PH-Responsive MRI Agents that can be Activated Beyond the Tissue MT Window

Abstract

Chemical Exchange Saturation Transfer (CEST) has emerged as a novel Magnetic Resonance Imaging (MRI) contrast mechanism and gained increasing attention in applications. The image contrast is obtained by utilizing slow exchange properties of CEST agents that contain protons in exchange with bulk water protons. And continuous transfer of saturation makes the solutes at low concentration indirectly observable. In CEST, application of a pre-saturation pulse results in an extra signal called the Magnetization Transfer (MT) effect, arising from immobile protons bound in proteins and other large macromolecules. It is worthwhile to note that the MT effects always accompany CEST in tissue; as a result, measuring the pure CEST contribution that is separated from MT effect becomes somewhat difficult. Up to now, for the CEST data processing, the most commonly method used is the MTratio (MTR) asymmetry analysis with respect to the water frequency. Good asymmetry analysis requires that the MT profile is symmetric around water. However, over the past few years, several studies have found that in tissue, the z-spectra associated with semi-solid molecular pool are slightly asymmetric around the water proton resonance frequency, probably due to the chemical shift center mismatch between bulk water and semi-solid macromolecules. Thus, the validity of the MTR asymmetry analysis has been compromised. The goal of the present work is to develop CEST-based pH sensors that can be activated without simultaneous activation of the tissue MT signal. Our research efforts are focused under the theme to develop CEST-based pH sensors with large hyperfine shifts, putting them well outside the range of the MT profile. Thus they can be activated via selective RF irradiation without MT interference. Terbium-based complexes were developed, which displayed a water exchange CEST resonance located in the range of -500 to -600 ppm, well-outside the normal MT frequency range of tissues. By using this type of agents, the macromolecule MT effect has no impact on contrast-to-noise ratios in biological systems and MTratio (MTR) asymmetry analysis is not considered as necessary as other agents, thus opening a new way of circumventing the MT contamination and complication. Deprotonation of the phenolic proton resulted in a frequency shift of about 60 ppm in a bound water molecule exchange peak between pH 5 and 8. This allows direct imaging pH without prior knowledge of the agent concentration. A new model for simultaneous measurement of pH and temperature parameters was also proposed. The chemical shift information extracted from imaging data could be used to obtain the local temperature and pH values by simultaneously solving equations in our established model.