Selective Binding and Quantitation of Calcium with a Cobalt-Based Magnetic Resonance Probe

We report a cobalt-based paramagnetic chemical exchange saturation transfer (PARACEST) magnetic resonance (MR) probe that is able to selectively bind and quantitate the concentration of Ca2+ ions under physiological conditions. The parent LCo complex features CEST-active carboxamide groups and an uncoordinated crown ether moiety in close proximity to a high-spin pseudo-octahedral CoII center. Addition of Na+, Mg2+, K+, and Ca2+ leads to binding of these metal ions within the crown ether. Single-crystal X-ray diffraction and solid-state magnetic measurements reveal the presence of a cation-specific coordination environment and magnetic anisotropy of CoII, with axial zero-field splitting parameters for the Na+- and Ca2+-bound complexes differing by over 90%. Owing to these differences, solution-based measurements under physiological conditions indicate reversible binding of Na+ and Ca2+ to give well-separated CEST peaks at 69 and 80 ppm for [LCoNa]+ and [LCoCa]2+, respectively. Dissociation constants for different cation-bound complexes of LCo, as determined by 1H NMR spectroscopy, demonstrate high selectivity toward Ca2+. This finding, in conjunction with the large excess of Na+ in physiological environments, minimizes interference from related cations, such as Mg2+ and K+. Finally, variable-[Ca2+] CEST spectra establish the ratio between the CEST peak intensities for the Ca2+- and Na+-bound probes (CEST80 ppm/CEST69 ppm) as a measure of [Ca2+], providing the first example of a ratiometric quantitation of Ca2+ concentration using PARACEST. Taken together, these results demonstrate the ability of transition metal PARACEST probes to afford a concentration-independent measure of [Ca2+] and provide a new approach for designing MR probes for cation sensing.