64Cu-Labeled l-histidine

Excerpt

Copper (Cu) metal is not commonly available in the environment, but is an important micronutrient that is required for the activity of many mammalian intracellular enzymes (1). Presence of free Cu is toxic for the cell because it can exist in the oxidized (Cu(I)) or the reduced (Cu(II)) forms, and conversion of Cu(I) to Cu(II) under physiological conditions leads to the generation of reactive oxygen species that disrupt the normal cellular pathways. Therefore, mammals tend to maintain extremely low concentrations of the metal within tissues, which is achieved by transporting it out of the cells into the circulatory system and eventually into the bile for excretion through the hepatobiliary system (2). In the liver, the Cu transporter 1 helps in the passage of the metal into the hepatocytes, and the ATP7B gene product, a Cu-transporting polypeptide (for details, see the Related Resource Links section), is responsible for removing Cu from the liver cells for excretion into the bile. However, genetic mutations in ATP7B result in impaired excretion and intracellular utilization of the metal in mammals. This culminates in accumulation of toxic amounts of Cu in various organs, particularly the liver and the brain, and leads to the development of Wilson disease (WD) in humans (3).

Although treatment is available for the therapy of WD, it is challenging to diagnose the disease because there are many variations in the symptoms of this condition (2, 3). Currently WD is diagnosed only after a liver biopsy; the Cu content of the hepatic tissues can be best determined with atomic force spectroscopy, a technique that is not commonly available in the clinic (4). The unsuccessful use of ⁶⁴Cu for the diagnosis of WD has been attributed to the wide distribution of the element in the body and to the constant release and reuptake of the metal by different organs in the body (4). Bahde et al. hypothesized that, because the Cu excretion process is ATP7B-dependent, the use of ⁶⁴Cu complexed with histidine ([⁶⁴Cu]-His) was probably suitable for the diagnosis of WD because it was shown that [⁶⁴Cu]-His can be utilized to determine the ⁶⁴Cu biliary excretion capacity in animals (4). The biodistribution of [⁶⁴Cu]-His was investigated in Long-Evans cinnamon (LEC) rats, which have a mutated ATP7B and show a very high accumulation of Cu in the liver, and this biodistribution was compared with the biodistribution in Long-Evans agouti (LEA) rats that have a normally functioning ATP7B. In addition, dynamic positron emission tomography (PET) imaging was performed on the animals to visualize the excretion of ⁶⁴Cu from the liver of these animals.