Design And Synthesis Of Near Infrared Fluorescent Molecular Probes: Application For Imaging Of β-amyloid Plaques

Alzheimer’s disease, a degenerative brain disease, is the most common form of dementia. Its clinical manifestations are divided into social disabilities, gradual memory diminishes, cognitive function weakening, recession of thinking, understanding ability and visuospatial function, as well as loss of daily self-care ability and personal characters indifferent. Patients’life may be threatened in the later stages of dementia. Since the onset of AD is concealed and it develops slowly and irreversibly, so the patient is often already in the middle or later stage when it is diagnosed based on clinical symptoms. Existing treatment options can help to ease the symptoms for the disease, but can not achieve significant efficacy and improvement. If the patients are diagnosed early, and get timely treatment, their life quality could be improved. Therefore, the early diagnosis of AD for the treatment of Alzheimer’s disease is critical.Near-infrared fluorescence (NIRF) molecular probe can be used for the early diagnosis of Alzheimer’s disease because of its safety, accuracy, high sensitivity and low cost. Thus, in recent years the development of new near-infrared fluorescence probe molecule attracts a lot of people’s attention. Currently, a dozen NIRF molecular probes have been reported in the literature, but are rarely used in clinical use.In this paper, a new series of phenothiazine derivatives and benzothiazole derivatives were designed and synthesized. The fluorescence properties were evaluated firstly, including absorbance spectrum, excitation and emission wavelengths of the compound, the fluorescence quantum yield and fluorescence intensity. Then screening and optimization were conducted to obtain near-infrared fluorescent probe. Subsequently, the inhibitory activity of Aβ aggregation and the affinity for Aβ aggregates of these molecules were further investigated, in order to research for the near-infrared fluorescent probe that can be used not only in treatment of Alzheimer’s disease but also in the diagnosis. They could be used to track the treatment of Alzheimer’s disease.The results showed that the expected target has been achieved with the phenothiazine derivatives. The emission wavelengths of most of these compounds were in the range of 650-700 nm, within the "biological window" in which near-infrared molecular probes needed to be detected. Some compounds have a strong affinity with Aβ aggregation, such as compound 6al. Its Kd was only 7.5 nM. Fluorescence quantum yield of the compound in binding with Aβ self-aggregation, after a substantial increase, such as 9a2, reached 66.4% Meanwhile, most of the compounds had good inhibitory activities to Aβ1-2 self aggregation, showing a stronger inhibitory effect than Curcumin as control, especially for the compound 12a,the inhibition rate is more than twice the curcumin, reaching 84.9%.Therefore, thiazide derivatives fluorescent probe that can not only be used to treat of Alzheimer’s disease but also plays a role in the diagnosis.However, concerning the benzothiazole derivatives, we have not obtained the compounds in the range of near-infrared fluorescence. Optimization of this series of compounds is still underway in our laboratory.