We present the synthesis and characterization of Copper-Gad-7 (CG7), a new copper-activated magnetic resonance imaging (MRI) contrast agent that possesses a Gd3+–DO3A scaffold with an appended thioether-rich receptor for copper recognition. Installation of additional carboxylate groups on the periphery of the CG scaffold affords a practical strategy to increase the absolute relaxivity of these types of copper-responsive MRI sensors as well as reduce their sensitivity to biologically abundant anions. Due in large part to restricted access of inner-sphere water molecules to the paramagnetic Gd3+ core, in the absence of copper ions, CG7 exhibits a relatively low relaxivity value of r1 = 2.6 mM−1 s−1; addition of Cu+ triggers a 340% enhancement in relaxivity to r1 = 11.4 mM−1 s−1. For comparison, the relaxivity of the analogous CG2 sensor without peripheral carboxylates increases from r1 = 1.5 to 6.9 mM−1 s−1 upon Cu+ binding. CG7 features high selectivity for Cu+ over a range of biologically relevant metal ions, including the cellular abundant alkali and alkaline earth cations and d-block ions Zn2+ and Cu2+. Moreover, the Cu+-response of the CG7 sensor is not significantly affected by bicarbonate, phosphate, citrate, and lactate anions at cellular levels. 17O NMR dysprosium-induced shift (DIS) and nuclear magnetic relaxation dispersion (NMRD) experiments suggest that the origin of the improved anion compatibility of CG7 is a reduced q modulation compared to previous members of the CG family, and T1-weighted phantom images confirm that CG7 can monitor changes in copper levels by MRI at clinically relevant field strengths.
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