Study Fluorescent Probe Of Metal Complexes For The Detection Of β-amyloid Oligomers

Alzheimer’s disease(AD)is a degenerative disease of the nervous system.At present,there is no effective medical method to prevent or reverse the development of the disease.The false folding and deposition of β-amyloid(Aβ)in the human brain is the main sign of AD pathology,and one of the driving factors of AD is the production of soluble Aβ oligomers.So far,the detection of Aβ plaque in postmortem brain samples is still the gold standard for clinical diagnosis of AD.However,Aβ plaque is only related to late AD,and the early diagnosis of AD is still invalid.Therefore,this thesis has designed and synthesized two kinds of metal complexes near-infrared fluorescence probes targeting Aβ oligomers.The thesis is divided into the following two parts:(1)At present,most small organic molecules are still limited in optical imaging for AD due to their poor stability,high toxicity,poor permeability of the blood-brain barrier(BBB)and high signal-to-noise ratio.However,it was noted that metal complexes as fluorescent probes have the advantages of good stability,low cytotoxicity,high fluorescence quantum yield and good Stokes shift,making them an ideal choice for biomolecular probes.Nd-DOTA has the potential to become a near-infrared two-region(NIR-Ⅱ,1000-1700 nm)imaging reagent,but it lacks the ability to specifically bind with Aβ.Curcumin can bind with Aβoligomers,and has the characteristics of inhibiting Aβ aggregation.Therefore,by linking NdDOTA with curcumin,the fluorescence probe of the metal complex still retains the excellent characteristics of the two molecules.Through cellular and animal experimental studies,it was found that the neodymium(Ⅲ)complex not only emit NIR-Ⅱ optical fluorescence,but also has low cytotoxicity,amphiphilic property,good BBB permeability and Aβ oligomersspecific response.In this chapter,we mainly studied the potential of neodymium(Ⅲ)complex fluorescent probe in the detection of Aβ in the near infrared region and inhibition of Aβ aggregation.(2)Ruthenium(Ⅱ)complexes as fluorescent probes not only have the advantages of high quantum yields as general metal complexes,but also show good advantages in water solubility and fluorescence lifetime.Based on this,we designed and synthesized a new ruthenium(Ⅱ)complex fluorescent probe that can target Aβ oligomers.The ligands were1,10-phenanthroline,maleic anhydride and 1,10-phenanthroline,which can make the molecule have a larger conjugated structure to reach the near-infrared region.Sulfhydryl groups were introduced to increase the lipophilicity which makes the probe easier to pass through the blood-brain barrier(BBB).The introduction of the motif KLVFF enables the probe to specifically bind with Aβ oligomers.The experimental results show that ruthenium(Ⅱ)complex is also an excellent choice for the detection of Aβ in vivo and in vitro.This paper aims to provide a new idea for the early diagnosis of AD.Two metal complexes that can target Aβ oligomers have been designed and synthesized.The emission wavelength of ruthenium(Ⅱ)complex was located in the near infrared region-I(600-900 nm),and the emission wavelength of neodymium(Ⅲ)complex probe was located in the near infrared region-II.The biological experiments show that the probe synthesized in this paper has important research value.