RATIONALE AND OBJECTIVES:The authors evaluated compact dimers, a new class of molecule designed to reduce the osmolality of concentrated solutions of x-ray contrast media without increasing their viscosity. MATERIALS AND METHODS:Molecular modeling was used to design a new hexaiodo dimeric structure with low viscosity and good shielding of hydrophobic areas. This design ends in the synthesis of different prototypes, the structure of which was characterized by a single bond between two perpendicular rings and the presence of tertiary amides. The validity of this approach was investigated with measurements of physicochemical properties (viscosity, osmolality, logP) and pharmacologic studies (urinary and biliary excretion, intravenous and intracerebral medial lethal dose). RESULTS:Solutions of the compact dimers at a concentration of 350 mg of iodine per milliliter combine osmolalities that are close to that of blood with viscosities at ambient temperature nearly half those of commercially available dimers. Furthermore, these new compounds have a tolerance level comparable with that of currently used nonionic media (intravenous median lethal dose, > 17.5 g of iodine per kilogram). CONCLUSION:The three-dimensional structure of the compact dimers has made it possible to control both physicotoxicity and chemotoxicity by combining isotonicity and low viscosity with good tolerance.

The chemotoxicity of iodinated contrast agents is essentially related to the spatial accessibilty of lipophilic and polarizable iodine atoms. This accessibility was examined in iobitridol by HPLC and 1H- and 13C-NMR spectroscopy,taking into account both the static distribution of the hydrophilic groups around the triiodinated benzene ring and in particular the dynamic modulation of this distribution. The aim of this latter parameter is to prevent distortion of the hydrophilic sphere of nonionic agents when faced with a hydrophobic environment. Iobitridol is characterized by 2 tertiary carbamoyl substituents whose high rotation barriers (deltaG*353=27.6 kcal for E/Z-rotation and deltaG*345=17.3 kcal for syn/anti-rotation) stabilize the hydrophilic sphere. The 3rd dihydroxylated anilide substituent does not undergo SMILES rearrangement and provides iobitridol with its even hydrophilic distribution. Iobitridol presents remarkable chemical solubility (>140% m/v) and stability. The iobitridol molecule was specifically designed with the aim of stabilizing the hydrophilic sphere around the triiodinated benzene ring, therefore permanently masking access to the iodine atoms. This new concept represents a further step forward towards the synthesis of new iodinated contrast agents which should be totally inert vis-a-vis biological membranes and proteins.

Purpose. The regular distribution in space and the stability in time of the hydrophilic sphere surrounding iobitridol were investigated. This is a novel yet important concept in the design of polyiodinated contrast agents since such a sphere is meant to hide their hydrophobic core and thus prevent hydrophobic interactions with biomacromolecules and hence chemotoxicity.