Study On Near-Infrared Fluorescent Probes For Early Diagnosis Of Alzheimer’s Disease

Alzheimer’s Disease(AD)is a progressive degenerative disease of the central nervous system.The disease is highly occult,and the latentperiod period can be as long as ten years.Senile plaques formed by Aβ deposition is the main toxic form of AD,but when senile plaques are formed,the central nervous system pathology is irreversible,and it is too late to consider removing Aβ aggregates.Current study suggests that the soluble Aβ oligomers are more neurotoxic than insoluble Aβ fibrils.Therefore,targeting Aβ oligomers is a breakthrough in early diagnosis.In this thesis,a series of near-infrared fluorescent probes for imaging Aβ oligomers were designed and synthesized,which provide tracers for AD research and it is beneficial to the early diagnosis of AD.This thesis is divided into the following two parts:(1)Studies have shown that the curcumin could bind to Aβ aggregates and inhibit its aggregation,but the curcumin cannot be used in in vivo studies because of its poor stability and inability to cross the blood-brain barrier.In order to solve these problems,we designed and synthesized a bioprobe using curcumin as the basic skeleton,which not only retains the excellent properties of curcumin,but also be used in in vivo research.The π-π stacking and the hydrogen bond between the probe and Aβ oligomers was predicted by molecular docking technology and the stability and selectivity were detected by fluorescence.Through the research of cytotoxicity,in vitro and in vivo experiments,it was found that the probe can cross the blood-brain barrier to reach the hippocampus quickly and target Aβ oligomers specifically.(2)The disadvantages of NIR-Ⅰ(600-900 nm)fluorescence probe is its poor penetrate depth and large background signal.These problems will no longer exist while the fluorescence emission wavelength reach NIR-Ⅱ reigion(1000-1700 nm).Based on this,we constructed a fluorescent probe for small organic molecules.The aniline structure at both ends of the molecule serves as the electron donor and recognition group,and the strong electron withdrawing groups formed by the coordination of boron difluoride in the middle serve as the electron acceptor.The electron donor and the electron acceptor were connected to each other through a bridge,so that the emission wavelength reaches the NIR-Ⅱ.This probe is very sensitive to environmental solvents,and basically does not emit light in aqueous solution,but has a significant fluorescence increasement after binding to Aβ.The aniline groups at both ends of the probe easily generate hydrogen bonds with Aβ aggregates,it guarantees the binding ability of the probe and Aβ aggregates.Due to the compact structure of the probe molecule,small molecular weight,and strong fat solubility,it has great potential to cross the blood-brain barrier,which enabling the probe molecule to perform deep brain imaging.In this study,Aβ aggregates were used as the target,and two fluorescent probes with emission wavelengths located in the NIR-Ⅰ and NIR-Ⅱ were designed and synthesized.These probes could be used in early diagnosis of AD.This research show important value in clinical.