J. Am. Chem. Soc., 127 (2), 799 -805, 2005. 10.1021/ja044688h S0002-7863(04)04688-8
Web Release Date: December 17, 2004

Copyright © 2004 American Chemical Society

Water-Soluble Gadofullerenes: Toward High-Relaxivity, pH-Responsive MRI Contrast Agents

Éva Tóth,* Robert D. Bolskar, Alain Borel, Gabriel González, Lothar Helm, André E. Merbach, Balaji Sitharaman, and Lon J. Wilson*

Contribution from the Laboratoire de Chimie Inorganique et Bioinorganique, Ecole Polytechnique Fédérale de Lausanne, EPFL-BCH, CH-1015 Lausanne, Switzerland; TDA Research, Inc., 12345 West 52nd Avenue, Wheat Ridge, Colorado 80033; Departament de Química Inorgànica, Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain; and Department of Chemistry, Center for Nanoscale Science and Technology, Center for Biological and Environmental Nanotechnology, Rice University, Houston, Texas 77251-1892

eva.jakabtoth@epfl.ch

Received September 2, 2004

Abstract:

The water-soluble endohedral gadofullerene derivatives, Gd@C60(OH)x and Gd@C60[C(COOH)2]10, have been characterized with regard to their MRI contrast agent properties. Water-proton relaxivities have been measured in aqueous solution at variable temperature (278-335 K), and for the first time for gadofullerenes, relaxivities as a function of magnetic field (5 × 10-4 to 9.4 T; NMRD profiles) are also reported. Both compounds show relaxivity maxima at high magnetic fields (30-60 MHz) with a maximum relaxivity of 10.4 mM-1 s-1 for Gd@C60[C(COOH)2]10 and 38.5 mM-1 s-1 for Gd@C60(OH)x at 299 K. Variable-temperature, transverse and longitudinal 17O relaxation rates, and chemical shifts have been measured at three magnetic fields (B = 1.41, 4.7, and 9.4 T), and the results point exclusively to an outer sphere relaxation mechanism. The NMRD profiles have been analyzed in terms of slow rotational motion with a long rotational correlation time calculated to be R298 = 2.6 ns. The proton exchange rate obtained for Gd@C60[C(COOH)2]10 is kex298 = 1.4 × 107 s-1 which is consistent with the exchange rate previously determined for malonic acid. The proton relaxivities for both gadofullerene derivatives increase strongly with decreasing pH (pH: 3-12). This behavior results from a pH-dependent aggregation of Gd@C60(OH)x and Gd@C60[C(COOH)2]10, which has been characterized by dynamic light scattering measurements. The pH dependency of the proton relaxivities makes these gadofullerene derivatives prime candidates for pH-responsive MRI contrast agent applications.

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