Synthesis and Evaluation of Butyrylcholinesterase Ligands for Brain Imaging in Dementia

Butyrylcholinesterase is an enzyme involved in the breakdown of acetylcholine, a chemical important in communication between brain cells, which is found in lesser amounts in Alzheimer's disease (AD). AD is also marked by loss of memory and the deposition of toxic proteins in the brain, forming abnormal structures called amyloid plaques and neurofibrillary tangles. Currently, these deposits can only be observed at autopsy, but the ability to detect them in the living brain could facilitate early diagnosis and treatment monitoring of the disease. In the AD brain, amyloid plaque and neurofibrillary tangle accumulations contain the enzyme butyrylcholinesterase. The presence of these butyrylcholinesterase "hot spots" in the brain may provide an opportunity for early detection of AD. We were awarded a CIHR grant in 2007 to develop chemical compounds that are specific for butyrylcholinesterase and that would permit the incorporation of radioactive atoms, such as iodine-123 or fluorine-18, for the detection of butyrylcholinesterase "hot spots" in the living brain, using current scanning techniques. Since then, we have synthesized a number of compounds specific for butyrylcholinesterase. We have also incorporated radioactive iodine-123 into such compounds and have shown their uptake in the normal living experimental rat, in brain regions known to contain butyrylcholinesterase activity. We propose to extend our studies with iodine-123 butyrylcholinesterase imaging agents by showing the presence of this enzyme in amyloid plaques in a mouse model of AD. Also, we wish to prepare comparable new butyrylcholinesterase imaging agents containing radioactive fluorine-18 to provide additional means to image AD plaques. It is anticipated that butyrylcholinesterase imaging agents will permit early detection of AD pathology in the living human brain, thus, will aid diagnosis and enable monitoring of the effects of drugs used to treat the disease.