Novel approaches for CEST labeling, detection, quantification and translation

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The prognosis of patients with malignant gliomas remains dismal. In addition, limitations in neuroimaging complicate the clinical management of these patients and impede efficient testing of new therapeutics. While extension of MRI to the cellular and molecular level has introduced new possibilities for imaging malignant gliomas, most molecular MRI studies have been limited to the pre-clinical setting. Recently, a new type of molecular MRI contrast has become available that detects the body's own building blocks: amino acids, proteins and carbohydrates. The magnetic contrast produced by these natural species is due to the presence of groups of protons (NH, NH2, OH) that can exchange with the protons on water and, as such, affect the signal in MRI images. The nomenclature for these compounds is based on their first mechanism of detection with MRI, namely “Chemical Exchange Saturation Transfer” or “CEST”. Amide proton transfer weighted (APTw) MRI is an endogenous CEST method with potential for improving cancer diagnosis (identifying and determining the extent of malignant disease), therapeutic monitoring (objective assessment of change in tumor burden), and distinguishing recurrent tumor from treatment effects. However, the current saturation-based approach has low specificity for amide protons due to interference of large confounding background signals from direct water saturation (DS) and conventional magnetization transfer contrast (MTC) from semisolid tissue components, as well as from signals from other endogenous CEST metabolites. We propose to address this by developing pulsed exchange transfer approaches, i.e. not based on RF saturation labeling but on proton excitation and proton frequency evolution labeling, that can remove such confounding effects. In AIM 1, we will develop pulse sequences that can achieve magnetic labeling of exchangeable protons using trains of RF excitation pulses with variable delays. We use these to encode the exchangeable protons based on their specific chemical shift evolution (frequency encoding) and their exchange transfer properties, which allows removal of the confounding effects mentioned above. In AIM 2, the goal is quantification of the exchange transfer contrast. Using the editing methods developed in AIM 1, we will design approaches to measure absolute concentrations and validate them using known concentrations in phantoms. In vivo, the water signal used for the detection of exchange transfer will be used as an internal standard. Finally, in AIM 3, we will translate the methodology to fast 3D whole-brain scanning on animal and human systems. These aims are expected to result in the availability of quantifiable APT contrast MRI in patients with gliomas. While we focus demonstration of the usefulness of the new methods on glioma animal models and patients, the technical developments in this proposal are expected to be important for tumor imaging in general, several other pathologies (e.g. stroke, neurodegeneration), and for the imaging of CEST contrast agents for which the interference of MTC, DS and endogeneous CEST background signals is a major problem.