title: Positron emission tomography of copper metabolism in the Atp7b-/- knock-out mouse model of Wilson's disease.
abstract: OBJECTIVE
  This study aims to determine feasibility and utility of copper-64(II) chloride (⁶⁴CuCl₂) as a tracer for positron emission tomography (PET) of copper metabolism imbalance in human Wilson's disease (WD).
  
  
  METHODS
  Atp7b⁻/⁻ mice, a mouse model of human WD, were injected with ⁶⁴CuCl₂ intravenously and subjected to PET scanning using a hybrid PET-CT (computerized tomography) scanner, with the wild-type C57BL mice as a normal control. Quantitative PET analysis was performed to determine biodistribution of ⁶⁴Cu radioactivity and radiation dosimetry estimates of ⁶⁴Cu were calculated for PET of copper metabolism in humans.
  
  
  RESULTS
  Dynamic PET analysis revealed increased accumulation and markedly reduced clearance of ⁶⁴Cu from the liver of the Atp7b⁻/⁻ mice, compared to hepatic uptake and clearance of ⁶⁴Cu in the wild-type C57BL mice. Kinetics of copper clearance and retention was also altered for kidneys, heart, and lungs in the Atp7b/⁻ mice. Based on biodistribution of ⁶⁴Cu in wild-type C57BL mice, radiation dosimetry estimates of ⁶⁴Cu in normal human subjects were obtained, showing an effective dose (ED) of 32.2 μ (micro)Sv/MBq (weighted dose over 22 organs) and the small intestine as the critical organ for radiation dose (61 μGy/MBq for males and 69 μGy/MBq for females). Radiation dosimetry estimates for the patients with WD, based on biodistribution of ⁶⁴Cu in the Atp7b⁻/⁻ mice, showed a similar ED of 32.8 μ (micro)Sv/MBq (p = 0.53), with the liver as the critical organ for radiation dose (120 μSv/MBq for male and 161 μSv/MBq for female).
  
  
  CONCLUSIONS
  Quantitative PET analysis demonstrates abnormal copper metabolism in the mouse model of WD with improved time-resolution. Human radiation dosimetry estimates obtained in this preclinical study encourage direct radiation dosimetry of ⁶⁴CuCl₂ in human subjects. The results suggest feasibility of utilizing ⁶⁴CuCl₂ as a tracer for noninvasive assessment of copper metabolism in WD with PET.
authors.affiliation: Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry 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* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D003301:Copper Radioisotopes; D000073840:Copper-Transporting ATPases; D006527:Hepatolenticular Degeneration / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D049268:Positron-Emission Tomography / Q000379:methods*; D011874:Radiometry; D014018:Tissue Distribution
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