Molecular Probes For Imaging Of Senile Plaques And Neurofibrillary Tangles In Alzheimer’s Disease

Senile plaques (SPs) and Neurofibrillary tangles (NFTs) are two major neuropathological features of Alzheimer’s disease (AD). Noninvasive detection of SPs and NFTs could, therefore, be a potential early diagnose of AD patients.Firstly, this dissertation describes the the synthesis and evaluation of a novel series of donepezil derivatives. The SPs and NFTs in AD brain sections were positively stained by donepezil derivative D8L that was similar to the stain pattern of Congo Red (CR) and ThS in adjacent sections. Furthermore, in vitro autoradiography and in situ micro-autoradiography of AD brain sections showed the similar stronger signal in [125Ⅰ]D8j,[125Ⅰ]D8L labeled the SPs and NFTs as to the signal of [125Ⅰ]IMPY labeled SPs and NFTs. When in vitro binding studies were carried out using [125Ⅰ]IMPY as the reference ligand, the derivative D8e showed high binding affinities for AD homogenate at the Ki values of16nM. The two radioiodinated derivatives [125Ⅰ]D8j,[125I]D8L had suitable lipophilicity with the Log P value of2.80and2.57, and the in vivo biodistribution in normal ICR mice displayed high brain uptake (2.74%and4.58%ID/g at2min) and good clearance from the brain (0.4%and0.45%ID/g at60min). These data strongly suggest that donepezil derivatives are worthy of further study and may be useful amyloid imaging agents for early detection of amyloid plaque in AD brain.Secondly, it describes the exploratory study of the complex of small molecular linked with the dendrimer, the primary result demonstrated that the complex could bind to the amyloid plaques similar to the small molecular itself and ThS in the adjacent brain sections. These data show that the complex of dendrimer and small molecular may be utilized as a MRI SPs contrast agent.Lastly, it also describes the curcumin studies and two collaborative PIB and DAPH derivatives studies. The data show that the curcumin> PIB and DAPH derivatives could stain the amyloid plaques in AD brain sections.To sum up the above studies, several methods were used in this dissertation, include organic chemical synthesis, adjacent AD brain sections staining, radioiodine labeling, receptor binding assay, partition coefficient assay, normal mice biodistribution, and autoradiography. The donepezil derivatives were synthesized and bio-evaluated, the data suggest that the derivatives may be useful in the in vivo imaging of the AD brain amyloid plaques。Furthermore, these primary data have laid a good foundation for the follow-up in vivo SPs imaging agents studies.