From chemical exchange to molecular imaging with CEST

Silvio Aime Dept of Molecular Biotechnologies & Health Sciences, University of Torino, Torino, Italy The possibility of exploiting the superb anatomical resolution of MRI continues to make this modality highly desirable for Molecular Imaging applications . Besides paramagnetic relaxation systems (e.g. Gd(III) or Mn(II) complexes), two new classes of frequency -encoding probes, namely the CEST agents (CEST= Chemical Exchange Saturation Transfer) an d the class of hyperpolarized molecules, have been considered as powerful tools for MR -Molecular Imaging applications. CEST agents are an emerging class of MRI agents that act through the transfer of saturated magnetization to the “ bulk ” water signal. Said in other words, CEST agents are chemicals that contain exchanging protons pools that can be selectively saturated by setting a proper radiofrequency ( rf ) irradiating field at their absorption frequency. Being frequency -encoding systems, CEST agents own tw o major advantages in respect to the established class of relaxation enhancers: i) more than one agent can be detected in the same anatomical region simply by setting the rf offset of the irradiating field at the absorption frequency of the exchanging prot ons of the specific agents, and ii) the presence of two (or more) pools of exchanging protons on the same molecule (or single pools on molecules with analogous biodistribution), as well as the exploitation of the relationship between exchanging rates/satur ation transfer and the irradiation field intensity ( B1 ), allows the set -up of ratiometric procedures for the design of responsive agents that do not need the prior knowledge of the actual concentration of the contrast agent. The major, very disappointing, drawback of CEST agent deals with their poor sensitivity. Therefore, much work has been devoted to seek for routes able to enhance the CEST contrast. The breakthrough innovation in term of increase of sensitivity was found by designing the LipoCEST agents . The naturally -inspired, liposomes vesicles, when loaded with paramagnetic Lanthanide - based shift reagents, can be transformed into CEST probes. The large number of water molecules entrapped inside the inner cavity of the nanovesicles represents an enormo us pool of exchanging protons for the generation of CEST contrast, whereas the presence of the shift reagent increases the separation in chemical shift of their NMR signal from that of the bulk water, thus allowing for a proper exchange regime for the acti vation of CEST contrast . From LipoCEST, it has been rather straightforward to evolve to CellCEST in order to exploit the cytoplasmatic water molecules as source of the CEST effect, once cells have been loaded with the proper shift reagent. 

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