Design,Synthesis And Application Of Fluorescent Probe In Alzheimer’s Disease

As the population aging of China is increasing year by year,Alzheimer’s disease has been a universal memory-destructive neurodegenerative disease that seriously endangers the physical and mental health of the elderly.High medical expenses have brought heavy burdens on families and society.Current research on AD mainly focuses on extracellular senile plaques（SP）formed by the deposition of amyloid-β（Aβ）.A large number of studies have shown that the abnormal accumulation of Aβprotein is one of the most important cause of AD.It leads to neurotoxicity through various physiological pathways and is the fuse of other neurological and physiological lesions in the brain.In addition,there is a close relationship between oxidative stress caused by reactive oxygen species and the etiology of AD.hypochlorous acid（HOCl）,one of the most common type of reactive oxygen species,not only plays an important role in the pathogenesis of AD,but also plays a crucial role in various inflammatory processes.Therefore,this dissertation focuses on the detection of Aβaggregates and HOCl.The main works are as follows.Firstly,we designed and synthesized a series of D-π-A probes（SDPY,ODPY,IDPY）for the detection of Aβaggregates.These probes were synthesized by the typical iodine substitution reaction,the Sonogashira coupling reaction,and the Knoevenogel condensation reaction.Among them,SDPY has good anti-interference ability,and was capable of specifically detecting Aβaggregates in phosphate buffered saline（PBS）solution.Additionally,it has higher affinity for Aβ₄₀ aggregates than Aβ₄₂ aggregates.More importantly,SDPY showed high affinity and good imaging ability for Aβ₄₀ aggregates on brain tissue sections from AD transgenic mouse models.Secondly,we focused on the detection of hypochlorous acid（HOCl）.Based on the good fluorescence properties of phenoxazine skeleton,we connected the N,N-dimethylcarbonyl group with the reduced phenoxazine skeleton to synthesize a novel fluorescent probe BR-O.The probe showed high sensitivity and selectivity towards HOCl in PBS solution,and displayed lower detection limit.More importantly,BR-O could detect exogenous and endogenous HOCl at the cell level.Finally,in order to realize the detection of HOCl in vivo,the N,N-dimethylthiocarbonyl（DMTC）group that specifically responds to HOCl was introduced into the phenoxazine skeleton to obtain the probe BR-1 through one-pot synthesis.the probe BR-1 showed quick response,high sensitivity and selectivity towards HOCl both in vitro and in vivo.In addition,the probe BR-1 showed good anti-interference.Moreover,BR-1 was capable of rapidly detecting and imaging endogenous HOCl in the inflammation area from the mouse models of arthritis.It is of great significance for its application on the early diagnosis and the alleviation of AD.