Diagnosis of abnormal biliary copper excretion by positron emission tomography with targeting of 64Copper-asialofetuin complex in LEC rat model of Wilson’s disease

摘要

Identification by molecular imaging of key processes in handling of transition state metals, such as copper (Cu), will be of considerable clinical value. For instance, the ability to diagnose Wilson’s disease with molecular imaging by identifying copper excretion in an ATP7B-dependent manner will be very significant. To develop highly effective diagnostic approaches, we hypothesized that targeting of radiocopper via the asialoglycoprotein receptor will be appropriate for positron emission tomography, and examined this approach in a rat model of Wilson’s disease. After complexing sup64/supCu to asialofetuin we studied handling of this complex compared with sup64/supCu in healthy LEA rats and diseased homozygous LEC rats lacking ATP7B and exhibiting hepatic copper toxicosis. We analyzed radiotracer clearance from blood, organ uptake, and biliary excretion, including sixty minute dynamic positron emission tomography recordings. In LEA rats, sup64/supCu-asialofetuin was better cleared from blood followed by liver uptake and greater biliary excretion than sup64/supCu. In LEC rats, sup64/supCu-asialofetuin activity cleared even more rapidly from blood followed by greater uptake in liver, but neither sup64/supCu-asialofetuin nor sup64/supCu appeared in bile. Image analysis demonstrated rapid visualization of liver after sup64/supCu-asialofetuin administration followed by decreased liver activity in LEA rats while liver activity progressively increased in LEC rats. Image analysis resolved this difference in hepatic activity within one hour. We concluded that sup64/supCu-asialofetuin complex was successfully targeted to the liver and radiocopper was then excreted into bile in an ATP7B-dependent manner. Therefore, hepatic targeting of radiocopper will be appropriate for improving molecular diagnosis and for developing drug/cell/gene therapies in Wilson’s disease.