The characterization of a new class of hydrophilic liver-targeted agents for gamma-scintigraphy and MRI, consisting, respectively, of [(153)Sm](3+) or
Gd(3+) complexes of
DOTA monoamide or bisamide linked
glycoconjugates (
DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
acid), is reported. In vitro studies show high uptake of radiolabeled [(153)Sm]-DOTAGal(2) by the human hepatocyte
carcinoma cell line Hep G2 containing the
asialoglycoprotein receptor (
ASGP-R), which is decreased to less than 50% by the presence of its high-affinity
ligand asialofetuin (ASF). In vivo biodistribution, gamma-imaging and pharmacokinetic studies on Wistar rats using the [(153)Sm](3+)-labeled
glycoconjugates show a high uptake in the receptor-rich organ liver of the radiolabeled compounds containing terminal galactosyl groups, but very little uptake for those compounds with terminal glycosyl groups. Blocking the receptor in vivo reduced liver uptake by 90%, strongly suggesting that the liver uptake of these compounds is mediated by their binding to the asyaloglycoprotein receptor (
ASGP-R). This study also demonstrated that the valency increase improves the targeting capability of the
glycoconjugates, which is also affected by their topology. However despite the specific liver uptake of the radiolabeled
galactose-bearing multivalent compounds, the animal MRI assessment of the corresponding
Gd(3+) chelates shows liver-to-kidney contrast effects which are not significantly better than those shown by GdDTPA. This probably results from the quick wash-out from the liver of these highly hydrophilic complexes, before they can be sufficiently concentrated within the hepatocytes via receptor-mediated endocytosis.