Detection of Microglial Activation in an Acute Model of Neuroinflammation Using PET and Radiotracers 11C-(R)-PK11195 and 18F-GE-180
Detection of Microglial Activation in an Acute Model of Neuroinflammation Using PET and Radiotracers 11C-(R)-PK11195 and 18F-GE-180
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DOI：
10.2967/jnumed.113.125625
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发表时间：
2014-03-01
影响因子：
9.3
通讯作者：
Airas, Laura
中科院分区：
文献类型：
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作者：
Dickens, Alex M.;Vainio, Susanne;Airas, Laura
目前尚不清楚不同的转运蛋白(TSPO)配体如何在不同的神经炎症条件下反映星形胶质细胞或小胶质细胞激活的空间范围。在这里，我们使用一个可重复性的脂多糖(LPS)诱导的急性中枢神经系统炎症模型来比较新的TSPO配体F-18-Ge-180与C-11-(R)-PK11195的结合性能。利用免疫组织化学方法，我们还探索了TSPO配体检测激活的小胶质细胞和星形胶质细胞的能力。方法：30只Lewis大鼠左侧纹状体内注射脂多糖(1或10mU)或生理盐水(L 1mU)。于注射后16h用放射性示踪剂F-18-Ge-180或C-11-(R)-PK11195活体显像，每组3只，随后处死动物行脑放射自显影。用免疫组织化学方法检测OX-42和胶质纤维酸性蛋白(GFAP)的表达，鉴定活化的小胶质细胞和反应性星形胶质细胞。结果：体内PET成像显示，与对侧大脑半球相比，注射10mgLPS后，同侧TSPO结合量增加。车辆组未见增加。放射自显影显示，纹状体内注射1或10mgLPS后，注射侧大脑半球TSPO放射性示踪剂结合电位增加。然而，只有在使用F-18-Ge-180时才能观察到显著的增加。CD11b表达的小胶质细胞的面积超出了增强的GFAP染色的范围，与F-18-Ge-180结合的程度比与C-11-(R)-PK11195结合的程度更接近。在GFAP免疫反应增强和OX-42共定位的区域，来自任一PET配体的信号显著增强，这意味着在给定区域同时存在激活的小胶质细胞和星形胶质细胞导致TSPO放射性示踪剂的结合增加。结论：F-18-GE-180能够显示灰质和白质中激活的小胶质细胞的部位。然而，激活的星形胶质细胞的存在会增加这一信号。因此，F-18-Ge-180是一种很有前途的新型氟化半衰期示踪剂，它以一种优于C-11-(R)-PK11195的方式揭示了激活的小胶质细胞的存在，因为观察到这种配体具有更高的结合潜力。
It remains unclear how different translocator protein (TSPO) ligands reflect the spatial extent of astrocyte or microglial activation in various neuroinflammatory conditions. Here, we use a reproducible lipopolysaccharide (LPS)-induced model of acute central nervous system inflammation to compare the binding performance of a new TSPO ligand F-18-GE-180 with C-11-(R)-PK11195. Using immunohistochemistry, we also explore the ability of the TSPO ligands to detect activated microglial cells and astrocytes. Methods: Lewis rats (n = 30) were microinjected with LPS (1 or 10 mu g) or saline (1 mu L) into the left striatum. The animals were imaged in vivo at 16 h after the injection using PET radiotracers F-18-GE-180 or C-11-(R)-PK11195 (n = 3 in each group) and were killed afterward for autoradiography of the brain. Immunohistochemical assessment of OX-42 and glial fibrillary acidic protein (GFAP) was performed to identify activated microglial cells and reactive astrocytes. Results: In vivo PET imaging revealed an increase in the ipsilateral TSPO binding, compared with binding in the contralateral hemisphere, after the microinjection of 10 mu g of LPS. No increase was observed with vehicle. By autoradiography, the TSPO radiotracer binding potential in the injected hemisphere was increased after striatal injection of 1 or 10 mu g of LPS. However, the significant increase was observed only when using F-18-GE-180. The area of CD11b-expressing microglial cells extended beyond that of enhanced GFAP staining and mapped more closely to the extent of F-18-GE-180 binding than to C-11-(R)-PK11195 binding. The signal from either PET ligand was significantly increased in regions of increased GFAP immunoreactivity and OX-42 colocalization, meaning that the presence of both activated microglia and astrocytes in a given area leads to increased binding of the TSPO radiotracers. Conclusion: F-18-GE-180 is able to reveal sites of activated microglia in both gray and white matter. However, the signal is increased by the presence of activated astrocytes. Therefore, F-18-GE-180 is a promising new fluorinated longer-half-life tracer that reveals the presence of activated microglia in a manner that is superior to C-11-(R)-PK11195 due to the higher binding potential observed for this ligand.