title: A potential Dubin-Johnson syndrome imaging agent: synthesis, biodistribution, and microPET imaging.
abstract: Dubin-Johnson syndrome (DJS) is caused by a deficiency of the human canalicular multispecific organic anion transporter (cMOAT). A new lipophilic copper-64 complex of 1,4,7-tris(carboxymethyl)-10-(tetradecyl)-1,4,7,10-tetraazadodecane (5) was prepared and evaluated for potential as a diagnostic tool for DJS. The prepared ligand was labeled with (64)Cu citrate in high radiochemical purity. In vivo uptake and clearance of the complex was determined through biodistribution studies using normal Sprague-Dawley rats and mutant cMOAT-deficient (TR(-)) rats. In normal rats, the radioactive copper complex was cleared quickly from the body exclusively through the hepatic pathway. The (64)Cu complex was taken up rapidly by the liver and quickly excreted into the small intestine and then the upper large intestine, whereas <1% ID/organ was found in the kidney at all time points post injection. Whereas activity was accumulated continuously in the liver of TR(-) rats, it was not excreted into the small intestine. MicroPET studies of normal and TR(-) rats were consistent with biodistribution data and showed dramatically different images. This study strongly suggests that cMOAT is involved in excretion of (64)Cu-5. The significant difference between the biodistribution data and microPET images of the normal and TR(-) rats demonstrates that this new (64)Cu complex may allow noninvasive diagnosis of DJS in humans.
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St. Louis, MO 63110, USA.
authors.forename: Jeongsoo
authors.initials: J
authors.lastname: Yoo
authors.forename: David E
authors.initials: DE
authors.lastname: Reichert
authors.forename: Joonyoung
authors.initials: J
authors.lastname: Kim
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Anderson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welch
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000818:Animals; D001671:Biochemistry / Q000379:methods; D003301:Copper Radioisotopes; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006801:Humans; D007553:Isotope Labeling; D007566:Jaundice, Chronic Idiopathic / Q000175:diagnosis*; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000085:Acetates; D003301:Copper Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C436944:1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane