Butyrylcholinesterase radioligands to image Alzheimer's disease brain.

Butyrylcholinesterase (BuChE) is found to have a brain distribution pattern that is distinct from that of acetylcholinesterase (AChE). Neurons containing BuChE are particularly located in the amygdala, hippocampal formation and the thalamus, structures involved in the normal functions of cognition and behavior that typically become compromised in Alzheimer's disease (AD). Progress of this disease is thought to result, at least in part, from the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. These structures characteristically become associated with cholinesterase activity, and are major determinants of AD diagnosis post-mortem. Early definitive AD diagnosis in the living brain could greatly facilitate specific timely treatment of the disorder and the search for novel drugs to preempt progress of this disease. Radioligands have been developed to detect deposition of Aβ plaques in the brain; however, since many cognitively normal individuals also exhibit Aβ plaque deposition, this approach has inherent disadvantages for definitive AD diagnosis during life. The association of BuChE with Aβ plaques appears to be a characteristic of AD. This has prompted the search for radioligands that target BuChE in association with Aβ plaques that accumulate in cortical grey matter, a region normally with very little of this enzyme activity. A number of BuChE radioligands have been synthesized and preliminary testing indicates that some such radioligands enter the brain and accumulate in regions known to contain BuChE. Radioligands targeting unusual BuChE activity in the brain may represent a means for early diagnosis and treatment monitoring of AD.