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.