The Molecular Probes For Imaging Of Beta-Amyloid Protein Aggregates

Visual Alzheimer’s disease is the most common form of dementia that afflicts millions of people in old age. Clinical detection of Alzheimer’s disease at the preliminary stage has a significant contribution in treatment and command. The primarily histopathological features of Alzheimer’s disease are senile plaques composed of P-amyloid protein aggregates and neurofibrillary tangles entwisted by abnormal phosphorylated tau protein. Thus, research of molecular imaging based on β-amyloid protein aggregates and neurofibrillary tangles could be the significant point of early diagnosis in Alzheimer’s disease. In this article, we provided several tracers targeted to β-amyloid protein aggregates in different imaging technology based on radiology and nuclear magnetic resonance.At first, we successfully synthesized and evaluated a series of compounds with the functional groups optimized from the indanone derivatives which were published in our team. The methods included fluorescent staining of AD human brain slices, in vitro binding assay, radioiodination of 125I, partition coefficient measurement, measurement of in vitro stability, biodistribution in normal mice, in vitro autoradiography, ex vivo experiment on transgene mouse, and so forth. Compared with those indanone derivatives published before, this series of compounds exhibited much higher affinities to P-amyloid protein aggregates, lower non-specific binding, better uptake in brain and faster clearance from brain. Especially, [125I]2d shows great potential to become an imaging probe for β-amyloid protein aggregates in vivo.Secondly, we evaluated and optimized the functional groups of naphthofuran derivatives based on the experience obtained from our research in small molecule binding to P-amyloid protein aggregates. This series of compounds shows improvement of affinities in the binding assay in vitro. On the other side, we evaluated a novel series of Homoisoflavonoid derivatives and found their high affinities to P-amyloid protein aggregates in vitro and well uptake in the brains of normal mice.At last, our team developed several exploratory researches in tracers for magnetic resonance imaging. For one, we selected a novel nanoparticle which called dendrimers modified by small molecule with binding affinity to β-amyloid protein aggregates and DTPA with the ability to chelate metals. On another point of view, we found that Angiopep with the ability of crossing blood-brain-barrier showed high affinity to senile plaques. In this article, we bound the metal-chelate agent DTPA to the amino terminal of this peptide and got a complex Gd-DTPA-Angiopep after chelation reaction. Then we used high resolution mass spectrum testing its molecular weight.In summary, we evaluated several series compounds which showed high affinities to β-amyloid protein aggregates and great potential to take part in early diagnosis in Alzheimer’s disease. The exploratory research in tracers for magnetic resonance imaging break the earlier views and provided a new way to develop imaging of β-amyloid protein aggregates in Alzheimer’s disease.