PET Imaging Analysis with sigma up 64 not equal to u in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

Menkes disease (MD), an X-linked recessive disorder of copper metabolism caused by mutations in the copper-transporting ATP7A gene, results in growth failure and severe neurodegeneration in early childhood. Subcutaneous copper-histidine injection is the standard treatment for MD, but it has limited clinical efficacy. Furthermore, long-term copper injection causes excess copper accumulation in the kidneys, resulting in renal dysfunction. To attempt to resolve this issue, we used PET imaging with 64Cu to investigate the effects of disulfiram on copper biodistribution in living mice serving as an animal model for MD (MD model mice). Macular mice were used as MD model mice, and C3H/He mice were used as wild-type mice. Mice were pretreated with 2 types of chelators (disulfiram, a lipophilic chelator, and d-penicillamine, a hydrophilic chelator) 30 min before 64CuCl2 injection. After 64CuCl2 injection, emission scans covering the whole body were performed for 4 h. After the PET scans, the brain and kidneys were analyzed for radioactivity with ... counting and autoradiography. After copper injection alone, marked accumulation of radioactivity (64Cu) in the liver was demonstrated in wild-type mice, whereas in MD model mice, copper was preferentially accumulated in the kidneys (25.56 plus or minus 3.01 percentage injected dose per gram [%ID/g]) and was detected to a lesser extent in the liver (13.83 plus or minus 0.26 %ID/g) and brain (0.96 plus or minus 0.08 %ID/g). Copper injection with disulfiram reduced excess copper accumulation in the kidneys (14.54 plus or minus 2.68 %ID/g) and increased copper transport into the liver (29.42 plus or minus 0.98 %ID/g) and brain (5.12 plus or minus 0.95 %ID/g) of MD model mice. Copper injection with d-penicillamine enhanced urinary copper excretion and reduced copper accumulation in most organs in both mouse groups. Autoradiography demonstrated that disulfiram pretreatment induced copper transport into the brain parenchyma and reduced copper accumulation in the renal medulla. PET studies with 64Cu revealed that disulfiram had significant effects on the copper biodistribution of MD. Disulfiram increased copper transport into the brain and reduced copper uptake in the kidneys of MD model mice. The application of 64Cu PET for the treatment of MD and other copper-related disorders may be useful in clinical settings. (ProQuest: ... denotes formulae/symbols omitted.)