopy in vivo: A review of theoretical approaches and methods. Phys. Med. Biol. 2013, 58, R221–R269.
- van Zijl, P.; Knutsson, L. In vivo magnetic resonance imaging and spectroscopy. Technological advances and opportunities for applications continue to abound. J. Magn. Reson. 2019, 306, 55–65.
- Han, Z.; Liu, G. Sugar-based biopolymers as novel imaging agents for molecular magnetic resonance imaging. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2019, 11, e1551.
- Chen, L.Q.; Howison, C.M.; Jeffery, J.J.; Robey, I.F.; Kuo, P.H.; Pagel, M.D. Evaluations of extracellular pH within in vivo tumors using acidoCEST MRI. Magn. Reson. Med. 2014, 72, 1408–1417.
- Longo, D.L.; Sun, P.Z.; Consolino, L.; Michelotti, F.C.; Uggeri, F.; Aime, S. A general MRI-CEST ratiometric approach for pH imaging: Demonstration of in vivo pH mapping with iobitridol. J. Am. Chem. Soc. 2014, 136, 14333–14336.
- Moon, B.F.; Jones, K.M.; Chen, L.Q.; Liu, P.; Randtke, E.A.; Howison, C.M.; Pagel, M.D. A comparison of iopromide and iopamidol, two acidoCEST MRI contrast media that measure tumor extracellular pH. Contrast Media Mol. Imaging 2015, 10, 446–455.
- Lock, L.L.; Li, Y.; Mao, X.; Chen, H.; Staedtke, V.; Bai, R.; Ma, W.; Lin, R.; Li, Y.; Liu, G.; et al. One-Component Supramolecular Filament Hydrogels as Theranostic Label-Free Magnetic Resonance Imaging Agents. ACS Nano 2017, 11, 797–805.
- Ngen, E.J.; Bar-Shir, A.; Jablonska, A.; Liu, G.; Song, X.; Ansari, R.; Bulte, J.W.; Janowski, M.; Pearl, M.; Walczak, P.; et al. Imaging the DNA Alkylator Melphalan by CEST MRI: An Advanced Approach to Theranostics. Mol. Pharm. 2016, 13, 3043–3053.
- Liu, H.; Jablonska, A.; Li, Y.; Cao, S.; Liu, D.; Chen, H.; Van Zijl, P.C.; Bulte, J.W.; Janowski, M.; Walczak, P.; et al. Label-free CEST MRI Detection of Citicoline-Liposome Drug Delivery in Ischemic Stroke. Theranostics 2016, 6, 1588–1600.
- Li, Y.; Chen, H.; Xu, J.; Yadav, N.N.; Chan, K.W.; Luo, L.; McMahon, M.T.; Vogelstein, B.; van Zijl, P.C.; Zhou, S.; et al. CEST theranostics: Label-free MR imaging of anticancer drugs. Oncotarget 2016, 7, 6369–6378.
- Walker-Samuel, S.; Ramasawmy, R.; Torrealdea, F.; Rega, M.; Rajkumar, V.; Johnson, S.P.; Richardson, S.; Goncalves, M.; Parkes, H.G.; Arstad, E.; et al. In vivo imaging of glucose uptake and metabolism in tumors. Nat. Med. 2013, 19, 1067–1072.
- Chan, K.W.; McMahon, M.T.; Kato, Y.; Liu, G.; Bulte, J.W.; Bhujwalla, Z.M.; Artemov, D.; van Zijl, P.C. Natural D-glucose as a biodegradable MRI contrast agent for detecting cancer. Magn. Reson. Med. 2012, 68, 1764–1773.
- Liu, G.; Moake, M.; Har-el, Y.E.; Long, C.M.; Chan, K.W.; Cardona, A.; Jamil, M.; Walczak, P.; Gilad, A.A.; Sgouros, G.; et al. In vivo multicolor molecular MR imaging using diamagnetic chemical exchange saturation transfer liposomes. Magn. Reson. Med. 2012, 67, 1106–1113.
- Haris, M.; Singh, A.; Mohammed, I.; Ittyerah, R.; Nath, K.; Nanga, R.P.; Debrosse, C.; Kogan, F.; Cai, K.; Poptani, H.; et al. In vivo magnetic resonance imaging of tumor protease activity. Sci. Rep. 2014, 4, 6081.
- Zhang, S.; Merritt, M.; Woessner, D.E.; Lenkinski, R.E.; Sherry, A.D. PARACEST agents: Modulating MRI contrast via water proton exchange. Acc. Chem. Res. 2003, 36, 783–790.
- Aime, S.; Carrera, C.; Delli Castelli, D.; Geninatti Crich, S.; Terreno, E. Tunable imaging of cells labeled with MRI-PARACEST agents. Angew. Chem. Int. Ed. 2005, 44, 1813–1815.
