Positron emission tomography of copper metabolism in the Atp7b ^-/- knock-out mouse model of Wilson's disease

Purpose: This study aims to determine feasibility and utility of copper-64(II) chloride ( ⁶⁴CuCl ₂) as a tracer for positron emission tomography (PET) of copper metabolism imbalance in human Wilson's disease (WD). Procedures: Atp7b ^-/- mice, a mouse model of human WD, were injected with ⁶⁴CuCl ₂intravenously 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 ⁶⁴CuCl ₂ in human subjects. The results suggest feasibility of utilizing ⁶⁴CuCl ₂ as a tracer for noninvasive assessment of copper metabolism in WD with PET.