Rationale and objectives: To investigate the effect of substituent lipophilicity, substituent position, and overall charge on the hepatobiliary clearance and tolerance of a series of aromatic ring-containing macrocyclic Gd chelates to select a candidate compound for evaluation as a hepatobiliary imaging agent.
Methods: Hepatobiliary clearance was studied in rats. Tissue distribution and tolerance were studied in mice. Imaging was performed in cats, rabbits, and Rhesus monkeys using T1-weighted pulse sequences or T1-weighted breath-hold pulse sequences.
Results: All the compounds were excreted bimodally. Gd-2,5-BPA-DO3A (15d) was found to have the optimal combination of hepatobiliary clearance (47% in rats, 29% in mice) and tolerance (minimum lethal dose 5.0 mmol/kg). Initial imaging studies in cats demonstrated the feasibility of Gd-2,5-BPA-DO3A for hepatic imaging. In rabbits with implanted VX-2 adenocarcinoma as a model for metastatic liver disease, Gd-2,5-BPA-DO3A provided sustained hepatic signal intensity (SI) enhancement and lesion conspicuity over a 120-minute imaging time course. In Rhesus monkeys with normal liver function, Gd-2,5-BPA-DO3A afforded sustained hepatic SI enhancement and a time-dependent increase in gallbladder SI over the entire 90-minute imaging time course.
Conclusions: Gd-2,5-BPA-DO3A provides dramatic and sustained SI enhancement of hepatic tissue in cats, rabbits, and Rhesus monkeys that was superior in all respects to the extracellular space MRI agent, Gd-HP-DO3A, that was employed as a control.