Senile Plaques Targeted Molecular Probes

The abnormal secretion and aggregation of β-amyloid(Aβ)which induce the formation of Senile plaques(SPs)is a major pathological feature of Alzheimer disease(AD).Sensitive,specific,non-invasive and cheap SPs targeting molecule probes,therefore,could be a potential diagnostic tool for the detection and evaluation of the development of AD.In this paper,some new structures of SPs targeting molecular probes based on Benzo heterocyclic/trans-styrene/peptide were designed.Then,bidirectional targeting mode and peptide binding mode were proposed.Finally,the potential of applicating CT technology in SPs imaging were explored.At present,most of the previous studies were based on radiolabeled small organic molecule probes with PET imaging technology.In the second chapter of this paper,some small organic molecule probes were designed and evaluated.Three kinds of core structures and its derivatives were screened,and the potential of SPs imaging agent was evaluated in different levels.The results of experiments show that these three classes of molecular probes have good affinity to Aβ aggregation in AD brain homogenates,and are able to stain SPs in sections of AD brain.F class of molecular probes reveals the best property of potential AD molecular probesin bio-distribution experiments and in autoradiography experiments in vitro,which is worthy for further study like in vivo imaging.While getting some new skeleten structures of small molecular probes,we have also proposed a design mode of bidirectional targeting to SPs,that both ends of the small molecule probes have equal affinity toSPs.This design strategy could give probes higher flexibility to modify and two targeting sites to Aβ depositions.In the third chapter,we proposed a tracer which is the first peptide based(non-Aβpeptide)SPs targeting molecular probe.This peptide,which named angiopep,unlike conventional organic small molecule probes penetrating the blood-brain barrier(BBB)by passive diffusion,can penetrate BBB utilizing receptors on BBB,specifically the lipoprotein receptor-related protein(LRP1)receptor.In the mean while,the existence of LRP1 in the Aβ depositions of AD patients and APP mice brain have been reported before.Results of in vitro fluorescence staining and fluorescence spectra experiments show that it can obviously stain Ap deposits both in AD human brain sections and APP mice brain sections.Furthermore it also have a certain affinity to Aβ aggregation.In vivo imaging data of APP mice show that angiopep accumulated in the brain of APP mice and cleared 20 hours after injection.APP mouse brain slices after administration also confirmed that angiopep really combine to amyloid depositions.At the same time,we also carried out some research to combine angiopep with nanoparticles(dendrimers).These results show that,angiopep is indeed a novel and useful AD molecular probes,which have great potential in ADearly diagnosis and evaluation.The fourth chapter described some explorations in imaging technologies.We tried to use CT imaging-a common clinical imaging technology-in our experiments.We chose gold nanoparticles as CT imaging agents and then synthesis and modify some different size gold nanoparticles.In ICR and tumor bearing mice,metabolism of gold nanoparticles was observed in vivo,and find that the level of gold nanoparticles in liver was significantly higher than in other organs.In a subsequent TEM analysis,we found a accumulation effect of gold nanoparticles in mitochondria of liver,which suggested that liver and liver mitochondria play important roles in the metabolism process of gold nanoparticles.This data makes a technical foundation of CT imaging for subsequent studies.In summary,this paper used radiolabeling,nanoparticles synthesize,tissue sections staining,affinity measurement,in vivo imaging,transmission electron microscopy observation and some other experimental methods.Novel design modes of probe structure were proposed and applicated.Some chemical structures based on benzo heterocyclic and trans-stilbene were designed and modified.New polypeptide molecular probes based on angiopep were designed and synthesisd.Gold nanoparticles were synthesisd and modified.In vivo imaging detection was carried out using near infrared and/or CT imaging technologies.Finally,we got some potential probes based on benzo heterocyclic/trans stilbene and angiopep for clinical application.Based on these works,two-way targeting mode and BBB penetrable peptide targeting modes were proposed.Breakthroughs both on structure design theory and practical application for SPs targeting probes were achived.