Butyrylcholinesterase (BCHE) is found to have a brain distribution pattern that is distinct from that of acetylcholinesterase (AChE). Neurons containing BCHE 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 beta-amyloid (Abeta) 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 Abeta plaques in the brain; however, since many cognitively normal individuals also exhibit Abeta plaque deposition, this approach has inherent disadvantages for definitive AD diagnosis during life. The association of BCHE with Abeta plaques appears to be a characteristic of AD. This has prompted the search for radioligands that target BCHE in association with Abeta plaques that accumulate in cortical grey matter, a region normally with very little of this enzyme activity. A number of BCHE radioligands have been synthesized and preliminary testing indicates that some such radioligands enter the brain and accumulate in regions known to contain BCHE. Radioligands targeting unusual BCHE activity in the brain may represent a means for early diagnosis and treatment monitoring of AD.
PURPOSE: The purpose of this study is to synthesize and evaluate specific agents for molecular imaging of butyrylcholinesterase (BuChE), known to be associated with neuritic plaques and neurofibrillary tangles in Alzheimer's disease (AD). In this study, these agents were tested in a normal rat model. The distribution of radiolabel was compared with known BuChE histochemical distribution in the rat brain. PROCEDURES: Iodobenzoate esters were synthesized and tested, through spectrophotometric analysis, as specific substrates for BuChE. These compounds were converted to the corresponding (123)I esters from tributyltin intermediates and purified for studies in the rat model. Whole body dynamic scintigraphic images were obtained for biodistribution studies. Autoradiograms of brain sections were obtained and compared to histochemical distribution of the enzyme in this model system. RESULTS: The three iodobenzoate esters studied were specific substrates for BuChE. Whole body biodistribution studies with (123)I-labeled compounds showed rapid disappearance from the body while radioactivity was retained in the head region. Brain section autoradiography of animals injected with these labeled compounds indicated that most areas known to contain BuChE corresponded to areas of radioactivity accumulation. CONCLUSION: BuChE-specific radiolabeled iodobenzoates enter the brain and, in general, label areas known to exhibit BuChE activity in histochemical studies. Such molecules may represent a new direction for the development of agents for the molecular imaging of BuChE in the living brain, especially in regions where BuChE-containing neuropathological structures appear in AD.
