Hepatocyte-directed MR contrast agents. Can we take advantage of bile acids?
A series of gadolinium complexes conjugated to bile acids was prepared and investigated as possible hepatospecific MR imaging contrast agents. In the design of such compounds, features such as the nature of the bile acid, the site of conjugation on the bile acid skeleton, and the global charge of the conjugate were taken into account. Relaxivity measurements carried out in human serum indicate interaction of the conjugates with human serum proteins; even small structural variations significantly affect relaxivity in human serum. Pharmacokinetic data (biliary elimination in the range of 18.4-45.6%) show that bile acids can be used as address moieties to transport gadolinium complexes through hepatocytes. For a homogeneous series of compounds, differing only in the bile acid residue conjugated, it was unexpectedly found that cholic acid is twice as efficient an address moiety as cholylglycine or cholyltaurine. Preliminary results show that none of the conjugates is transported through the basolateral membrane of hepatocytes by the Na+/taurocholate carrier.
Anelli
P L
PL
Milano Research Center, Bracco SpA, Milan, Italy.
Calabi
L
L
de Haën
C
C
Lattuada
L
L
Lorusso
V
V
Maiocchi
A
A
Morosini
P
P
Uggeri
F
F
D000818:Animals; D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000032:analysis / Q000138:chemical synthesis / Q000493:pharmacokinetics; D003287:Contrast Media / Q000032:analysis / Q000138:chemical synthesis / Q000493:pharmacokinetics; D004337:Drug Carriers; D015195:Drug Design; D005682:Gadolinium / Q000032:analysis / Q000493:pharmacokinetics; D006801:Humans; D008099:Liver / Q000033:anatomy & histology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors
D001647:Bile Acids and Salts; D003287:Contrast Media; D004337:Drug Carriers; D005682:Gadolinium