^(18)F-FINH-Me检测阿尔茨海默病模型鼠脑内β-淀粉样斑块沉积

β-amyloid plaque deposition in the brain of Alzheimer′s disease mouse model by ^(18)F-FINH-Me imaging

目的制备新型β-淀粉样蛋白(Aβ)显像剂(2-((2-6-[18F]氟-5-(甲氨基)吡啶-2-基)苯并噻唑-6-基)硫代)乙醇(18F-FINH-Me),评价其生物学分布及其与Aβ的亲和性。方法使用GE FN自动化模块合成18F-FINH-Me,采用高效液相色谱(HPLC)对产品进行质量控制及稳定性检测。研究18F-FINH-Me在正常C57BL/6小鼠(n=25)体内的生物学分布;对阿尔茨海默病(AD)模型鼠(n=5)和与其年龄及背景匹配的正常C57BL/6小鼠(n=5)进行microPET/CT显像。取小鼠脑组织进行Aβ免疫组织化学染色;取AD患者(女,69岁)和健康志愿者(女,66岁)死后的人脑切片进行18F-FINH-Me放射自显影。结果18F-FINH-Me衰减校正后的产率为(53±4)%(n>20);放射性纯度>98%(n>20);比活度达79.90~122.00 GBq/μmol(n=10);室温下在磷酸盐缓冲液(PBS)中温育4 h无脱氟现象,稳定性好。生物学分布表明,18F-FINH-Me主要经过肝肾排泄。MicroPET/CT显像示AD小鼠脑内18F-FINH-Me有明显放射性摄取,注射后1~2 min达到峰值,且洗脱速度快(全脑标准摄取值:注射后1 min 0.73±0.17,注射后30 min 0.31±0.06)。免疫组织化学结果显示AD模型鼠脑内有丰富的Aβ斑块沉积,而正常C57BL/6小鼠脑内无斑块沉积。放射性自显影结果表明18F-FINH-Me对AD患者脑内沉积的Aβ斑块高标记,而在健康志愿者的脑切片中未出现特异性标记。结论18F-FINH-Me可能是一种有效检测脑内Aβ斑块的PET显像剂。

Objective To synthesize a newβ-amyloid(Aβ)radioactive tracer(2-((2-6-[18F]fluoro-5-(methylamino)pyridin-2-yl)benzothiazol-6-yl)thio)ethanol(18F-FINH-Me),and evaluate its biological distribution and affinity to Aβplaques.Methods 18F-FINH-Me was synthesized by GE FN automated module,and the quality control and stability of 18F-FINH-Me were determined with high performance liquid chromatography(HPLC).The biodistribution of 18F-FINH-Me was observed in normal C57BL/6 mice(n=25).MicroPET/CT imaging was performed in Alzheimer′s disease(AD)model mice(n=5)and matched normal C57BL/6 mice(n=5).The brain tissues of mice were taken for Aβimmunohistochemical staining.18F-FINH-Me autoradiography was performed in postmortem brain sections of one AD patient(female,69 years old)and one healthy volunteer(female,66 years old).Results The decay correction yield of 18F-FINH-Me was(53±4)%(n>20)with the radioactive purity of more than 98%(n>20)and the specific activity of 79.90-122.00 GBq/μmol(n=10).18F-FINH-Me was stable in phosphate buffered solution(PBS)after incubation for 4 h at room temperature.The biodistribution showed that 18F-FINH-Me was mainly excreted through the liver and kidneys.MicroPET/CT imaging showed that 18F-FINH-Me was obviously uptaken in the brain of AD mice.After injection for 1-2 min,the uptake of 18F-FINH-Me reached the peak,and the elution speed was fast(whole brain standardized uptake value:0.73±0.17 for 1 min,0.31±0.06 for 30 min).The immunohistochemistry showed that there were abundant Aβplaques in the brain of AD model mice but not in the normal C57BL/6 mice brain.The autoradiographic results showed that 18F-FINH-Me exhibited substantial plaque labeling in brain sections of one AD patient but not in the healthy volunteer.Conclusion 18F-FINH-Me may be an effective PET agent for detecting Aβplaques in brain.