PRECLINICAL EVALUATION OF GADOBUTROL - A NEW, NEUTRAL, EXTRACELLULAR CONTRAST AGENT FOR MAGNETIC-RESONANCE-IMAGING

The Gd3+-complex of 10-(2,3-dihydroxy-l-hydroxymethylpropyl)- 1,4,7,10 -tetraazacyclododecane-1,4,7-triacetic acid(gadobutrol) is a new, neut ral Gd-chelate for use as an extracellular contrast agent in magnetic resonance imaging (MRI). The blood level in dogs after intravenous (i. v.) injection decreased with a terminal half-life of about 45 min, the clearance was about 3.75 ml/min per kg and the distribution volume of 0.23 If 1/kg suggested an extracellular distribution. Biodistribution experiments in rats revealed that only a very small amount (0.16%) of the dose was left in the body 7 days after i.v. injection. Measurable amounts of Gd could be detected only in the liver, kidneys and bones. The osmolality (0.57 osmol/kg at 0.5 mol/l and 1.39 osmol/kg at 1 mol /l) is in the range of other low osmolality contrast media for MRI. On ly very little interaction with biologically relevant molecules was su ggested by a histamine release test and a lysozyme inhibition test. An i.v.-LD(50),, of 23 mmol/kg in mice combined with a comparatively hig h T-1,-relaxivity (5.6 l/mmol per s at 0.47 T and 6.1 l/mmol per s at 2 T) in plasma promises a high margin of safety. In preliminary imagin g experiments, gadobutrol caused high enhancement in different lesions (cerebral infarct, brain tumor) of the rat. Tripling of the typical c linical dose of 0.1 mmol/kg was shown to provide additional diagnostic gain in lesions of this type.