Copper-responsive magnetic resonance imaging contrast agents.
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 Gd(3+)-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 Gd(3+) chelate is restricted, resulting in low longitudinal relaxivity values (r(1) = 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 Cu(2+) to CG6 triggers marked enhancements in relaxivity (r(1) = 2.3-6.9 mM(-1) s(-1)). CG2 and CG3 exhibit the greatest turn-on responses, going from r(1) = 1.5 mM(-1) s(-1) in the absence of Cu(+) to r(1) = 6.9 mM(-1) s(-1) upon Cu(+) binding (a 360% increase). The CG sensors are highly selective for Cu(+) and/or Cu(2+) over competing metal ions at cellular concentrations, including Zn(2+) at 10-fold higher concentrations. (17)O NMR dysprosium-induced shift and nuclear magnetic relaxation dispersion measurements support a mechanism in which copper-induced changes in the coordination environment of the Gd(3+) core result in increases in q and r(1). T(1)-weighted phantom images establish that the CG sensors are capable of visualizing changes in copper levels by MRI at clinical field strengths.
Que
Emily L
EL
Department of Chemistry, University of California, Berkeley, California 94720, USA.
Gianolio
Eliana
E
Baker
Suzanne L
SL
Wong
Audrey P
AP
Aime
Silvio
S
Chang
Christopher J
CJ
D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*
D003287:Contrast Media; D009942:Organometallic Compounds; D003300:Copper