Improvement On The Synthesis Of PIB Precursor Of Aβ Plaque Imaging Agent And Evaluation Of Bioactivity

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder characterized by irreversible memory impairment, continuous cognitive decline and behavioral disturbances. The production and accumulation ofβ-amyloid plaques (Aβ) is believed to be pivotal to the pathogenesis and progression of AD, and the formation of AP plaques precedes the appearance of clinical symptoms. Developing of AD imaging agents forβ-amyloid plaques are of great significance to early diagnosis of AD. The 2-arylbenzothiazole (BTA) derivatives represent one of the most promising families. Among BTA Aβimaging agents currently under clinical evaluation, 2-(4-[11C]methylaminophenyl)-6-hydroxybenzothiazole (Pittsburgh Compound-B, 11C-PIB) has achieved highest signal-to-noise ratio and has high affinity to AP[Kd=4.7nM/L (Aβ1-40)] and fast nonspecific clearance, and has been adopted to perform AD-related research studies at more than 40 research centers worldwide. 6-OH-BTA-0 is the precursor of 11C-PIB.It can only be available from ABX company present and is very expensive (680yuan/mg). So it is necessary to find a high effective and simply method to synthesize 6-OH-BTA-0. In this paper,we described the improved synthesis of 2-(4'-aminophenyl)-6-hydroxyl benzothiazole (6-OH-BTA-0). We used Jacobson's cyclization to obtain 2-(4'-nitrophenyl)-6-methoxy benzothiazole and next synthesize the objective product 6-OH-BTA-0 by one-step with concentrated HI as the demethylation and reduction reagent,which simplified the synthetic route. The total yield was improved to 50.4% from reported 31.8%.The purity of end product 6-OH-BTA-0 is 99.72%(HPLC:sunfireTM C18 column,mobile phase:35/65 acetonitrile/phosphate buffer,pH7.2).The cost was reduced.6-OH-BTA-0 continued to react with ICD3 to produce 6-CD3O-BTA-Me as a binding substrate to evaluate the binding affinity constant of PIB.6-OH-BTA-0 reacted with CH3I to produce 6-OH-BTA-1.The assay of binding affinity of 6-OH-BTA-0 and 6-OH-BTA-1 to homogenates of postmortem brain in AD was performed in vitro and the value of Ki calculated by specific softwares was 33.5nM and 8.8nM respectively(the smaller the value,the better of the affinity) and the results were better than literatures reported(45.6nM and 8.89nM),especially the result of 6-OH-BTA-1.The results of high affinity for Ap indicated that self-made PIB were not worse than literatures reported and could be available for further experiments in early diagnosis of AD.Key Words:6-OH-BTA-0; HI; Alzheimer's disease; Aβimaging agent; affinity...