- Chang, N.; Kaufman, S.; Milstien, S. The mechanism of the irreversible inhibition ofrat liver phenylalanine hydroxylase due to treatment with p-chlorophenylalanine. The lack of effect on turnover of phenylalanine hydroxylase. J. Biol. Chem. 1979, 254, 2665–2668.
- Gilad, A.A.; van Laarhoven, H.W.; McMahon, M.T.; Walczak, P.; Heerschap, A.; Neeman, M.; van Zijl, P.C.; Bulte, J.W. Feasibility of concurrent dual contrast enhancement using CEST contrast agents and superparamagnetic iron oxide particles. Magn. Reson. Med. 2009, 61, 970–974.
- McMahon, M.T.; Gilad, A.A.; DeLiso, M.A.; Berman, S.M.; Bulte, J.W.; van Zijl, P.C. New “multicolor” polypeptide diamagnetic chemical exchange saturation transfer (DIACEST) contrast agents for MRI. Magn. Reson. Med. 2008, 60, 803–812.
- Klippel, S.; Freund, C.; Schroder, L. Multichannel MRI labeling of mammalian cells by switchable nanocarriers for hyperpolarized xenon. Nano Lett. 2014, 14, 5721–5726.
- Xu, X.; Chan, K.W.; Knutsson, L.; Artemov, D.; Xu, J.; Liu, G.; Kato, Y.; Lal, B.; Laterra, J.; McMahon, M.T.; et al. Dynamic glucose enhanced (DGE) MRI for combined imaging of blood-brain barrier break down and increased blood volume in brain cancer. Magn. Reson. Med. 2015, 74, 1556–1563.
- Rivlin, M.; Navon, G. CEST MRI of 3-O-methyl-D-glucose on different breast cancer models. Magn. Reson. Med. 2018, 79, 1061–1069.
- Rivlin, M.; Tsarfaty, I.; Navon, G. Functional molecular imaging of tumors by chemical exchange saturation transfer MRI of 3-O-Methyl-D-glucose. Magn. Reson. Med. 2014, 72, 1375–1380.
- Sehgal, A.A.; Li, Y.; Lal, B.; Yadav, N.N.; Xu, X.; Xu, J.; Laterra, J.; van Zijl, P.C.M. CEST MRI of 3-O-methyl-D-glucose uptake and accumulation in brain tumors. Magn. Reson. Med. 2019, 81, 1993–2000.
- Jin, T.; Mehrens, H.; Wang, P.; Kim, S.G. Glucose metabolism-weighted imaging with chemical exchange-sensitive MRI of 2-deoxyglucose (2DG) in brain: Sensitivity and biological sources. Neuroimage 2016, 143, 82–90.
- Nasrallah, F.A.; Pages, G.; Kuchel, P.W.; Golay, X.; Chuang, K.H. Imaging brain deoxyglucose uptake and metabolism by glucoCEST MRI. J. Cereb. Blood Flow Metab. 2013, 33, 1270–1278.
- Rivlin, M.; Horev, J.; Tsarfaty, I.; Navon, G. Molecular imaging of tumors and metastases using chemical exchange saturation transfer (CEST) MRI. Sci. Rep. 2013, 3, 3045.
- Li, Y.; Qiao, Y.; Chen, H.; Bai, R.; Staedtke, V.; Han, Z.; Xu, J.; Chan, K.W.Y.; Yadav, N.; Bulte, J.W.M.; et al. Characterization of tumor vascular permeability using natural dextrans and CEST MRI. Magn. Reson. Med. 2018, 79, 1001–1009.
- Liu, G.; Banerjee, S.R.; Yang, X.; Yadav, N.; Lisok, A.; Jablonska, A.; Xu, J.; Li, Y.; Pomper, M.G.; van Zijl, P. A dextran-based probe for the targeted magnetic resonance imaging of tumours expressing prostate-specific membrane antigen. Nat. Biomed. Eng. 2017, 1, 977–982.
- Bagga, P.; Haris, M.; D’Aquilla, K.; Wilson, N.E.; Marincola, F.M.; Schnall, M.D.; Hariharan, H.; Reddy, R. Non-caloric sweetener provides magnetic resonance imaging contrast for cancer detection. J. Transl. Med. 2017, 15, 119.
- Longo, D.L.; Moustaghfir, F.Z.; Zerbo, A.; Consolino, L.; Anemone, A.; Bracesco, M.; Aime, S. EXCI-CEST: Exploiting pharmaceutical excipients as MRI-CEST contrast agents for tumor imaging. Int. J. Pharm. 2017, 525, 275–281.
- Rivlin, M.; Navon, G. Glucosamine and N-acetyl glucosamine as new CEST MRI agents for molecular imaging of tumors. Sci. Rep. 2016, 6, 32648.
