Synthesis and Evaluation of Butyrylcholinesterase Ligands as Brain Molecular Imaging Biomarkers for Alzheimer Disease

Cholinesterases are enzymes involved in the breakdown of acetylcholine, a neurotransmitter important in brain cell communication, and which is reduced in Alzheimer's disease (AD). AD is marked by loss of memory and deposition of toxic brain proteins, forming abnormal structures called amyloid plaques and neurofibrillary tangles. The ability to detect these in the living brain could facilitate early diagnosis of the disease. In AD brains, plaques and tangles contain the enzyme butyrylcholinesterase. The presence of these butyrylcholinesterase "hot spots" in the brain may provide an opportunity for early detection of AD. We received a CIHR grant in 2007 to develop radiolabelled imaging compounds that bind to butyrylcholinesterase for the detection of this enzyme activity in the living brain, using current scanning techniques. Since then, we have synthesized a number of compounds and have incorporated radioactive iodine-123 into such compounds. We have shown their uptake in brain regions known to contain butyrylcholinesterase in the normal living experimental rat. Our preliminary experiments have also shown that these compounds are indeed taken up in abnormally located butyrylcholinesterase "hot spots" in a transgenic mouse model of AD. Furthermore, we have been able to visualize abnormal deposits, typical of disease, in human AD brain tissue. With this significant advance in our preliminary experiments, we now propose to extend our studies, based on these lead imaging compounds, to identify those molecules with optimum ability to detect butyrylcholinesterase associated with abnormal AD structures. It is anticipated that butyrylcholinesterase imaging agents will permit early detection of AD pathology in the living human brain and will aid accurate diagnosis of this condition during life.