title: Conjugates of gadolinium complexes to bile acids as hepatocyte-directed contrast agents for magnetic resonance imaging.
abstract: A series of structurally different Gd(III) conjugates incorporating a bile acid moiety have been prepared. Polyaminopolycarboxylic ligands such as diethylenetriaminepentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA) have been selected as chelating subunit for the Gd(III) ion. Cholic acid, cholylglycine, and cholyltaurine have been incorporated as the bile acid moieties. In first generation conjugates the Gd(III) complex is linked to the carboxyl group of cholic acid. Second generation conjugates feature the attachment of the Gd(III) complex to the 3 position of the steroidic backbone of the bile acid. Finally, in third generation conjugates the Gd(III) complex is attached to the epsilon nitrogen atom of cholyllysine. The conjugates are eliminated through the biliary route to a various extent (7.5 to 77% in rats) according to their structural features. Among the most promising terms, a second generation conjugate in which the Gd(III) complex is linked to cholic acid through the 3alpha hydroxy group seems to enter hepatocytes using the Na(+)/taurocholate transporter. Noticeably, some of the second generation conjugates are characterized by very high tolerabilities (LD(50) up to 9.5 mmol/kg) after intravenous administration in mice.
authors.affiliation: Bracco Imaging spa, Milano Research Centre, via E. Folli 50, 20134 Milan, Italy. pier.lucio.anelli@bracco.com
authors.forename: Pier Lucio
authors.initials: PL
authors.lastname: Anelli
authors.forename: Luciano
authors.initials: L
authors.lastname: Lattuada
authors.forename: Vito
authors.initials: V
authors.lastname: Lorusso
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lux
authors.forename: Alberto
authors.initials: A
authors.lastname: Morisetti
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Morosini
authors.forename: Michele
authors.initials: M
authors.lastname: Serleti
authors.forename: Fulvio
authors.initials: F
authors.lastname: Uggeri
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry*; D002614:Chelating Agents / Q000737:chemistry*; D003287:Contrast Media / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D005682:Gadolinium / Q000737:chemistry*; D006439:Hemodynamics / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D007928:Lethal Dose 50; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D004369:Pentetic Acid / Q000737:chemistry; D011817:Rabbits; D051381:Rats
chemical_list: D001647:Bile Acids and Salts; D002614:Chelating Agents; D003287:Contrast Media; D006573:Heterocyclic Compounds, 1-Ring; D009942:Organometallic Compounds; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D004369:Pentetic Acid; D005682:Gadolinium