第一部份:開發組蛋白去乙醯化酶正子探針作為阿茲海默症之新穎研究工具 第二部分:豬隻毛髮暨飼料添加物中新興瘦肉精成分─甲飆妥巴胺及飆妥巴胺─之鑑別

Abstract

Part 1 Development of histone deacetylase PET tracers as a novel research tool for Alzheimer’s disease Alzheimer’s disease (AD) is the most common type of dementia, accounting for 60 to 80% of dementia cases. It is a progressive disease with no cure, causing severe burden to patients’ families and the society. Although a lot of effort have been made for studying AD formation and developing treatments for AD, the progression remain slow. Several studies have indicated that histone deacetylases (HDACs) might play an important role in AD formation. Hence, [18F]-labeled HDAC molecular probes have been developed for AD study through real-time in vivo visualization and quantification of the contents and activity of HDACs in brain, yet most of them exhibited poor blood-brain barrier permeability and lack of subtype-selectivity. In this thesis, a series of novel fluoroalkyl-substituted benzamide derivatives with high subtype-selectivity toward HDAC1 and HDAC2 were designed and synthesized. The physicochemical and pharmacokinetic properties were also evaluated. These compounds demonstrated potent and selective inhibition against HDAC1 (IC50 = 0.011-1.24 uM) and HDAC2 (IC50 = 0.14-2.59 uM). In addition, most of these compounds demonstrated moderate to high BBB permeability (>70%) in the PAMPA assay. 24h is a HDAC1 selective HDACI (HDAC1 IC50: 0.013 uM; HDAC2: 50% inhibition at 0.3 uM) with BBB permeability >99% and was chosen to be the imaging probe in PET study. [18F]24h was found to be able to penetrate BBB with rapid washout which can be a potential imaging tool for studying the roles HDACs play in AD. Part 2 Identification of novel beta-2 receptor agonists, mebuctopamine and buctopamine, in swine hair and feed additives beta-2 receptor agonists are often used illegally for their growth promoting effect as feed additives. Recently, a novel beta-2 receptor agonist and its metabolite have been detected in swine hair and were further identified by using triple quadrupole LC/MS/MS and nuclear magnetic spectrometry as 4-[2-(tert-butylamino)-1-hydroxyethyl]phenol (buctopamine) and 4-[2-(tert-butylamino)-1-hydroxyethyl]-2-methoxyphenol (mebuctopamine). Both compounds exhibited high hydrophilicity comparing to ractopamine and clenbuterol as well as moderate binding affinity toward beta-2 receptor with no affinity toward other subtypes and alpha adrenoceptors. This study has successfully prevented the illegal use of beta-2 receptor agonists as feed additive in livestock industry through adding these two compounds into the library of feed additives for routine drug-residue screening and further enhance and food safety in Taiwan.