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

• Published in: Journal of the American Chemical Society 2005-01, Vol.127 (2), p.799-805
• Main Authors: Tóth, Éva, Bolskar, Robert D, Borel, Alain, González, Gabriel, Helm, Lothar, Merbach, André E, Sitharaman, Balaji, Wilson, Lon J
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Chemistry; Contrast Media - chemistry; Contrast media. Radiopharmaceuticals; Electron Spin Resonance Spectroscopy; Exact sciences and technology; Fullerenes - chemistry; Gadolinium - chemistry; Hydrogen-Ion Concentration; Inorganic chemistry and origins of life; Life Sciences; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Medical sciences; Miscellaneous; Organometallic Compounds - chemistry; Oxygen Isotopes; Pharmacology. Drug treatments; Preparations and properties; Protons; Solubility; Water - chemistry
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja044688h

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 τR 298 = 2.6 ns. The proton exchange rate obtained for Gd@C60[C(COOH)2]10 is k ex 298 = 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.