Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.
Department of Medicine (Geriatric Medicine & Neurology), Halifax, Nova Scotia, Canada.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2225797. doi: 10.1080/14756366.2023.2225797. Epub 2023 Jun 26.
Cholinesterase (ChE) enzymes have been identified as diagnostic markers for Alzheimer disease (AD). Substrate-based probes have been synthesised to detect ChEs but they have not detected changes in ChE distribution associated with AD pathology. Probes are typically screened using spectrophotometric methods with pure enzyme for specificity and kinetics. However, the biochemical properties of ChEs associated with AD pathology are altered. The present work was undertaken to determine whether the Karnovsky-Roots (KR) histochemical method could be used to evaluate probes at the site of pathology. Thirty thioesters and esters were synthesised and evaluated using enzyme kinetic and KR methods. Spectrophotometric methods demonstrated all thioesters were ChE substrates, yet only a few provided staining in the brain with the KR method. Esters were ChE substrates with interactions with brain ChEs. These results suggest that the KR method may provide an efficient means to screen compounds as probes for imaging AD-associated ChEs.
胆碱酯酶（ChE）已被确定为阿尔茨海默病（AD）的诊断标志物。已经合成了基于底物的探针来检测 ChE，但它们没有检测到与 AD 病理相关的 ChE 分布变化。探针通常使用分光光度法与纯酶一起进行特异性和动力学筛选。然而，与 AD 病理相关的 ChE 的生化特性发生了改变。本研究旨在确定 Karnovsky-Roots（KR）组织化学方法是否可用于评估病理部位的探针。合成了 30 种硫代酯和酯，并使用酶动力学和 KR 方法进行了评估。分光光度法表明所有硫代酯都是 ChE 的底物，但只有少数几种用 KR 方法在大脑中提供了染色。酯是 ChE 的底物，与脑 ChE 相互作用。这些结果表明，KR 方法可能是筛选化合物作为 AD 相关 ChE 成像探针的有效手段。
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