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.

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

Introduction

Theory

Post-Processing

Conclusion

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

Summary

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

Conclusion

Section III: diaCEST/paraCEST/lipoCEST Contrast Probes

Current Landscape of diaCEST Imaging Agents

Introduction

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

Introduction

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

Conclusion

ParaCEST Agents: Design, Discovery, and Implementation

Introduction

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

Summary

Transition Metal paraCEST Probes as Alternatives to Lanthanides

Introduction

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

NMR Spectra, CEST Spectra, and Imaging

Responsive Agents

Toward In Vivo Studies

Summary

Responsive paraCEST MRI Contrast Agents and Their Biomedical Applications

Introduction

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

Introduction

Basic Features of lipoCEST/cellCEST Agents

Applications

Section IV: Emerging Clinical Applications of CEST imaging

Principles and Applications of Amide Proton Transfer Imaging

Introduction

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

Introduction

Composition and Organization of Cartilage

Composition and Organization of Intervertebral Disc

MRI Techniques for Measuring GAG (Other than CEST)

GagCEST

Conclusion

GlucoCEST: Imaging Glucose in Tumors

Introduction

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

Introduction

Study of Energy Metabolism: 31P MRS

Development of Creatine CEST

Summary

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

Conclusion