Boutin Hervé, Chauveau Fabien, Thominiaux Cyrille, Grégoire Marie-Claude, James Michelle L, Trebossen Régine, Hantraye Philippe, Dollé Frédéric, Tavitian Bertrand, Kassiou Michael
CEA, Institut d'Imagerie Biomédicale, Service hospitalier Frédéric Joliot, Laboratoire d'Imagerie Moléculaire Expérimentale, Orsay, France.
J Nucl Med. 2007 Apr;48(4):573-81. doi: 10.2967/jnumed.106.036764.
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.
We compared PK11195, 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-a]pyrimidin-3-yl]acetamide), using a small-animal dedicated PET camera in a model of neuroinflammation in rats. Seven days after intrastriatal injection of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), a PET scan was performed using (11)C-PK11195 or (11)C-DPA-713. Immunohistochemistry for neuronal (NeuN), astrocyte (glial fibrillary acidic protein), and microglial (CD11) specific markers as well as (3)H-PK11195 autoradiographic studies were then correlated with the imaging data.
Seven days after a unilateral injection of AMPA in the striatum, (11)C-DPA-713 exhibits a better contrast between healthy and damaged brain parenchyma than (11)C-PK11195 (2.5-fold +/- 0.14 increase vs. 1.6-fold +/- 0.05 increase, respectively). (11)C-DPA-713 and (11)C-PK11195 exhibit similar brain uptake in the ipsilateral side, whereas, in the contralateral side, (11)C-DPA-713 uptake was significantly lower than (11)C-PK11195. Modeling of the data using the simplified reference tissue model shows that the binding potential was significantly higher for (11)C-DPA-713 than for (11)C-PK11195.
(11)C-DPA-713 displays a higher signal-to-noise ratio than (11)C-PK11195 because of a lower level of unspecific binding that is likely related to the lower lipophilicity of (11)C-DPA-713. Although further studies in humans are required, (11)C-DPA-713 represents a suitable alternative to (11)C-PK11195 for PET of PBR as a tracer of neuroinflammatory processes induced by neuronal stress.
以小胶质细胞表达的外周苯二氮䓬受体（PBR）上调为特征的神经炎症过程的诱导，与神经退行性疾病和急性神经元丢失密切相关。发达国家神经退行性疾病的发病率持续上升，已成为一个重大的健康问题，因此需要开发诊断和随访工具。在此，我们研究了一种适用于正电子发射断层扫描（PET）的新型PBR配体，以监测神经炎症过程，作为神经退行性变的间接标志。
我们将PBR结合位点的参考化合物PK11195与新型配体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）进行比较，在大鼠神经炎症模型中使用小动物专用PET相机。在纹状体内注射α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）7天后，使用（11）C-PK11195或（11）C-DPA-713进行PET扫描。然后将神经元（NeuN）、星形胶质细胞（胶质纤维酸性蛋白）和小胶质细胞（CD11）特异性标志物的免疫组织化学以及（3）H-PK11195放射自显影研究与成像数据相关联。
在纹状体单侧注射AMPA 7天后，（11）C-DPA-713在健康和受损脑实质之间的对比度比（11）C-PK11195更好（分别增加2.5倍±0.14和1.6倍±0.05）。（11）C-DPA-713和（11）C-PK11195在同侧脑内摄取相似，而在对侧，（11）C-DPA-713的摄取明显低于（11）C-PK11195。使用简化参考组织模型对数据进行建模显示，（11）C-DPA-713的结合潜能明显高于（11）C-PK11195。
由于非特异性结合水平较低，这可能与（11）C-DPA-713较低的亲脂性有关，（11）C-DPA-713比（11）C-PK11195显示出更高的信噪比。尽管需要在人体中进行进一步研究，但（11）C-DPA-713是（11）C-PK11195的合适替代品，可用于PET检测PBR，作为神经元应激诱导的神经炎症过程的示踪剂。
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