Target Audience

This talk contains a combination of both basic NMR and biological research elements concerning preclinical CEST, and is therefore aimed at potential practitioners that are considering entering this field.

Abstract

CEST is an extremely ingenious experiment combining some of the most appealing aspects of NMR and MRI [1-4]. On one hand it provides molecular-level spectroscopic information a-la NMR; at the same time it relies on a water-based acquisition, and thereby provides a sensitivity and a spatial resolution that comparable to that in conventional MRI. This encoding of NMR, site-specific information onto the observable bulk water signal, is mediated by chemical exchanges of labile sites in selected molecules operating in unison with RF-based perturbations of these special sites. These exchanges can endow orders-of-magnitude signal enhancements to the labile, low-abundance resonances, in a remarkably simple way. The ensuing CEST experiment is thus applicable to a large number of metabolites and to a variety of biological problems, and during the last decade it has been used to measure important physiological parameters such as pH, to follow tumor growths, to highlight neural degeneration processes, and to quantify the concentration of important energy-related metabolites including glucose, glycogen, creatine/phosphocreatine. All this, under non-invasive, high-definition imaging conditions. As research based on this approach has progressed, however, it has also evidenced that complexities may arise in the interpretation of CEST data. Common complications may involve the overlap of multiple components that prevent the one-to-one relation between the observed CEST effects and individual metabolites; field heterogeneities that complicate the definition of an exact saturation offset; motions that perturb the stability of these difference experiments; exchange rates that are simply too slow or too fast for an optimal performance of the signal amplification. Some of these complications become particularly challenging when trying to target species whose resonance are overtly close to the frequency of the water peak. This talk will explain the origin of these complications, as well as the research that in response to it has been done in recent years to alleviate these effects. Among the robustness-enhancing methods that will be discussed are rapid field mapping techniques, alternative CEST pulse sequences that are less susceptible to field heterogeneities and/or to the exact position of the targeted resonance than the original low-power CW approach, and experiments that distinguish particular chemical sites by relying on how the environment of the targeted site modulates its coupling to neighbours and/or its chemical exchange rate with the water. Emphasis will also be placed on the advantages arising upon porting the experiments to higher fields, which benefit from several multiplicative factors including a larger separation between the targeted metabolites and water, the capability of accommodating larger rates of exchange, and a longer T1 relaxation time of water allowing one to accumulate a stronger contrast. The potential of these approaches will be exemplified with ongoing preclinical research being done on developmental models, on brain function and on cancer progression.

Acknowledgements

Our research in this area has been funded by the Israel Science Foundation (ISF grants 965/18 and 2508/17) and by the National Science Foundation (Cooperative Agreement DMR-1644779)