title: PET imaging analysis with 64Cu in disulfiram treatment for aberrant copper biodistribution in Menkes disease mouse model.
abstract: 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 (64)Cu to investigate the effects of disulfiram on copper biodistribution in living mice serving as an animal model for MD (MD model mice).
  
  
  METHODS
  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 (64)CuCl2 injection. After (64)CuCl2 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 γ counting and autoradiography.
  
  
  RESULTS
  After copper injection alone, marked accumulation of radioactivity ((64)Cu) in the liver was demonstrated in wild-type mice, whereas in MD model mice, copper was preferentially accumulated in the kidneys (25.56 ± 3.01 percentage injected dose per gram [%ID/g]) and was detected to a lesser extent in the liver (13.83 ± 0.26 %ID/g) and brain (0.96 ± 0.08 %ID/g). Copper injection with disulfiram reduced excess copper accumulation in the kidneys (14.54 ± 2.68 %ID/g) and increased copper transport into the liver (29.42 ± 0.98 %ID/g) and brain (5.12 ± 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.
  
  
  CONCLUSIONS
  PET studies with (64)Cu 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 (64)Cu PET for the treatment of MD and other copper-related disorders may be useful in clinical settings.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Nomura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nozaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Hamazaki
authors.forename: Taisuke
authors.initials: T
authors.lastname: Takeda
authors.forename: Eiichi
authors.initials: E
authors.lastname: Ninomiya
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kudo
authors.forename: Emi
authors.initials: E
authors.lastname: Hayashinaka
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Wada
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hiroki
authors.forename: Chie
authors.initials: C
authors.lastname: Fujisawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kodama
authors.forename: Haruo
authors.initials: H
authors.lastname: Shintaku
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry; D003300:Copper / Q000737:chemistry / Q000493:pharmacokinetics*; D003301:Copper Radioisotopes; D004195:Disease Models, Animal; D004221:Disulfiram / Q000737:chemistry*; D005720:Gamma Rays; D007668:Kidney / Q000000981:diagnostic imaging; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism; D007706:Menkes Kinky Hair Syndrome / Q000000981:diagnostic imaging* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D010396:Penicillamine / Q000737:chemistry; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D013997:Time Factors; D014018:Tissue Distribution; D051598:Whole Body Imaging
chemical_list: D002614:Chelating Agents; D003301:Copper Radioisotopes; D019275:Radiopharmaceuticals; D003300:Copper; D010396:Penicillamine; D004221:Disulfiram
keywords: Menkes disease; PET; copper; d-penicillamine; disulfiram