Contrast agent design: Some aspects on the synthesis of water soluble contrast agents of low osmolality

Abstract

All the modern radiographic contrast agents (diatrizoate, iodamide, iothalamate, metrizoate) for use in studies of the blood vessels (angiography) consist of a benzene ring, in which three hydrogen atoms have been replaced by three firmly-bound iodine atoms. In order to provide high water solubility and low toxicity one of the remaining three hydrogen atoms in the benzene ring has been replaced by a salt-forming carboxyl group while two of them have been replaced by other hydrophilic radicals, each containing a chain of one nitrogen and two to three carbon atoms. A high absorption of X-rays requires high iodine concentration and consequently the angiographic contrast agents are very concentrated solutions with osmolalities in the magnitude of 1500 to 2500 mOsm. For fast injection through narrow catheters, an angiographic contrast agent should have a low viscosity. Several of the toxic effects of angiographic contrast agents are related to their high osmolality. There is thus a need for a water-soluble contrast agent for which the ratio osmolality/iodine content is lower than for the contrast agents available today. The ratio osmolality/iodine content could be decreased if oligomers or polymers of the modern contrast agents were synthesized. However, measurements of the viscosity of such agents showed that already oligomers had a high viscosity. A discussion of physico-chemical laws gives the following conclusions. (1) The viscosity of polymeric contrast agents could be kept at a minimum if the axial ratio of the contrast medium molecule is kept as close to one as possible. (2) The synthesis of a non-electrolytic contrast agent, that does not contain any salt-forming radicals, raises the possibility of combining low osmolality with low viscosity in a water soluble contrast agent. A monomer of a non-electrolytic contrast agent could get a lower osmolality than a polymer of an electrolytic contrast agent.