Thirty-three HIDA (hepatobiliary IDA) derivatives were tested and correlations drawn between physicochemical parameters, structural effects, and in vivo characteristics. Capacity factors of the ligands on reverse-phase HPLC were used as a measure of lipophilicity, and to predict protein binding and in vivo distribution of the complexes. Fragmentary pi values were used to derive theoretical lipophilicities, which showed that ortho substituents have reduced lipophilic activity, probably because of self-shielding. Ortho substitution was found to affect hepatocellular transit times. Various combinations of substituents with the desired overall lipophilicity were tested. The best compound, Tc-3-bromo-2,4,6-trimethyl HIDA, possessed high hepatic specificity, and rapid hepatocellular transit; it was also resistant to competition for hepatobiliary excretion from bilirubin.