Development Of Organic Fluorescent Probes And Their Applications In Alzheimer’s Disease

As one of common neurodegenerative diseases,Alzheimer’s disease is a serious threat to the health of the elderly population,and brings a heavy burden to the society and economy.Alzheimer’s disease has been researched for over 100 years,but no good treatment has been achieved.Currently,most of the studies on Alzheimer’s disease were focused onβ-amyloid（Aβ）and Tau protein.The abnormal accumulation of these two proteins in the brain is an important cause of nerve damage and neurological death.Therefore,the detection of these two proteins remains one of the most important areas of research in Alzheimer’s disease.Fluorescence detection technique is known to be easy to use,low cost and free radiation.Therefore,this dissertation focuses on the design and synthesis of several organic fluorescent molecular probes based on benzothiazole,methoxyquinoline and BODIPY for the fluorescence detection of Aβand Tau protein.The main work is as follows:In the first work,fluorescent probes WBQ-1 and WBQ-5 were designed and synthesized based on benzothiazole structure for the detection of Aβ40 aggregates.The probe WBQ-1 showed good specificity and binding affinity for Aβ40 aggregates(λ_em=480 nm,Kd=3.472μM)and was able to achieve selective detection of Aβ40aggregates in solution.However,its short fluorescence emission wavelength is not suitable for the applications in bioimaging.Herein,the probe WBQ-5 was designed and synthesized,which achieved performance improvements such as fluorescence wavelength(λ_em=585 nm)and binding affinity（Kd=1.531μM）.In order to further develop probes with more excellent properties such as high sensitivity,excellent fluorescence wavelength,high quantum efficiency and high signal-to-noise ratio,we carried out the second work.In this work,fluorescent probes A-1 and C-1 were designed and synthesized based on methoxyquinoline structure for the detection of Aβ40 aggregates.Probe A-1 exhibits high binding affinity（Kd=1.013μM）,while probe C-1 has a better fluorescence emission wavelength(λ_em=640 nm)and a higher signal-to-noise ratio.These properties enable molecular probes to be further extended to better imaging and application prospects in biological tissues.In addition to Aβ40 aggregates,Aβ42 aggregates are more hydrophobic and more neurotoxic,making the detection of Aβ42 aggregates more difficult and important.Fluorescent probe BQ-2(λ_em=520 nm,Kd=2.376μM)was designed and synthesized based on fluorescent BODIPY structure for the detection of Aβ42 aggregates in the third work.The probe features good biocompatibility,a large Stokes shift（200 nm）and has the potential to be further used for fluorescent staining and calibration of Aβplaques,which can play an important role especially in the detection and diagnosis of late AD.Tau protein,another pathological marker of AD,also plays an important role in the pathogenesis of AD.A growing number of studies have confirmed a close correlation between Tau protein and the development of AD.However,the structure of Tau protein is relatively more complex,which makes its detection more difficult.Based on this,we designed and synthesized a fluorescent probe TY-67 for the detection of Tau protein in the forth work.Probe TY-67 showed a good fluorescence response(λ_em=310 nm)to a peptide VQIVYK from Tau protein and was able to realize the selective detection of VQIVYK in solution.The probes designed in this dissertation have a series of advantages,including simple preparation,low cost,good binding with the target protein and excellent fluorescence performance.They have great potential to be applied to biological tissue imaging in AD,and further accumulate and provide some experience for the development of fluorescent probes for AD detection.