- Zhang, J.; Li, Y.; Slania, S.; Yadav, N.N.; Liu, J.; Wang, R.; Zhang, J.; Pomper, M.G.; van Zijl, P.C.; Yang, X.; et al. Phenols as Diamagnetic T2 -Exchange Magnetic Resonance Imaging Contrast Agents. Chemistry 2018, 24, 1259–1263.
- McMahon, M.T.; Gilad, A.A.; Zhou, J.; Sun, P.Z.; Bulte, J.W.; van Zijl, P.C. Quantifying exchange rates in chemical exchange saturation transfer agents using the saturation time and saturation power dependencies of the magnetization transfer effect on the magnetic resonance imaging signal (QUEST and QUESP): Ph calibration for poly-L-lysine and a starburst dendrimer. Magn. Reson. Med. 2006, 55, 836–847.
- Longo, D.L.; Dastru, W.; Digilio, G.; Keupp, J.; Langereis, S.; Lanzardo, S.; Prestigio, S.; Steinbach, O.; Terreno, E.; Uggeri, F.; et al. Iopamidol as a responsive MRI-chemical exchange saturation transfer contrast agent for pH mapping of kidneys: In vivo studies in mice at 7 T. Magn. Reson. Med. 2011, 65, 202–211.
- Chan, K.W.; Liu, G.; Song, X.; Kim, H.; Yu, T.; Arifin, D.R.; Gilad, A.A.; Hanes, J.; Walczak, P.; van Zijl, P.C.; et al. MRI-detectable pH nanosensors incorporated into hydrogels for in vivo sensing of transplanted-cell viability. Nat. Mater. 2013, 12, 268–275.
- Bar-Shir, A.; Liu, G.; Chan, K.W.; Oskolkov, N.; Song, X.; Yadav, N.N.; Walczak, P.; McMahon, M.T.; van Zijl, P.C.; Bulte, J.W.; et al. Human protamine-1 as an MRI reporter gene based on chemical exchange. ACS Chem. Biol. 2014, 9, 134–138.
- Liu, G.; Liang, Y.; Bar-Shir, A.; Chan, K.W.; Galpoththawela, C.S.; Bernard, S.M.; Tse, T.; Yadav, N.N.; Walczak, P.; McMahon, M.T.; et al. Monitoring enzyme activity using a diamagnetic chemical exchange saturation transfer magnetic resonance imaging contrast agent. J. Am. Chem. Soc. 2011, 133, 16326–16329.
- Jin, T.; Wang, P.; Zong, X.; Kim, S.G. Magnetic resonance imaging of the Amine-Proton EXchange (APEX) dependent contrast. Neuroimage 2012, 59, 1218–1227.
- Bar-Shir, A.; Liu, G.; Liang, Y.; Yadav, N.N.; McMahon, M.T.; Walczak, P.; Nimmagadda, S.; Pomper, M.G.; Tallman, K.A.; Greenberg, M.M.; et al. Transforming thymidine into a magnetic resonance imaging probe for monitoring gene expression. J. Am. Chem. Soc. 2013, 135, 1617–1624.
- Snoussi, K.; Bulte, J.W.; Gueron, M.; van Zijl, P.C. Sensitive CEST agents based on nucleic acid imino proton exchange: Detection of poly(rU) and of a dendrimer-poly(rU) model for nucleic acid delivery and pharmacology. Magn. Reson. Med. 2003, 49, 998–1005.
- Yang, X.; Song, X.; Li, Y.; Liu, G.; Banerjee, S.R.; Pomper, M.G.; McMahon, M.T. Salicylic acid and analogues as diaCEST MRI contrast agents with highly shifted exchangeable proton frequencies. Angew. Chem. Int. Ed. Engl. 2013, 52, 8116–8119.
- Yang, X.; Song, X.; Ray Banerjee, S.; Li, Y.; Byun, Y.; Liu, G.; Bhujwalla, Z.M.; Pomper, M.G.; McMahon, M.T. Developing imidazoles as CEST MRI pH sensors. Contrast Media Mol. Imaging 2016, 11, 304–312.
- Jones, C.K.; Huang, A.; Xu, J.; Edden, R.A.; Schär, M.; Hua, J.; Oskolkov, N.; Zacà, D.; Zhou, J.; McMahon, M.T. Nuclear Overhauser enhancement (NOE) imaging in the human brain at 7T. Neuroimage 2013, 77, 114–124.
- Zhang, X.-Y.; Wang, F.; Afzal, A.; Xu, J.; Gore, J.C.; Gochberg, D.F.; Zu, Z. A new NOE-mediated MT signal at around−1.6 ppm for detecting ischemic stroke in rat brain. Magn. Reson. Imaging 2016, 34, 1100–1106.