碳-11标记的6-羟基哒嗪酮衍生物在小鼠体内的生物学分布研究

Biodistribution of a C-labeled 6-Hydroxypyridazinone Derivative in Mice

目的:研究碳-11标记的6-羟基哒嗪酮衍生物[^(11)C]HCC923在小鼠体内和脑内的分布情况。方法:加速器中产生的[^(11)C]CO2通过TRACERlab FX-MeI模块中的两步反应生成[^(11)C]CH3I,然后与前体化合物反应生成放射性示踪剂[^(11)C]HCC923。在快速纯化和制剂后,用尾静脉注射的方式给正常小鼠注射[^(11)C]HCC923,每只注射100~150μCi。然后经PET/CT成像得到影像数据,并分析各个时间点[^(11)C]HCC923在体内重要脏器以及在脑内亚结构脑区的放射性摄取分布。结果:通过[^(11)C]CH3I的^(11)C-甲基化反应成功制备了[^(11)C]HCC923,从加速器开启到制备完成的合成时间为60~80 min,放射化学产率约为12%(未经时间校正),放射化学纯度大于95%。小鼠PET/CT的影像数据表明,注射[^(11)C]HCC923后在体内主要脏器都有分布,其在肝脏和肾脏中代谢较快,无明显蓄积。[^(11)C]HCC0923能较快地通过血脑屏障达到脑内,在5~10 min后放射性摄取达到最大,并在脑中持续稳定的的结合;对各个脑内亚结构脑区的放射性摄取分析中可看到,[^(11)C]HCC0923在海马和下丘脑中有相对较高的吸收,其中在海马中%ID/cc为7.65,而在大脑皮质,脑干中则分布较少。结论:[^(11)C]HCC923的放射合成方法可靠有效;[^(11)C]HCC923在体内分布和代谢正常,且能快速通过血脑屏障在脑内特异性的分布,其中主要分布在海马内,并能在扫描时间范围内维持一定的平衡,表明其原型化合物HCC0923具有较高的靶向Sigma-1受体的中枢神经系统小分子药物的研发潜力。

Objective:To evaluate the biodistribution in major organs and brain of a^(11)C-labeled 6-hydroxypyridazinone derivative[^(11)C]HCC923 in mice.Methods:[^(11)C]CH3I was synthesized by[^(11)C]CO2 from the cyclotron through a two-step reaction in TRACERlab FX-MeI module,and then reacted with the precursor to produce the radiotracer[^(11)C]HCC923.After a fast purification and formulation,[^(11)C]HCC923 was administered in normal mice through intravenous bolus injection,100-150μCi per mouse.The image data was acquired by PET/CT,and the biodistribution of[^(11)C]HCC923 in major organs and substructural brain regions at all time points were evaluated through the data analysis.Results:[^(11)C]HCC923 was successfully synthesized through^(11)C-methylation of[^(11)C]CH3I.The procedure from the start of cyclotron to completion of preparation spent 60-80 min with a radio-chemical yield around 12%and a radio-chemical purity over 95%.The PET/CT imaging data of mouse showed that[^(11)C]HCC923 was distributed in the main organs of body after injection,and metabolized rapidly in liver and kidney without significant accumulation.It also exhibited the brain-blood barrier penetration and fast uptake in brain.The concentration of[^(11)C]HCC0923 in brain reached a maximum uptake within 5-10 min after injection,and[^(11)C]HCC0923 could sustained binding in brain during the imaging test.The distribution of[^(11)C]HCC0923 in selected brain substructure regions was investigated,and it was showed higher uptakes in hippocampus and hypothalamus(the maximum radioactive uptake was in hippocampus,%ID/cc=7.65)as compared to cortex and brain stern.Conclusion:The radiolabeling method of[^(11)C]HCC923 is practical and effective.The biodistribution of[^(11)C]HCC923 and its in vivo clearance in major organs are appropriate.It can also penetrate into brain with specific bound to brain regions,mainly in hippocampus,and also maintain relative balance during scanning.Therefore,the original compound HCC923 can be potentially developed as a specific sigma-1 receptor targeted small molecular drug for central nervous system diseases.