Study On Biological Activity Of AD Molecular Imaging Agents Targeting Amyloid

Alzheimer’s disease (AD) is a neurodegenerative disease which disrupts dailylife of patients. The treatment in late-stage is almost useless, while in the earlierwould improve symptoms, even change the course of the disease. To establish anefficient diagnostic method is significant. There are two key pathological featuresin the Alzheimer’s disease: the first one is the presence of abundant senile plaques(SP) in the cerebral cortex and hippocampus which are composed ofβ-sheet-containing fibrils formed by the aggregation of short β-amyloid peptides(Aβ), and the second one is highly phosphorylated tau proteins namedneurofibrillary tangles (NFT). Currently, the β-amyloid plaque is considered themost significant factor in AD. In all, the imaging agents targeting Aβ is meaningfulfor the diagnosis of AD.(1) The design of imaging agents: we chose three main framework structureson the basis of natural products and three Linkers to develop molecular probestargeting β-amyloid plaques which are one of key pathological features. With theComputer Aided Drug Design (CADD) docking methods we finally chose thebenzothiazole schiff-base as the main structure.(2) The synthesis of compounds: we designed the scheme of the reaction andthen these conditions were optimized. According to the optimized conditions wesynthesized these compounds, and characterized by~1H NMR and IR.(3) The determination of binding forces for the compounds: we evaluated theaffinity characteristics through Radioligand Binding Assay of Receptor and SurfacePlasmon Resonance. The Radioligand Binding Assay of Receptor experimentsshowed compound3a has best affinity (K_i=4.38nM), and the second ones werecompound3c (K_i=10.82nM) and3f (K_i=34.72nM). The results of Surface PlasmonResonance indicated compound3f (K_D=10.48nM) and compound3a (K_D=379.7nM)have good affinity with Aβ. The docking results proved electron-donating groupsplay a critical role in the binding affinity to Aβ aggregates. And the paraffin sectionof AD brain assay showed compound3a has great affinity with senile plaques.