Cyclotron isotopes and radiopharmaceuticals--XXXIII. Synthesis and structural effect of selective biliary excretion of halogenated indotricarbocyanines.

Five indotricarbocyanines of structure I were synthesized and labeled with 131I in the 5 position. The substituent, R, was varied [formula: see text] R = H, F, Cl, Br and I. The dynamics of hepatic uptake and blood clearance of the labeled compounds were determined in mice. Kidney uptake in all cases was negligible. The hepatic excretion displayed 2 components. The initial hepatic disappearance rates of R = H and R = F were 7.3 and 4.5%/min, respectively. The maximum liver activity in mice occurred at 2--5 min and the % remaining in the liver at 0.5 h was 3.6, 8.6, 19, 29 and 47% for R = H, F, Cl, Br and I substitution. It is notable that a small change in the substituent at the 5' position in the molecule has such a pronounced effect. Whether electronic and/or steric effects are controlling the mechanism of hepatobiliary clearance is not obvious. A correlation of the liver activity with the covalent radius of R was noted. The comparative studies were at an injected dose of 0.4--0.6 mumol/kg, and typically at a specific activity of 200 mCi/mol. Loading dose effects were not appreciable under these conditions. Scintigraphic results are reported for dogs and a rabbit. The results suggest that indotricarbocyanines of structure (I) labeled with 123I or with 18F are potential radiopharmaceuticals for dynamic hepatobiliary function studies.