1st Edition

Chemical Exchange Saturation Transfer Imaging Advances and Applications

    496 Pages 87 Color & 65 B/W Illustrations
    by Jenny Stanford Publishing

    496 Pages 87 Color & 65 B/W Illustrations
    by Jenny Stanford Publishing

    This is the first textbook dedicated to CEST imaging and covers the fundamental principles of saturation transfer, key features of CEST agents that enable the production of imaging contrast, and practical aspects of preparing image-acquisition and post-processing schemes suited for in vivo applications. CEST is a powerful MRI contrast mechanism with unique features, and the rapid expansion it has seen over the past 15 years since its original discovery in 2000 has created a need for a graduate-level handbook describing all aspects of pre-clinical, translational, and clinical CEST imaging. The book provides an illustrated historical perspective by leaders at the five key sites who developed CEST imaging, from the initial saturation transfer NMR experiments performed in the 1960s in Stockholm, Sweden, described by Sture Forsén, to the work on integrating the basic principles of CEST into imaging by Robert Balaban, Dean Sherry, Silvio Aime, and Peter van Zijl in the United States and Italy.

    The editors, Drs. Michael T. McMahon, Assaf A. Gilad, Jeff W. M. Bulte, and Peter C. M. van Zijl, have been pioneers developing this field at the Johns Hopkins University School of Medicine and the Kennedy Krieger Institute including contributions to Nature Medicine, Nature Biotechnology, Nature Materials, and the Proceedings of the National Academy of Sciences. As recognition for their initial development of the field, Drs. van Zijl and Balaban were awarded the Laukien Prize in April 2016, established in 1999 to honor the memory of Professor Gunther Laukien, a co-founder of Bruker Biospin GmbH.

    Section I: From the 1960s to the 2010s: How Saturation Transfer Was First Discovered and Then Migrated Into Imaging

    Discovery of the "Saturation Transfer" Method

    Development of Chemical Exchange Saturation Transfer in Bethesda

    History of In Vivo Exchange Transfer Spectroscopy and Imaging in Baltimore

    Before There Was CEST

    Early CEST Experiments

    Amide Proton Transfer–Weighted MRI

    Expansion of the CEST Efforts

    Translation to Human Scanners

    Active Growth in CEST

    Early Discovery and Investigations of paraCEST Agents in Dallas

    Birth of CEST Agents in Torino

    Section II: Pulse Sequence, Imaging, and Post-processing Schemes for Detecting CEST Contrast

    General Theory of CEST Image Acquisition and Post-Processing





    Uniform-MT Method to Separate CEST Contrast from Asymmetric MT Effects

    Saturation of a Spin-1/2 System

    Uniform Saturation of a Dipolar-Coupled Spin-1/2 System

    Uniform-MT Methodology

    Application to Brain MRI

    Application to Knee MRI


    HyperCEST Imaging

    HyperCEST in the Historic Context of CEST Development

    Hyperpolarized Xenon NMR

    Xenon Host Structures

    Phospholipid Membrane Studies/Delta Spectroscopy

    Live Cell NMR of Exchanging Xenon


    Section III: diaCEST/paraCEST/lipoCEST Contrast Probes

    Current Landscape of diaCEST Imaging Agents


    Molecules with Alkyl Amines and Amides

    Molecules with Alkyl Hydroxyls

    N-H Containing Heterocyclic Compounds

    Salicylic Acid and Anthranilic Acid Analogues

    Macromolecules with Labile Protons

    Fluorine and Chemical Exchange Saturation Transfer

    Evolution of Genetically Encoded CEST MRI Reporters: Opportunities and Challenges


    CEST MRI Contrast Generation Mechanism

    Genetically Encoded CEST MRI Reporters

    Genetically Encoded Hyperpolarized Xenon (129Xe) CEST MRI Reporters

    Considerations in Developing CEST MRI Genetically Encoded Reporters

    Current Challenges and Future Directions


    ParaCEST Agents: Design, Discovery, and Implementation


    Lanthanide-Induced Shifts

    T1 and T2 Considerations in the Design of paraCEST Agents

    Water Molecule Exchange, Proton Exchange, and CEST Contrast

    Modulation of Inner-Sphere Water Exchange Rates

    Techniques to Measure Exchange Rates


    Transition Metal paraCEST Probes as Alternatives to Lanthanides


    Coordination Chemistry of Iron(II), Cobalt(II), and Nickel(II)

