A MOLECULAR RECEPTOR-BINDING CONTRAST AGENT FOR MAGNETIC-RESONANCE-IMAGING OF THE LIVER

Rationale and Objectives. A gadolinium complex of polydiethylenetriami ne pentaacetic acid polyneogalactosyl polylysine (Gd-DTPA-gal-PL) was developed and tested as a paramagnetic contrast agent for magnetic res onance (MR) imaging of the liver. The agent was designed for receptor- mediated uptake by the asialoglycoprotein receptor (ASGP-R), which is unique to hepatocyces and exhibits high specificity for galactose-term inated glycoconjugates. Methods. Polylysine was alkylated with a mixed anhydride of diethylenetriamine pentaacetic acid. This product was co mplexed with gadolinium and N-alkylated with 3-oxopropyl-1-thio-beta-D -galactopyranoside. With this b reaction sequence, we prepared a gadol inium complex consisting of 2284 galactose groups and 858 chelators pe r polylysine having 2136 amino b groups. Hepatic enhancement was teste d by MR imaging of nine rats with liver-implanted mammary adenocarcino ma before and after injection of 20 x 10(-9) mol/kg Gd-DTPA(858)-gal(2 284)-PL(2136). The conjugate was labeled with technetium-99m and teste d (1.5 x 10(-10) mol/kg) for hepatic specificity via nuclear imaging. Results. Mean hepatic enhancement was 86% within 10 min and remained c onstant for 25 min. Hepatic relative intensity exceeded preinjection i ntensities by at least four times the standard deviation of the preinj ection values (p < .01), The tumors, which are devoid of ASGP-R, did n ot exhibit significant enhancement (p > .1). The liver accumulated 90% of the technetium-99m-labeled conjugate. Conclusion. A molecular para magnetic ligand to the asialoglycoprotein receptor has been developed for hepatocyte-specific MR contrast enhancement.