Variations in the tissue microenvironment are closely associated with diseases and disorders. In particular, acidic extracellular pH is a prominent feature of pathological conditions such as cancer, ischemia, and inflammation. Thus the ability to accurately quantitate and spatially map tissue pH is of great importance for improving the early diagnosis and treatment of many pathologies. Toward this end, my research focuses on applying coordination chemistry to develop pH-responsive molecular probes that are able to measure and spatially map pH in a concentration-independent manner and with high sensitivity through a Magnetic Resonance Imaging (MRI) technique called PARAmagnetic Chemical Exchange Saturation Transfer (PARACEST). These probes are highly tunable paramagnetic dinuclear cobalt(II) complexes that feature highly-shifted exchangeable protons that interact with the bulk water protons to generate a pH-dependent MRI contrast, owing to the inherent pH sensitivity of their proton exchange rates. Specifically, we have demonstrated that by incorporating two distinct ligand scaffolds on a single complex, where the two ligands exhibit PARACEST effects with opposing pH dependences, the ratio of the two PARACEST peak intensities changes dramatically as a function of pH in the physiological pH range. Furthermore, the pH sensitivity and detection window can be finely controlled through chemical modifications of the two CEST-active ligands, thus allowing for optimization of the pH sensing performance for targeted applications. These ratiometric dicobalt pH probes exhibit remarkably high sensitivity and excellent stability in physiological environments, which underscores their potential suitability for <i>in vivo</i> applications. Ongoing efforts are geared towards synthesizing related compounds with stronger PARACEST effects and higher sensitivity and biocompatibility.

Ratiometric imaging of pH with dicobalt PARACEST MRI probes

2019 Fall National Meeting

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