Evaluation of N,N′-bis-dimethyldiatrizoic acid analogs as liver imaging agents

The detection of focal hepatic lesions by computed tomography using water-soluble ionic (ICM) or nonionic (NICM) contrast agents (CA) is a widely used radiological procedure (1). Limitations stemming from nonspecific tissue distribution and short residence time, which render small lesions undetectable, make this procedure less than optimal for hepatic imaging. Liver specificity and increased residence time provide agents of higher sensitivity (2), in addition to enabling the requisite longer imaging window. Examples of such agents that target the nonparenchymal (Kupffer) system are ethiodized-oil emulsions (3), iodinated starch particles (4), liposomat CA formulations (5), water-insoluble esters of ICM (6), and triiodinated PEG-based micelles (7). However, this approach is accompanied by unacceptable side effects (1) and hence has been abandoned. An alternative approach targeting the parenchymal (hepatocytes) system using polyiodinated triglycerides is currently under active investigation (8). In this paper we present another approach for the development of liver-specific agents by the hydrophobic modification of diatrizoic acid (la). Hydrophobic modification is known (9,10) to favor liver uptake by promoting plasma protein binding and thereby reducing kidney excretion. Amphophils, mimicking bile acids (11), are also taken up by hepatocytes by specific transport pathways. Our approach for the synthesis of hydrophobic and amphophilic diatrizoate derivatives consisted in N,N' bis-methylation to obtain N,N'-bis-