The design, synthesis, and evaluation of the Copper-Gad (CG) family, a new class of copper-activated magnetic resonance imaging (MRI) contrast agents, are presented. These indicators comprise a Gd3+−DO3A core coupled to various thioether-rich receptors for copper-induced relaxivity switching. In the absence of copper ions, inner-sphere water binding to the Gd3+ chelate is restricted, resulting in low longitudinal relaxivity values (r1 = 1.2−2.2 mM−1 s−1 measured at 60 MHz). Addition of Cu+ to CG2, CG3, CG4, and CG5 and either Cu+ or Cu2+ to CG6 triggers marked enhancements in relaxivity (r1 = 2.3−6.9 mM−1 s−1). CG2 and CG3 exhibit the greatest turn-on responses, going from r1 = 1.5 mM−1 s−1 in the absence of Cu+ to r1 = 6.9 mM−1 s−1 upon Cu+ binding (a 360% increase). The CG sensors are highly selective for Cu+ and/or Cu2+ over competing metal ions at cellular concentrations, including Zn2+ at 10-fold higher concentrations. 17O NMR dysprosium-induced shift and nuclear magnetic relaxation dispersion measurements support a mechanism in which copper-induced changes in the coordination environment of the Gd3+ core result in increases in q and r1. T1-weighted phantom images establish that the CG sensors are capable of visualizing changes in copper levels by MRI at clinical field strengths.

Copper-responsive magnetic resonance imaging contrast agents

GIANOLIO, Eliana;AIME, Silvio;
2009-01-01

Abstract

The design, synthesis, and evaluation of the Copper-Gad (CG) family, a new class of copper-activated magnetic resonance imaging (MRI) contrast agents, are presented. These indicators comprise a Gd3+−DO3A core coupled to various thioether-rich receptors for copper-induced relaxivity switching. In the absence of copper ions, inner-sphere water binding to the Gd3+ chelate is restricted, resulting in low longitudinal relaxivity values (r1 = 1.2−2.2 mM−1 s−1 measured at 60 MHz). Addition of Cu+ to CG2, CG3, CG4, and CG5 and either Cu+ or Cu2+ to CG6 triggers marked enhancements in relaxivity (r1 = 2.3−6.9 mM−1 s−1). CG2 and CG3 exhibit the greatest turn-on responses, going from r1 = 1.5 mM−1 s−1 in the absence of Cu+ to r1 = 6.9 mM−1 s−1 upon Cu+ binding (a 360% increase). The CG sensors are highly selective for Cu+ and/or Cu2+ over competing metal ions at cellular concentrations, including Zn2+ at 10-fold higher concentrations. 17O NMR dysprosium-induced shift and nuclear magnetic relaxation dispersion measurements support a mechanism in which copper-induced changes in the coordination environment of the Gd3+ core result in increases in q and r1. T1-weighted phantom images establish that the CG sensors are capable of visualizing changes in copper levels by MRI at clinical field strengths.
2009
131(24)
8527
8536
http://pubs.acs.org/doi/abs/10.1021/ja900884j
Que EL; Gianolio E; Baker SL; Wong AP; Aime S; Chang CJ
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/78053
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