The relayed nuclear Overhauser effect in magnetization transfer and chemical exchange saturation transfer MRI

Magnetic resonance (MR) is a powerful technique for noninvasively probing molecular species in vivo but suffers from low signal sensitivity. Saturation transfer (ST) MRI approaches, including chemical exchange saturation transfer (CEST) and conventional magnetization transfer contrast (MTC), allow imaging of low‐concentration molecular components with enhanced sensitivity using indirect detection via the abundant water proton pool. Several recent studies have shown the utility of chemical exchange relayed nuclear Overhauser effect (rNOE) contrast originating from nonexchangeable carbon‐bound protons in mobile macromolecules in solution. In this review, we describe the mechanisms leading to the occurrence of rNOE‐based signals in the water saturation spectrum (Z‐spectrum), including those from mobile and immobile molecular sources and from molecular binding. While it is becoming clear that MTC is mainly an rNOE‐based signal, we continue to use the classical MTC nomenclature to separate it from the rNOE signals of mobile macromolecules, which we will refer to as rNOEs. Some emerging applications of the use of rNOEs for probing macromolecular solution components such as proteins and carbohydrates in vivo or studying the binding of small substrates are discussed. Comparison of possible magnetization transfer pathways from tissue molecules to water. In addition to direct chemical exchange saturation transfer (CEST), three of these pathways include relayed nuclear Overhauser (rNOE) effects, leading to signals in the aliphatic frequency range of the water saturation spectrum (Z‐spectrum). These occur in mobile macromolecules, semisolid macromolecules (magnetization transfer contrast or MTC) and upon binding of ligands to immobile receptors (IMaging of MOlecular BInding using Ligand Immobilization and Saturation Exchange [IMMOBILISE]). Some emerging applications of the use of rNOEs for probing macromolecular solution components such as proteins and carbohydrates in vivo or studying the binding of small substrates are discussed.