Rapid intracerebroventricular delivery of Cu-DOTA-etanercept after peripheral administration demonstrated by PET imaging

Abstract

Background. The cytokines interleukin-1 and tumor necrosis factor (TNF), and the cytokine blocker interleukin-1 receptor antagonist, all have been demonstrated to enter the cerebrospinal fluid (CSF) following peripheral administration. Recent reports of rapid clinical improvement in patients with Alzheimer's disease and related forms of dementia following perispinal administration of etanercept, a TNF antagonist, suggest that etanercept also has the ability to reach the brain CSF. To investigate, etanercept was labeled with a positron emitter to enable visualization of its intracranial distribution following peripheral administration by PET in an animal model. Findings. Radiolabeling of etanercept with the PET emitter 64Cu was performed by DOTA (1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid) conjugation of etanercept, followed by column purification and 64Cu labeling. MicroPET imaging revealed accumulation of 64Cu-DOTA- etanercept within the lateral and third cerebral ventricles within minutes of peripheral perispinal administration in a normal rat anesthesized with isoflurane anesthesia, with concentration within the choroid plexus and into the CSF. Conclusion. Synthesis of 64Cu-DOTA-etanercept enabled visualization of its intracranial distribution by microPET imaging. MicroPET imaging documented rapid accumulation of 64Cu-DOTA-etanercept within the choroid plexus and the cerebrospinal fluid within the cerebral ventricles of a living rat after peripheral administration. Further study of the effects of etanercept and TNF at the level of the choroid plexus may yield valuable insights into the pathogenesis of Alzheimer's disease. © 2008 Tobinick et al.