title: A copper-activated magnetic resonance imaging contrast agent with improved turn-on relaxivity response and anion compatibility.
abstract: We present the synthesis and characterization of Copper-Gad-7 (CG7), a new copper-activated magnetic resonance imaging (MRI) contrast agent that possesses a Gd(3+)-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 Gd(3+) core, in the absence of copper ions, CG7 exhibits a relatively low relaxivity value of r(1) = 2.6 mM(-1) s(-1); addition of Cu(+) triggers a 340% enhancement in relaxivity to r(1) = 11.4 mM(-1) s(-1). For comparison, the relaxivity of the analogous CG2 sensor without peripheral carboxylates increases from r(1) = 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 Zn(2+) and Cu(2+). Moreover, the Cu(+)-response of the CG7 sensor is not significantly affected by bicarbonate, phosphate, citrate, and lactate anions at cellular levels. (17)O 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 T(1)-weighted phantom images confirm that CG7 can monitor changes in copper levels by MRI at clinically relevant field strengths.
authors.affiliation: Department of Chemistry, University of California, Berkeley, CA 94720, USA.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Que
authors.forename: Eliana
authors.initials: E
authors.lastname: Gianolio
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Baker
authors.forename: Silvio
authors.initials: S
authors.lastname: Aime
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Chang
mesh_terms: D000838:Anions / Q000737:chemistry*; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D004419:Dysprosium / Q000737:chemistry; D008279:Magnetic Resonance Imaging; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D000838:Anions; D003287:Contrast Media; D009942:Organometallic Compounds; D004419:Dysprosium; D003300:Copper