11C-DPA-713:: A novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation
11C-DPA-713:: A novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation
复制标题
DOI：
10.2967/jnumed.106.036764
复制
发表时间：
2007-04-01
影响因子：
9.3
通讯作者：
Kassiou, Michael
中科院分区：
文献类型：
--
作者：
Boutin, Herve;Chauveau, Fabien;Kassiou, Michael
神经炎症过程的诱导，其特征在于由小胶质细胞表达的外周苯二氮卓受体（PBR）的上调，与神经退行性疾病和急性神经元损失密切相关。在发达国家，神经退行性疾病的发病率不断增加，已成为一个主要的健康问题，需要开发诊断和随访工具。在这里，我们研究了一种新的PBR配体适合PET监测神经炎症过程作为神经退行性变的间接标志。研究方法：我们在大鼠神经炎症模型中使用小动物专用PET相机比较了PK 11195（PBR结合位点的参考化合物）与新配体DPA-713（N，N-二乙基-2-[2-（4-甲氧基苯基）-5，7-二甲基吡唑并[1，5-a]嘧啶-3-基]乙酰胺）。纹状体内注射顺氨基-3-羟基-5甲基-4-异恶唑丙酸酯（AMPA）后7天，使用C-11-PK 11195或C-11-DPA-713进行PET扫描。然后将神经元（NeuN）、星形胶质细胞（胶质细胞酸性蛋白）和小胶质细胞（CD 11）特异性标志物的免疫组织化学以及H-3-PK 11195放射自显影研究与成像数据相关联。结果如下：在纹状体中单侧注射AMPA后7天，C-11-DPA-713在健康和受损脑实质之间表现出比C-11-PK 11195更好的对比度（分别增加2.5倍-4-0.14 vs. 1.6倍+/-0.05）。（11）CDPA-713和C-11-PK 11195在同侧表现出相似的脑摄取，而在对侧，C-DPA-713摄取显著低于C-11-PK 11195。使用简化的参考组织模型对数据进行建模，结果表明，C-DPA-713的结合潜力显著高于C-11-PK 11195。结论：C-DPA-713显示出比C-11-PK 11195更高的信噪比，因为非特异性结合水平较低，这可能与C-DPA-713的亲脂性较低有关。尽管需要在人体中进行进一步研究，但C-11-DPA-713是C-11-PK 11195的合适替代品，可用于PBR的PET，作为神经元应激诱导的神经炎症过程的示踪剂。
The induction of neuroinflammatory processes, characterized by upregulation of the peripheral benzodiazepine receptor (PBR) expressed by microglial cells, is well correlated with neurodegenerative diseases and with acute neuronal loss. The continually increasing incidence of neurodegenerative diseases in developed countries has become a major health problem, for which the development of diagnostic and follow-up tools is required. Here we investigated a new PBR ligand suitable for PET to monitor neuroinflammatory processes as an indirect hallmark of neurodegeneration. Methods: We compared PK1 1195, the reference compound for PBR binding sites, with the new ligand DPA-713 (N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-ajpyrimidin-3-yl]acetamide), using a small-animal dedicated PET camera in a model of neuroinflammation in rats. Seven days after intrastriatal injection of ci-amino-3-hydroxy-5methyl-4-isoxazolepropionate (AMPA), a PETscan was performed using C-11-PK11195 or C-11-DPA-713. Immunohistochemistry for neuronal (NeuN), astrocyte (glial fibrillary acidic protein), and microglial (CD1 1) specific markers as well as H-3-PK11195 autoradiographic studies were then correlated with the imaging data. Results: Seven days after a unilateral injection of AMPA in the striatum, C-11-DPA-713 exhibits a bettercontrast between healthy and damaged brain parenchyma than C-11-PK11195 (2.5-fold-4-0.14 increase vs. 1.6-fold +/- 0.05 increase, respectively). (11)CDPA-713 and C-11-PK11195 exhibit similar brain uptake in the ipsilateral side, whereas, in the contralateral side, "C-DPA-713 uptake was significantly lower than C-11-PK11195. Modeling of the data using the simplified reference tissue model shows that the binding potential was significantly higher for "C-DPA-713 than for C-11-PK11195. Conclusion: "C-DPA-713 displays a higher signal-to-noise ratio than C-11-PK11195 because of a lower level of unspecific binding that is likely related to the lower lipophilicity of "C-DPA-713. Although further studies in humans are required, C-11-DPA-713 represents a suitable alternative to C-11-PK11195 for PET of PBR as a tracer of neuroinflammatory processes induced by neuronal stress.