Synthesis, characterization, and imaging performance of a new class of macrocyclic hepatobiliary MR contrast agents.
OBJECTIVE
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.
Marinelli
E R
ER
Bracco Research USA, Princeton, New Jersey 08540, USA.
Neubeck
R
R
Song
B
B
Wagler
T
T
Ranganathan
R S
RS
Sukumaran
K
K
Wedeking
P W
PW
Nunn
A
A
Runge
V M
VM
Tweedle
M F
MF
D000818:Animals; D001659:Biliary Tract / Q000033:anatomy & histology; D002415:Cats; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry; D005682:Gadolinium; D006571:Heterocyclic Compounds; D008099:Liver / Q000033:anatomy & histology; D008114:Liver Neoplasms, Experimental / Q000473:pathology; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D051379:Mice; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry; D011817:Rabbits; D051381:Rats; D014018:Tissue Distribution
D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C103343:gadolinium 2,5-BPA-DO3A; C062402:gadoteridol; D005682:Gadolinium