    NMR Spectra, CEST Spectra, and Imaging

    Responsive Agents

    Toward In Vivo Studies


    Responsive paraCEST MRI Contrast Agents and Their Biomedical Applications


    ParaCEST Agents That Detect Enzyme Activities

    ParaCEST Agents That Detect Nucleic Acids

    ParaCEST Agents That Detect Metabolites

    ParaCEST Agents That Detect Ions

    ParaCEST Agents That Detect Redox State

    ParaCEST Agents That Measure pH

    ParaCEST Agents That Measure Temperature

    Future Directions for Clinical Translation of paraCEST Agents

    Saturating Compartmentalized Water Protons: Liposome- and Cell-Based CEST Agents


    Basic Features of lipoCEST/cellCEST Agents


    Section IV: Emerging Clinical Applications of CEST imaging

    Principles and Applications of Amide Proton Transfer Imaging


    APT Imaging Principle and Theory

    APT Imaging of Stroke

    Differentiation between Ischemia and Hemorrhage

    APT Imaging of Brain Tumors

    Differentiation between Active Glioma and Radiation Necrosis

    Conclusions and Future Directions

    Cartilage and Intervertebral Disc Imaging and Glycosaminoglycan Chemical Exchange Saturation Transfer (gagCEST) Experiment


    Composition and Organization of Cartilage

    Composition and Organization of Intervertebral Disc

    MRI Techniques for Measuring GAG (Other than CEST)



    GlucoCEST: Imaging Glucose in Tumors


    Cancer Metabolism and the Warburg Effect

    Imaging Methods Targeting Metabolism

    GlucoCEST: The Concept

    GlucoCEST: State of the Art

    GlucoCEST: Good Practices

    Conclusion: Remaining Open Questions

    Creatine Chemical Exchange Saturation Transfer Imaging


    Study of Energy Metabolism: 31P MRS

    Development of Creatine CEST


    Iodinated Contrast Media as pH-Responsive CEST Agents

    Iopamidol as a diaCEST Agent in Preclinical Studies

    Iopamidol as diaCEST Agent on a Clinical MRI Scanner (3 T)

    Iopromide as a diaCEST Agent in Preclinical Studies

    Iobitridol as a diaCEST Agent in Preclinical Studies



    Michael T. McMahon, Ph.D, is an Associate Professor of Radiology at the Johns Hopkins University School of Medicine and a Research Scientist in the F.M. Kirby Research Center for Functional Brain Imaging at the Kennedy Krieger Institute. Dr. McMahon earned his Ph.D. in physical chemistry from the University of Illinois at Urbana-Champaign in 1999 and was awarded a fellowship to continue his training at the Massachusetts Institute of Technology before taking a Research Associate position with Peter van Zijl in 2003. His research at Johns Hopkins University and Kennedy Krieger Institute is focused on the development of diaCEST contrast agents for medical applications and imaging schemes to maximize their potential. Dr. McMahon has been elected to the position of Program Director for the Cellular and Molecular Imaging Study Group at the International Society for Magnetic Resonance in Medicine (ISMRM) and together with Drs. Gilad, Bulte and van Zijl organized the third CEST imaging workshop (OctoberCEST) in Annapolis, MD.

    Dr. Jeff W.M. Bulte, Ph.D, is a Professor of Radiology in the Division of MR Research, with joint appointments in Oncology, Biomedical Engineering, and Chemical & Biomolecular Engineering. He serves as the Director of the Cellular Imaging Section in the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. In 1991, Dr. Bulte obtained his Ph.D. summa cum laude from the University of Groningen, The Netherlands. He then spent 10 years in the Laboratory of Diagnostic Radiology Research at the National Institutes of Health before moving to Johns Hopkins University in 2001. He has won several awards, including an ISMRM Gold Medal and the Torsten Almén Award for Pioneering Research in Contrast Media.

