Dual-frequency irradiation CEST-MRI of endogenous bulk mobile proteins

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Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) has emerged as an important contrast mechanism for the detection of organic compounds in low concentration such as metabolites or proteins. The major advantage of CEST-MRI is that it allows information to be obtained at the molecular level without the application of contrast media and with a spatial resolution comparable to conventional MRI. However, in living tissue the CEST signals of many diverse solutes are spectrally overlapping preventing the selective detection of one specific compound of interest in vivo. The improvement of specificity has become one of the most important issues in the research field of CEST-MRI. Recently, we developed a novel CEST-based technique – dualCEST – which overcomes this limitation and enables the selective detection of endogenous bulk mobile proteins in vivo (i.e. mainly cytosolic proteins). Such a noninvasive imaging technique may be of particular interest for the diagnosis of diseases associated with profound alterations of protein expression, like cancer and Alzheimer’s. In comparison to conventional CEST, the exclusion of contributions from other cellular compounds is expected to improve the specificity of the image contrast in terms of delineating healthy and diseased tissue.With regards to examinations in humans, the dualCEST technique can be readily implemented on 3T MR scanners making it widely applicable for practical applications in clinical settings. We have already verified the applicability of the dualCEST technique in humans by a proof-of-principle examination of a brain tumor patient at 3 T. However, currently a dualCEST examination still takes about 20 min, and moreover only allows acquisition of 2D images. In addition, an unequivocal validation of its significance as a diagnostic tool by a pilot study is required to allow its incorporation into routine clinical examinations.Thus, the central aim of this proposal is to establish the novel technique of dualCEST-MRI as a diagnostic tool to detect changes of endogenous bulk mobile proteins in humans. Firstly, the dualCEST pulse sequence will be further developed to enable a fast and robust imaging permitting a high-resolution 3D examination of the human brain in approximately 5 min. The diagnostic significance of the dualCEST approach will then be evaluated in two separate pilot studies with brain tumor and Alzheimer’s patients. The dualCEST image contrast is expected to provide complementary information for the identification of tumorous tissue at a molecular level, thus leading to improved treatments. For Alzheimer's disease, a diagnostic tool avoiding radiation exposure would allow regular and frequent examinations, and thus an improved level of patient care. In parallel, a previously utilized cell model with a genetic modification will be investigated to verify the detectability of proteomic changes on a physiologically relevant scale.