Design and Development of Biomarker-Responsive Transition Metal-Based Magnetic Resonance Imaging ProbesPublic
The invention of GdIII-based magnetic resonance imaging (MRI) probes substantially expanded the capability of MRI in visualizing details in tissue. Building upon the achievement of GdIII-based complexes, more ideal probes should feature contrast that is responsive to biomarkers, such as redox status and ion concentrations. The abnormality of these biomarkers are oftentimes associated with pathologies. Importantly, the responsive contrast from these probes should be independent of the local probe concentration, in order to avoid ambiguity caused by uneven bio-distribution of the probes, and enable quantitative measurement of the biomarkers. Transition metal complexes are attractive candidates for responsive MRI probes, due to the highly tunable magnetic and electronic properties of transition metals. This dissertation reports the development of transition metal-based MRI probes for ratiometric quantitation of biomarkers. Chapter One provides a brief introduction of paramagnetic chemical exchange saturation transfer (PARACEST) and the advantages and design criteria of PARACEST probes. Chapter Two describes a case study in which a CuII2 PARACEST probe was enabled by magnetic coupling. Such result suggests that magnetic coupling can reduce electronic relaxation time (taus), allowing a much broader range of metals to be considered for PARACEST probes. Building on the strategy developed in Chapter Two, Chapter Three demonstrates that a Fe2 probe, which is NMR-active in both the FeIIFeII and FeIIFeIII states, can quantitate solution redox status in a concentration-independent manner. Chapter Four applies the magnetic coupling strategy to reduce the intrinsic relaxivity of GdIII complexes by decreasing the taus of the GdIII center. This study forms the foundation for designing responsive GdIII-based probes with low background signals. In addition to manipulating the electronic properties of transition metals, Chapter Five demonstrates the utilization of the magnetic anisotropy of CoII to distinguish Ca2+ and Na+ in solution. The resulting Ca2+ to Na+ CEST intensity ratio provides a concentration-independent parameter for quantitating Ca2+, which is a prominent biomarker for bone-related diseases.
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