    Assaf A. Gilad, Ph.D, is an Associate Professor of Radiology at the Johns Hopkins University School of Medicine and the Institute for Cell Engineering. After obtaining his Ph.D. from the Weizmann Institute of Science, Rehovot, Israel in 2003, he received his postdoctoral training under the supervision of Drs. Jeff Bulte and Peter van Zijl at Johns Hopkins University. In 2007 he joined the Radiology department as junior faculty and has continued to develop new genetically encoded technologies for cellular and sub-cellular molecular CEST imaging.

    Peter C.M. van Zijl, Ph.D., is a Professor of Radiology in the Division of MR Research of the Department of Radiology at Johns Hopkins University School of Medicine, and the founding Director of the F.M. Kirby Research Center for Functional Brain Imaging at Kennedy Krieger Research Insitute. Dr. van Zijl received his Ph.D. in mathematics and physics (Physical Chemistry) from the Free University, Amsterdam in 1985. He did fellowships in Chemistry, Carnegie Mellon University (1985-87) and in vivo spectroscopy (National Cancer Institute, NIH from 1987–1990) and was Assistant Professor at Georgetown University from 1990–1992. He moved to Johns Hopkins University in 1992. Dr. van Zijl is a Fellow of both the ISMRM and the ISMAR. He received the Gold medal of the ISMRM in 2007 for contributions in MR spectroscopy, diffusion imaging, and functional MRI. He is a distinguished Investigator of the Academy of Radiology Research (2012) and in 2016, together with Robert Balaban, received the Laukien Prize for his contributions to developing the CEST field.

    "This textbook is very helpful for those who are eager to fully understand the principles and development of chemical exchange saturation transfer (CEST) techniques. One strength of this book is in the discussion of probes, and another strength is having Sture Forsén and Robert Balaban describe their early studies. This book will have a great impact promoting the clinical translation of CEST imaging."

    —Prof. Renhua Wu, Shantou University, China

    "This book presents an in-depth and comprehensive description of CEST physics, techniques, and applications. It is in time for the dawn of label-free molecular imaging that explores chemical exchange phenomena the nature offers. It is also a collection of very updated perspectives of the future of CEST magnetic resonance imaging (MRI), quite informative, and fun to read for imaging physicists, radiologists, and clinician scientists."

    —Prof. Ed X. Wu, The University of Hong Kong, Hong Kong

    "This is an excellent book on CEST MRI with state-of-the-art chapters from thought leaders in the field. It touches on all aspects of CEST: image acquisition methods and data processing, development of exogenous CEST probes, and applications of CEST in clinical and biomedical imaging. A very valuable addition to biomedical imaging canon, and a text that will be beneficial to students and experts alike."

    —Prof. Peter Caravan, Harvard Medical School, USA

    "This book has been edited by faculty from one of the leading centers with extensive experience of chemical exchange saturation transfer (CEST) MRI and is the first to focus exclusively on this specific imaging technique. The authors include many of the leaders in the field, and it belongs on the shelf of anyone seriously involved in CEST work.  It has broad breadth of coverage which makes it a go-to reference for overviews of many sub-specialty applications.  It is clearly valuable as a standard in the field and I expect it will serve as the essential starting point for in-coming graduate students beginning CEST research and for established researchers delving into a new area."

    —Dr. Daniel F. Gochberg, Vanderbilt University Institute of Imaging Science, USA

    "Chemical exchange saturation transfer (CEST) can be used to detect proteins, peptides, metabolites, and probe molecules in 1H MR images of tissue water, with observation via the water resonance massively increasing the sensitivity of their detection. This timely book describes the history of the technique’s development and the underlying theory and then goes on to review its latest applications. It is a comprehensive and insightful book written by the leaders in the field. It is a must read book for anyone already in the CEST field, or thinking of entering the field and, given the growing popularity of the methods described here, should be read by anybody working in the field of in vivo MR."

    —Prof. Kevin Brindle, University of Cambridge, UK, Molecular Imaging and Biology, 2017