title: Imaging copper metabolism imbalance in Atp7b (-/-) knockout mouse model of Wilson's disease with PET-CT and orally administered 64CuCl2.
abstract: OBJECTIVE
  This study aims to determine the feasibility and utility of functional imaging of copper metabolism imbalance in Atp7b                            (-/-) knockout mouse model of Wilson's disease (WD) with positron emission tomography-computed tomography (PET-CT) using orally administered copper-64 chloride ((64)CuCl(2)) as a tracer.
  
  
  METHODS
  Atp7b                            (-/-) KO mice (N = 5) were subjected to PET scanning using a hybrid PET-CT scanner, after oral administration of (64)CuCl(2) as a tracer. Time-dependent PET quantitative analysis was performed to assess gastrointestinal absorption and biodistribution of (64)Cu radioactivity in the Atp7b                            (-/-) KO mice, using C57BL wild-type (WT) mice (N = 5) as a normal control. Estimates of human radiation dosimetry were calculated based on biodistribution of (64)Cu radioactivity in live animals.
  
  
  RESULTS
  PET-CT analysis demonstrated higher (64)Cu radioactivity in the liver of Atp7b                            (-/-) knockout mice compared with that in the control C57BL WT mice (p < 0.001), following oral administration of (64)CuCl(2) as a tracer. In addition, (64)Cu radioactivity in the lungs of the Atp7b                            (-/-) knockout mice was slightly higher than those in the control C57BL WT mice (p = 0.01). Despite initially higher renal clearance of (64)Cu, there was no significant difference of (64)Cu radioactivity in the kidneys of the Atp7b                            (-/-) KO mice and the control C57BL WT mice at 24 h post-oral administration of (64)CuCl(2) (p = 0.16). There was no significant difference in low (64)Cu radioactivity in the blood, brain, heart, and muscles between the Atp7b                            (-/-) knockout mice and control C57BL WT mice (p > 0.05). Based on the biodistribution of (64)Cu radioactivity in C57BL WT mice, radiation dosimetry estimates of (64)Cu in normal human subjects were obtained. An effective dose (ED) of 42.4 μSv/MBq (weighted dose over 22 organs) was calculated and the lower large intestines were identified as the critical organ for radiation exposure (120 μGy/MBq for males and 135 μGy/MBq for females). Radiation dosimetry estimates for patients with WD, derived from the biodistribution of (64)Cu in Atp7b                            (-/-) KO mice, showed a slightly lower ED of 37.5 μSv/MBq, with the lower large intestines as the critical organ for radiation exposure (83 μSv/MBq for male and 95 μSv/MBq for female).
  
  
  CONCLUSIONS
  PET-CT quantitative analysis demonstrated an increased level of (64)Cu radioactivity in the liver of Atp7b                            (-/-) KO mice compared with that in the control C57BL WT mice, following oral administration of (64)CuCl(2) as a tracer. The results of this study suggest the feasibility and utility of PET-CT using orally administered (64)CuCl(2) as a tracer ((64)CuCl(2)-PET/CT) for functional imaging of copper metabolism imbalance in WD.
authors.affiliation: Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Hines Blvd, Dallas, TX 75390-8542, USA. Fangyu.Peng@UTSouthwestern.edu
authors.forename: Fangyu
authors.initials: F
authors.lastname: Peng
authors.forename: Svetlana
authors.initials: S
authors.lastname: Lutsenko
authors.forename: Xiankai
authors.initials: X
authors.lastname: Sun
authors.forename: Otto
authors.initials: O
authors.lastname: Muzik
mesh_terms: D000251:Adenosine Triphosphatases / Q000172:deficiency* / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D000818:Animals; D027682:Cation Transport Proteins / Q000172:deficiency* / Q000378:metabolism; D003300:Copper / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D003301:Copper Radioisotopes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006527:Hepatolenticular Degeneration / Q000000981:diagnostic imaging*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D057054:Molecular Imaging / Q000379:methods*; D064847:Multimodal Imaging; D049268:Positron-Emission Tomography; D011874:Radiometry; D013997:Time Factors; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D003301:Copper Radioisotopes; D003300:Copper; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases; C029892:cupric chloride