A Potential Dubin-Johnson Syndrome Imaging Agent: Synthesis, Biodistribution, and MicroPET Imaging

摘要

Dubin-Johnson syndrome (DJS) is caused by a deficiency of the human canalicular multispecific organic anion transporter (cMOAT). A new lipophilic copper-64 complex of 1,4,7-tris(carboxymethyl)-10-(tetradecyl)-1,4,7,10-tetraazadodecane (5) was prepared and evaluated for potential as a diagnostic tool for DJS. The prepared ligand was labeled with ~(64)Cu citrate in high radiochemical purity. In vivo uptake and clearance of the complex was determined through biodistribution studies using normal Sprague-Dawley rats and mutant cMOAT-defi-cient (TR~-) rats. In normal rats, the radioactive copper complex was cleared quickly from the body exclusively through the hepatic pathway. The ~(64)Cu complex was taken up rapidly by the liver and quickly excreted into the small intestine and then the upper large intestine, whereas < 1% ID/organ was found in the kidney at all time points post injection. Whereas activity was accumulated continuously in the liver of TR~- rats, it was not excreted into the small intestine. MicroPET studies of normal and TR~- rats were consistent with biodistribution data and showed dramatically different images. This study strongly suggests that cMOAT is involved in excretion of ~(64)Cu-5. The significant difference between the biodistribution data and microPET images of the normal and TR~- rats demonstrates that this new ~(64)Cu complex may allow noninvasive diagnosis of DJS in humans.