在活鼠大脑中检测硫化氢：在神经炎症模型中的应用。
In vivo detection of hydrogen sulfide in the brain of live mouse: application in neuroinflammation models.
机构信息
Department of Molecular Medicine, Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea.
Department of Pharmacology, Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Brain Science & Engineering Institute, Kyungpook National University, Daegu, 41944, South Korea.
出版信息
Eur J Nucl Med Mol Imaging. 2022 Oct;49(12):4073-4087. doi: 10.1007/s00259-022-05854-1. Epub 2022 Jun 10.
PURPOSE
Hydrogen sulfide (HS) plays important roles in brain pathophysiology. However, nuclear imaging probes for the in vivo detection of brain HS in living animals have not been developed. Here, we report the first nuclear imaging probe that enables in vivo imaging of endogenous HS in the brain of live mice.
METHODS
Utilizing a bis(thiosemicarbazone) backbone, a fluorescent ATSM-FITC conjugate was synthesized. Its copper complex, Cu(ATSM-FITC) was thoroughly tested as a biosensor for HS. The same ATSM-FITC ligand was quantitatively labeled with [Cu]CuCl to obtain a radioactive [Cu][Cu(ATSM-FITC)] imaging probe. Biodistribution and positron emission tomography (PET) imaging studies were performed in healthy mice and neuroinflammation models.
RESULTS
The Cu(ATSM-FITC) complex reacts instantly with HS to release CuS and becomes fluorescent. It showed excellent reactivity, sensitivity, and selectivity to HS. Endogenous HS levels in living cells were successfully detected by fluorescence microscopy. Exceptionally high brain uptake of [Cu][Cu(ATSM-FITC)] (> 9% ID/g) was observed in biodistribution and PET imaging studies. Subtle changes in brain HS concentrations in live mice were accurately detected by quantitative PET imaging. Due to its dual modality feature, increased HS levels in neuroinflammation models were characterized at the subcellular level by fluorescence imaging and at the whole-body scale by PET imaging.
CONCLUSION
Our biosensor can be readily utilized to study brain HS function in live animal models and shows great potential as a novel imaging agent for diagnosing brain diseases.
目的
硫化氢（HS）在脑病理生理学中发挥着重要作用。然而，尚未开发出用于在活体动物中检测脑内 HS 的核医学成像探针。在此，我们报告了首例能够在活体小鼠脑内进行内源性 HS 体内成像的核医学成像探针。
方法
利用双（硫代缩氨基甲酸盐）骨架，合成了荧光 ATSM-FITC 缀合物。其铜配合物 Cu（ATSM-FITC）被彻底测试为 HS 的生物传感器。相同的 ATSM-FITC 配体与 [Cu]CuCl 定量标记，得到放射性 [Cu][Cu（ATSM-FITC）]成像探针。在健康小鼠和神经炎症模型中进行了生物分布和正电子发射断层扫描（PET）成像研究。
结果
Cu（ATSM-FITC）配合物与 HS 立即反应释放 CuS 并变得荧光。它对 HS 表现出优异的反应性、灵敏度和选择性。荧光显微镜成功检测到活细胞内的内源性 HS 水平。在生物分布和 PET 成像研究中，[Cu][Cu（ATSM-FITC）]的脑摄取量极高（>9% ID/g）。通过定量 PET 成像可以准确检测活体小鼠脑内 HS 浓度的细微变化。由于其具有双重模态特征，荧光成像可在亚细胞水平，PET 成像可在全身水平对神经炎症模型中的 HS 水平升高进行特征描述。
结论
我们的生物传感器可用于研究活体动物模型中的脑 HS 功能，并有望成为诊断脑部疾病的新型成像剂。
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