Lipophilic Group-Modified Manganese(II)-Based Contrast Agents for Vascular and Hepatobiliary Magnetic Resonance Imaging

Effective vascular and hepatic enhancement and better
safety are
the key drivers for exploring gadolinium-free hepatobiliary contrast
agents. Herein, a facile strategy proposes that the high lipophilicity
may be favorable to enhancing sequentially vascular and hepatobiliary
signal intensity based on the structure–activity relationship
that both hepatic uptake and interaction with serum albumins partly
depend on lipophilicity. Therefore, 11 newly synthesized derivatives
of manganese o-phenylenediamine-N,N,N′,N′-tetraacetic acid (MnLs) were evaluated as vascular and hepatobiliary
agents. The maximum signal intensities of the heart, liver, and kidneys
were strongly correlated with log P, a key indicator
of lipophilicity. The most lipophilic agent, MnL6, showed
favorable relaxivity when binding with serum albumin, good vascular
enhancement, rapid excretion, and reliable hepatobiliary phases comparable
to a classic hepatobiliary agent, gadolinium ethoxybenzyl diethylenetriamine
pentaacetic acid (Gd-EOB-DTPA) for in vivo liver tumor imaging. Inhibition
experiments confirmed the hepatic targeting of MnL6 is
mediated by organic anion-transporting polypeptides.