Next Generation Molecular Probes for Magnetic Resonance Imaging and Sensing: Design, Synthesis, Evaluation and Application

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Nuclear magnetic resonance can be used for both spectroscopy (NMR) and imaging (MRI) studies, and thus is widely applied in chemistry, biology and medicine. The hallmark limitation of both MR-based techniques is their low sensitivity. Clinical MRI has to rely on the 1H NMR signal of water, the most abundant molecule in vivo. Many molecular events with biological or medical significance, such as protein expression and pH fluctuation, are inaccessible by NMR or MRI. This research program aims to develop new chemical probes to improve the sensitivity and molecular specificity of MR imaging and spectroscopic sensing. Their application will non-invasively reveal structural and functional information about living biological systems at the molecular level, ideal for advanced biomedical research as well as for clinical diagnosis.****The program consists of two complementary parts, based on the working mechanism. Part 1 focuses on next-generation MRI contrast agents (CAs). Paramagnetic metal chelates with unpaired electrons can catalytically accelerate the 1H-NMR relaxation of surrounding H2O molecules. They are widely used in clinics as CAs to enhance signal intensity and tissue contrast. Conventional MRI CAs are mainly based on chelated Gd(III) which has seven unpaired f-electrons (S = 7/2) and thus a high magnetic dipole moment. The intrinsic limitations of Gd agents include low relaxation-enhancement efficiency (relaxivity) and the risk of releasing toxic free Gd from the chelates in vivo. During the past NSERC cycle, we established a non-Gd system based on Mn(III)porphyrin (MnP), offering better sensitivity and biocompatibility. Part 1 of the current program aims to achieve the following breakthroughs:****• To understand and to further improve the high relaxivity of MnPs at high magnetic fields;****• To develop novel MnPs for specific applications, including vascular imaging, cellular imaging and disease-targeted molecular imaging;****• To develop new approaches to manipulate relaxivity, and utilize them for MRI sensor development.****Part 2 aims to develop diamagnetic NMR spectroscopic sensors based on novel chemical mechanisms. It includes two projects:****• Ratiometric NMR pH sensors with a slow proton exchange (SPE) mechanism;****• Ultrasensitive NMR sensors based on the modulation of chemical exchange rate.****By developing novel strategies and choosing appropriate targets, highly sensitive and accurate NMR sensors may be applied for imaging applications. This approach complements the MRI CA-based methods of Part 1.****Our program integrates multidisciplinary research approaches, including theory-based molecular design, chemical synthesis, spectroscopic investigations, evaluations in biological systems, and applications for disease diagnosis. It is thus an ideal platform for training highly qualified personnel at the interfaces between chemistry, biology and translational medical technology.**