title: Synthesis, characterization, and imaging performance of a new class of macrocyclic hepatobiliary MR contrast agents.
abstract: 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.
authors.affiliation: Bracco Research USA, Princeton, New Jersey 08540, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Marinelli
authors.forename: R
authors.initials: R
authors.lastname: Neubeck
authors.forename: B
authors.initials: B
authors.lastname: Song
authors.forename: T
authors.initials: T
authors.lastname: Wagler
authors.forename: R S
authors.initials: RS
authors.lastname: Ranganathan
authors.forename: K
authors.initials: K
authors.lastname: Sukumaran
authors.forename: P W
authors.initials: PW
authors.lastname: Wedeking
authors.forename: A
authors.initials: A
authors.lastname: Nunn
authors.forename: V M
authors.initials: VM
authors.lastname: Runge
authors.forename: M F
authors.initials: MF
authors.lastname: Tweedle
mesh_terms: 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
chemical_list: D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C103343:gadolinium 2,5-BPA-DO3A; C062402:gadoteridol; D005682:Gadolinium