Development Of Fluorescent Probes Based On D-?-A Backbone And Their Applications In Imaging ?-amyloid And Viscosity

Alzheimer's Disease(AD)is a neurodegenerative disease that occurs in the elderly over 65 years old.There will be one new case of dementia every three seconds around the world,which has affected tens of millions of people and received the extensive attention from public and scientific community.However,the pathogenesis of AD is not yet clear and the clinically drugs approved by FDA were not effective but only to relieve the symptoms.Therefore,early diagnosis and prevention of AD is critical.In fact,the A? plaques have existed in the brain 10-15 years ago before the onset of AD,and are currently recognized as biomarkers for early diagnosis of AD.In addition,many studies have revealed that there is a close relationship between A? peptide and lipid droplets,and the acidic lysosomal system involved in the autophagy pathway may be related to the production of A? peptide and its neurotoxicity.Therefore,developing dual-functional fluorescent probes for imaging A? plaques and its related organelles such as lipid droplets and lysosomes would provide a tracer tool for AD basic pathological research,which is good for early diagnosis and drug development of AD.This paper systematically carried out the following three parts of work:(1)Based on the A? fluorescent probe backbone(MC-1)previously reported by our group,a series of fluorescent probes were rationally designed and synthesized through the introduction of different amine chains as electron donor.Compared with MC-1,the probes has higher fluorescence quantum yield.After systematical screening,the excellent probe 2c was selected for in vivo imaging of A? plaques to differentiate the transgenic APP/PS1 mice from wild-type WT mice,besides,the probe 2c could detect A? aggregates and monitor viscosity changes at cellular level.(2)Based on the A? fluorescent probe backbone(MC-1),a dual-functional red-emitting fluorescent probe(Lyso-MC)was rationally designed and synthesized by introducing the morpholine as the lysosomal targeting group for simultaneous detection of lysosomal viscosity and intracellular A? aggregates.The probe Lyso-MC was successfully applied in detecting intracellular A? aggregates and monitoring lysosomal viscosity fluctuation.It is the first dual-functional fluorescent probe for monitoring lysosomal viscosity and detecting A?aggregates at cellular level..(3)Based on the quinoline structure,five fluorescent probes were designed and synthesized.The lipid droplet targeting AIE fluorescence probe 4b showed good selectivity and specificity,high sensitivity,moderate affinity to A? aggregates This would provide a good reference for the development of dual-functional AIE fluorescent probes imaging A?aggregates and lipid droplets at cellular level in the future.