Butyrylcholinesterase (BuChE) is a serine hydrolase enzyme that, along with
acetylcholinesterase (AChE), catalyzes the hydrolysis of acetylcholine. These enzymes
are associated with the pathology of neurologic disorders such as Alzheimer's disease
(AD) and multiple sclerosis (MS). In particular, AChE and BuChE accumulate in B-
amyloid (AB) plaques and tau neurofibrillary tangles in the AD brain. Thus, imaging
cholinesterase activity associated with plaques and tangles in the brain has the potential
to provide definitive diagnosis of AD during life. This would be advantageous since, at
present, confirmation of AD relies on detecting pathology through post-mortem
examination of the brain. In a similar respect, BuChE is associated with the characteristic lesions in MS brain and thus, is a promising target for diagnosis and monitoring of pathology in this disease. It is hypothesized that cholinesterase-binding
radiopharmaceuticals can be used in SPECT or PET imaging to visualize these enzymes associated with AD and MS pathology in the living brain.
Several classes of cholinesterase ligands were synthesized and exhibited potent
binding and specificity towards AChE and BuChE using enzyme kinetic analysis. These
compounds were rapidly radiolabelled with 123I and purified. Radiolabelled molecules
accumulated in vitro in areas known to contain cholinesterase activity in transgenic AD
mice and post-mortem human AD brain tissues, using autoradiography. Furthermore,
cholinesterase activity associated with AB plaques was visualized in human and
transgenic mouse AD brain tissues.
An enzyme kinetic approach was employed to determine critical residues in the
BuChE active site gorge for ligand binding. In particular, residues pertaining to the
peripheral site of the enzyme were identified and found to be involved in the binding of
various ligands. These results are crucial for optimizing the enzyme binding properties of
cholinesterase imaging agents. Finally, PET imaging of a transgenic mouse model of AD was performed as a vanguard for pre-clinical evaluation of cholinesterase imaging agents. PET imaging identified similar characteristics between this AD mouse model and the human condition. This is a promising approach for evaluation of cholinesterase imaging agents.
Radioligands specific for cholinesterases have the potential to provide a noninvasive
means for early diagnosis of neurological diseases using brain scanning.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:NSHD.ca#10222/35303 |
| Date | 12 June 2013 |
| Creators | Macdonald, Ian |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
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