Synthesis and evaluation of butyrylcholinesterase ligands for brain imaging in dementia

Background: Butyrylcholinesterase (BuChE) is an enzyme that is part of the system involved in cholinergic neurotransmission, important in memory as well as other cognitive functions and behaviour. In diseases such as Alzheimer's disease (AD), there is an increased level of BuChE activity in the brain where high levels are found in the plaques and tangles that are the neuropathological hallmarks of AD. Objectives: To develop a series of compounds that would be highly specific for interaction with BuChE and that would have potential for incorporation of radioactive atoms, such as 11C, 18F or 123I, to facilitate BuChE detection by SPECT or PET scanning in the living brain. The overall objective is to develop compounds as ligands for BuChE that could be used for early diagnosis of dementia and to follow changes in the BuChE activity during the course of treatment. Research Plan: We will synthesize a number of molecules that will be highly specific for BuChE. Our preliminary results show that this is a feasible goal. We will perform enzyme kinetic studies in the test tube to determine the extent of specificity for BuChE of each molecule. Such molecules will have appropriate functional groups so that a radioactive atom can be introduced for detection by brain scanner. Molecules that show high specificity for BuChE will be injected in anesthetized experimental rats and the distribution of label will be determined in various organs, including the brain. Those molecules showing accumulation in the brain will be injected in anesthetized experimental rats and SPECT or PET scanning will be performed. Relevance: Such molecules have the potential for use in SPECT or PET imaging of BuChE activity in the human brain to aid in early diagnosis of dementia such as AD. In addition, follow-up scans, using these molecules, could be used to observe changes in BuChE after treatment of these disorders.