Early development of chemical exchange saturation transfer (CEST)

The demonstration of saturation transfer (ST) between exchanging chemical species by Forsén and Hoffman in 1963 established a fundamental application of NMR spectroscopy. Initially developed for solution chemistry, ST evolved into a noninvasive method for measuring tissue enzymatic activity and metabolite concentrations. Its first biological application quantified ATP, the cell's primary energy currency, exchanging with phosphate in living cells. Saturation transfer was subsequently extended to numerous enzymatic reactions in tissues and humans. In our laboratory, we recognized that applying ST to small pools of metabolites exchanging with water protons could greatly amplify their detection by exploiting ST to the larger water proton pool. This concept became the basis of Chemical Exchange Saturation Transfer (CEST), enabling the detection of endogenous metabolites and the development of exchange-based MRI contrast agents. Although CEST was first demonstrated in simple aqueous systems, its application to tissues was masked by the extensive magnetization exchange between water and immobilized macromolecular protons. This competing process gave rise to magnetization transfer contrast (MTC), now a valuable clinical MRI technique. By exploiting the approximate symmetry of the macromolecular background about the water resonance, we removed its contribution and recovered metabolite CEST signals, enabling the detection of numerous metabolites in tissues and the diagnosis of disease. From its origins in a simple ST experiment, two major MRI methodologies, MTC and CEST, have emerged, continuing to transform biomedical research and clinical imaging.