Metal Ion Sensing Using Ion Chemical Exchange Saturation Transfer ¹⁹F Magnetic Resonance Imaging

Although metal ions are involved in a myriad of biological processes, noninvasive detection of free metal ions in deep tissue remains a formidable challenge. We present an approach for specific sensing of the presence of Ca²⁺ in which the amplification strategy of chemical exchange saturation transfer (CEST) is combined with the broad range of chemical shifts found in ¹⁹F NMR spectroscopy to obtain magnetic resonance images of Ca²⁺. We exploited the chemical shift change (Δω) of ¹⁹F upon binding of Ca²⁺ to the 5,5′-difluoro derivative of 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (5F-BAPTA) by radiofrequency labeling at the Ca²⁺-bound ¹⁹F frequency and detection of the label transfer to the Ca²⁺-free ¹⁹F frequency. Through the substrate binding kinetics we were able to amplify the signal of Ca²⁺ onto free 5F-BAPTA and thus indirectly detect low Ca²⁺ concentrations with high sensitivity.