20 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 Despite its potential, even in an in vivo setup (Figure 5), the fact that 19F-GEST relies on synthetic organic molecular hosts restricts the values of the Dws of incorporated fluorinated guests to a fewppm.This limits not only the number of artificial 19F-GEST colors that can be obtained, but also compromises the spectral resolution of 19F-GEST. To overcome this and expand the number of artificial 19F-GEST colors and enhance 19F-GEST spectral resolution, we proposed a paramagnetic GEST (paraGEST) approach for multiplexed imaging based on paramagnetic supramolecular systems. Inspired by paramagnetic CEST (paraCEST) [29] and the potential to induce pseudo contact shifts (PCSs) to exchangeable fluorinated guests, paraGEST was developed. To do so, we synthesized a library of paramagnetic cavitands based on a lanthanide-cradled α-CD (Figure 6a) and identified a putative fluorinated guest (para-trifluoromethyl-benzylamine), which adopts the GEST principles and is capable of producing artificial paraGEST MRI colors (Figure 6b). Establishing an approach we termed CODE-HD (COlor Display by Exploiting Host-guest Dynamics), where principles of hostguest binding kinetics with paraCEST and 19F-MRI were combined, we demonstrated a unique approach to generate artificial MRI colors. By inducing PCSs to the chemical shift of dynamically exchanging fluorinated guests in a 19F-NMR framework, which is controlled by the lanthanide element of the paramagnetic host, spectrally resolved artificial colors can be obtained (Figure 6). We demonstrated the versatility of CODE-HD by showing the ability to convert a given color code to another just by replacing the fluorinated guest (and using 3,5-difluorobenzylamine) and enhancing the spectral resolution of the 19F-GEST spectrum as well as enriching the 19F-GEST color palette with additional artificial colors [30]. Such features provide CODE-HD with a convertible colorcode capability - a property that is not possible for classical luminescence-based colors or for MRI-based artificial colors. Proposing GEST 19F-NMR for the study of binding kinetics in a variety of host-guest supramolecular systems, our group demonstrated how this GEST technique, which can be applied using conventional NMR setups, can expand the NMR toolbox currently available to study dynamic host–guest systems in solution without any special expertise or dedicated hardware [31]. Demonstrating the performance of 19F-GEST NMR to study systems composed of cucurbit[n]urils [26, 32], molecular capsules [27], bambusurils [25], cyclodextrins [30], and their mixtures [28] showed its potential to obtain even more artificial MRI colors than those demonstrated above. Nevertheless, although the 19F-GEST MRI provides unique multicolor MRI features that are not applicable in either 1H-CEST MRI or 19F-MRI, it is important to stress that much more effort is needed before GEST and/or paraGEST are implemented for routine use in imaging setups. localized MR spectroscopy (MRS) approaches applied with a pre-saturation pulse at the desired frequencies (Figures 4f,g). Using a fluorinated anesthetic as an inhalable 19F-guest (i.e., fluroxene), the potential use of 19F-GEST for in vivo studies was demonstrated (Figure 5a). To do so, aqueous solutions of either CB7 or OA (in its dimeric form) were delivered intracranially to two opposite hemispheres in the brain of a live mouse (Figure 5b). The examined mouse was then anesthetized with the inhalable 19F-guest fluroxene for the in vivo 19F-GEST examination following confirmation of a homogenous distribution of the 19F-guest in the brain with 19F- MRI (Figure 5d-e). In vivo localized 19F-GEST MRS (Figures 5f,g) was then performed using two voxels localized at the injection sites of either CB7 (pink square, Figure 5d) or dimeric-OA (green square, Figure 5d) showing the in vivo applicability of 19F-GEST through a clear saturation transfer effect observed in the obtained 19F-NMR spectra (Figures 5f and 5g) [28]. This 19F-GEST MR approach offers an alternative strategy with which to detect very low levels of thermal ly polarized pools of fluorine-19 spins with readily available hardware and may open new avenues for the development of additional molecular architectures for multicolor 19F-MRI, which, so far, has relied on the ability to detect high concentrations of fluorinated pools (Figure 1b). Figure 5. In vivo 19F-GEST. (a,b) Schematic illustration of the in vivo experimental setup, (c) 1H-MRI, (d) UTE-19F-MRI, and (e) 19F-MRI signal overlaid on the 1H-MRI of a livemouse anesthetizedwith 4%fluroxene. (f,g) Localized 19F-GEST MRS data.
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