16 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 types, as well as on developing methods for pseudo-color in vivo MR imaging. I here provide an overview of our recent developments, emphasizing the newly proposed MRI sensors that are based on inorganic nanocrystals (NCs), host-guest systems, and engineered proteins, which have the potential to extend the MRI toolbox with features that have been, thus far, inaccessible. Principles of generating pseudo-colors for MRI Several strategies have been proposed to generate pseudocolors for MRI applications. One example is the use of the chemical exchange saturation transfer (CEST) contrast mechanism to produce artificial MRI colors (Figure 1a). By applying a saturation pulse at the specific resonance of an exchangeable proton of a putative CEST agent, it can be “tagged.” This tag (manifested by its MR signal nullification) is transferred to the water protons in the surrounding area and leads to 1H-MRI signal reduction as a result of the dynamic exchange process of the “tagged” protons with the water protons. Using multiple CEST agents with exchangeable protons that resonate at different and specific chemical shift offsets (Dws) from the resonance of the water protons (set at 0.0), artificial MRI colors can be generated, as demonstrated for several applications [6, 8]. The relatively large chemical shift range of fluorinatedmaterials in a 19F-MR framework was also exploited for spectral differentiation between different fabrications and presents this range in a pseudo-color manner (Figure 1b) [7, 9, 10]. Benefitting from the negligible tissue background in 19F-MRI and the 19F-MR signal quantifiability, multicolor 19F-MRI studies provide unique multicolor MRI features that are not accessible to a 1H-CEST-based approach. Combining the two strategies for multicolor MRI, i.e., CEST and 19F-MR to obtain 19F-CEST [11] (Figure 1c), provides a novel MRI platform that can be implemented for applications in which both 1H-CEST and 19F-MRI are not applicable. Nanofluorides Fluorine-19 is the second most NMR-sensitive nucleus (after 1H) and is therefore favorable for MR-based studies (NMR and MRI) and fluorinated materials have been proposed as 19F-MR imaging tracers [12], overcoming some of the major drawbacks (i.e., strong background signal, non-quantifiable, challenging in multiplexing, etc.) of paramagnetic contrast agents. Combining this with the fact that 19F-nuclei do not exist in soft biological tissues, the 19F-MR signal of an introduced 19F-tracer can be directly monitored and presented Moreover, the versatility of MRI contrast mechanisms [4, 5], and the variability in imaging probe identities (including non-1H tracers), create many possibilities for the design of MRI sensors. One feature that is unique to MRI is that this technique relies on MR properties, which allows, among other advantages, differentiation between molecular entities based on their chemical environment, which is reflected by a characteristic chemical shift. If spectrally resolved, the frequencies of multiple chemical shifts of properly designed molecular probes can be exploited for multiplexed imaging by introducing MRI maps with pseudo-color features [6, 7]. Such pseudo-MRI-colors can be generated using several strategies, including the use of non-1H nuclei, which frequently provide improved spectral resolution, or through magnetization transfer mechanisms that benefit from the high sensitivity of 1H-MRI. In recent years, our lab has focused on the development of novel molecular formulations of a variety of Figure 1. Strategies to generate artificial colors in 1H- and 19F-MRI frameworks. (a) Artificial colors can be generated in CEST-MRI by exploiting the different chemical shift offsets of different exchangeable protons of 1H-CEST agents. (b) In 19F-MRI, artificial colors can be generated by using different 19F-agents based on the difference in the 19F-chemical shifts of their fluorinated content. (c) In the 19F-CEST approach, which is applied on host-guest systems (termedguest exchange saturation transfer, GEST), the sameprinciples used to generate artificial colors in 1H-CEST are used. In this case, the different chemical shift offsets are obtained from the complexation of a 19F-guest with a different molecular host in the solution. 0 Frequency offset from 1H2O [ppm] ω2 ω3 R-NH R-NH2 1H2O R-OH ω1 19F chemical shift [ppm] ω1 ω2 R319F R219F R1 19F ω3 0 Frequency offset from free 19F-guest [ppm] ω2 ω3 19F-guest ω1 F F F F a) 1H-CEST b) 19F-MRI c) 19F-CEST
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