title: PET with 64Cu-histidine for noninvasive diagnosis of biliary copper excretion in Long-Evans cinnamon rat model of Wilson disease.
abstract: Excretion of copper into bile requires the copper transporter Atp7b, which is deficient in Wilson disease. We hypothesized that a radiocopper-histidine complex would be effective for diagnosing Wilson disease by molecular imaging and tested this hypothesis in the Long-Evans cinnamon (LEC) rat model with Atp7b deficiency.
  
  
  METHODS
  We complexed (64)Cu to l-histidine and analyzed clearance from blood, uptake in tissues, and excretion in bile of healthy Long-Evans agouti (LEA) rats versus LEC rats modeling Wilson disease. Sixty-minute dynamic PET recordings were obtained in LEA and LEC rats. Possible effects of acute and chronic liver injury induced by carbon tetrachloride were studied in LEA rats. Atp7b deficiency in LEC rats was reconstituted by transplantation of healthy cells to establish the specificity of findings.
  
  
  RESULTS
  Examination of blood, tissue, and bile showed that in healthy rats, radiocopper was incorporated in the liver, followed by rapid excretion in bile. Corresponding blood, tissue, and bile studies in LEC rats showed incorporation of radiocopper in the liver but without copper excretion in bile, leading to hepatic retention of the radiotracer. PET showed onset of copper clearance in the liver of LEA rats, whereas liver copper content progressively increased in LEC rats during the 1-h period. Hepatic radiocopper excretion was not altered by either acute or chronic liver injury. In LEC rats with liver repopulation by transplanted healthy hepatocytes, excretion of radiocopper confirmed that Atp7b was responsible for this effect.
  
  
  CONCLUSIONS
  Imaging with the radiocopper-histidine complex successfully identified Atp7b-dependent biliary copper excretion. This principle will advance molecular imaging for Wilson disease.
authors.affiliation: Marion Bessin Liver Research Center, Department of Medicine and Pathology, Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bahde
authors.forename: Sorabh
authors.initials: S
authors.lastname: Kapoor
authors.forename: Kuldeep K
authors.initials: KK
authors.lastname: Bhargava
authors.forename: Michael L
authors.initials: ML
authors.lastname: Schilsky
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Palestro
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D003301:Copper Radioisotopes; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000637:transplantation; D006527:Hepatolenticular Degeneration / Q000000981:diagnostic imaging* / Q000378:metabolism; D006639:Histidine / Q000493:pharmacokinetics*; D008107:Liver Diseases / Q000378:metabolism; D008657:Metabolic Clearance Rate; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D011916:Rats, Inbred F344; D020332:Rats, Inbred LEC
chemical_list: D003301:Copper Radioisotopes; D006639:Histidine; D003300:Copper