The Synthesis and Enzymatic Activity of Thioate Derivatives As Potential Neuroimaging

The Synthesis and Enzymatic Activity of Thioate Derivatives as Potential Neuroimaging Agents for the Diagnosis of Alzheimer’s Disease

Courtney Jollymore,a,b Ian Macdonald,c Eric Joy,aEarl Martin,b Sultan Darvesh,b,c,d,* and Ian R. Pottieb,*

aMount Saint Vincent University, Department of Biology, Halifax, NS, B2M 2J6

bMount Saint Vincent University, Department of Chemistry & Physics, Halifax, NS, B2M 2J6

cDalhousie University, Department of Anatomy & Neurobiology, Halifax, NS, B3H 1X5

dDalhousie University, Department of Medicine, Halifax, NS, B3Y 2Y9

Alzheimer’s disease (AD) is characterized by decline in cognition, memory and behavior. Autopsy of AD brains is at present the only definitive way to diagnose AD, identifying neurofibrillary tangles and neuritic plaques. These disease hallmarks have elevated levels of the enzyme butyrylcholinesterase (BuChE). Although such microscopic examination of brain tissue is key for a definitive AD diagnosis, some methods are now used to facilitate AD diagnosis during life by employing neuroimaging agents developed for PET or SPECT scanning that bind to abnormal amyloid or tau. Current methods present two problems; the first, amyloid plaques are also present in normal older adult brains and second, this methodology does not allow for treatment monitoring. It has been shown that increased levels of BuChE are present in brain plaques of AD patients but not in normal brains. For this reason, BuChE is an important potential target for early diagnoses of AD. Imaging of BuChE with experimental radiopharmaceutical molecules, such as the oxyester 1-[C11]-methyl-4-piperidinyl n-butyrate, has been attempted but the generated images have not recapitulated the known BuChE histochemical distribution within the brain. This may be due to a lack of specificity for BuChE. However, because such molecules lack a chromophore, their specificity and affinity for BuChE have only been inferred and not measured. Therefore, we have synthesized analogue compounds which contain a thiol functionality, which, when reacted with Ellman’s reagent to produce a chromophore, can be detected spectrophotometrically. This allows determination of affinity and specificity of these molecules for BuChE. Thus far, four aromatic sulfur analogues have been prepared, tested and compared with corresponding oxyesters that have an aromatic chromophore. The kinetic parameters were comparable. Presently, alkyl sulfur analogues are being prepared to test for BuChE specificity. This work will facilitate the search for molecules with BuChE specificity and affinity for use as diagnostic radioligands for Alzheimer’s disease.

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