Redox-active paraCEST (paramagnetic Chemical Exchange Saturation Transfer) MRI agents utilizing redox properties of transition metal (TM) ions will be reported. The most promising Co(II)/Co(III) and Fe(II)/Fe(III) agents are obtained with a six-coordinate ligand based on TACN macrocycle containing three H-pyrazol-3-ylmethyl pendants. While in paramagnetic MRI-active Co(II) state, the exchangeable pyrazole NH protons give highly shifted CEST peak at +135 ppm from bulk water. Upon reaction with oxygen, this paramagnetic MRI-active Co(II) agent switches to diamagnetic MRI-silent Co(III) complex. This redox switch can be turned back on to MRI-active Co(II) state by reducing it with dithionite, glutathione, or cysteine. Experiments in rabbit serum demonstrated that CEST signal intensity did not change over a period of 48h at pH 7.0 and 37oC. While the CEST effect had similar intensity and a peak shift of +135 ppm and +133 ppm in HEPES buffer and serum, respectively, a new CEST peak at +62 ppm was observed in serum (Fig.1).Both the Co(II) and Co(III) complexes were found to be kinetically inert towards dissociation in the presence of biologically relevant cations, such as Ca2+ and Zn2+, and anions, such as PO43-, CO32-, and Cl-. These complexes are also kinetically inert over a wide range of pH 5.0-8.5. The combination of a highly-shifted CEST peak, and redox-responsiveness make TM-paraCEST promising for in vivo mapping of disease states that involve reducing environment and low levels of pO2.

Redox-activated transition metal paraCEST contrast agents

247th National Meeting (2014)

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