Boutin Hervé, Chauveau Fabien, Thominiaux Cyrille, Kuhnast Bertrand, Grégoire Marie-Claude, Jan Sébastien, Trebossen Régine, Dollé Frédéric, Tavitian Bertrand, Mattner Filomena, Katsifis Andrew
CEA, DSV, I2BM, SHFJ, Laboratoire d'Imagerie Moléculaire Expérimentale, Orsay, France.
Glia. 2007 Nov 1;55(14):1459-68. doi: 10.1002/glia.20562.
The peripheral benzodiazepine receptor (PBR) is expressed by microglial cells in many neuropathologies involving neuroinflammation. PK11195, the reference compound for PBR, is used for positron emission tomography (PET) imaging but has a limited capacity to quantify PBR expression. Here we describe the new PBR ligand CLINME as an alternative to PK11195. In vitro and in vivo imaging properties of [(11)C]CLINME were studied in a rat model of local acute neuroinflammation, and compared with the reference compound [(11)C]PK11195, using autoradiography and PET imaging. Immunohistochemistry study was performed to validate the imaging data. [(11)C]CLINME exhibited a higher contrast between the PBR-expressing lesion site and the intact side of the same rat brain than [(11)C]PK11195 (2.14 +/- 0.09 vs. 1.62 +/- 0.05 fold increase, respectively). The difference was due to a lower uptake for [(11)C]CLINME than for [(11)C]PK11195 in the non-inflammatory part of the brain in which PBR was not expressed, while uptake levels in the lesion were similar for both tracers. Tracer localization correlated well with that of activated microglial cells, demonstrated by immunohistochemistry and PBR expression detected by autoradiography. Modeling using the simplified tissue reference model showed that R(1) was similar for both ligands (R(1) approximately 1), with [(11)C]CLINME exhibiting a higher binding potential than [(11)C]PK11195 (1.07 +/- 0.30 vs. 0.66 +/- 0.15). The results show that [(11)C]CLINME performs better than [(11)C]PK11195 in this model. Further studies of this new compound should be carried out to better define its capacity to overcome the limitations of [(11)C]PK11195 for PBR PET imaging.
在许多涉及神经炎症的神经病理学中，外周苯二氮䓬受体（PBR）由小胶质细胞表达。PBR的参考化合物PK11195用于正电子发射断层扫描（PET）成像，但定量PBR表达的能力有限。在此，我们描述了新型PBR配体CLINME作为PK11195的替代品。在局部急性神经炎症大鼠模型中研究了[(11)C]CLINME的体外和体内成像特性，并使用放射自显影和PET成像与参考化合物[(11)C]PK11195进行比较。进行免疫组织化学研究以验证成像数据。[(11)C]CLINME在表达PBR的病变部位与同一只大鼠脑的完整侧之间显示出比[(11)C]PK11195更高的对比度（分别增加2.14±0.09倍和1.62±0.05倍）。差异是由于[(11)C]CLINME在不表达PBR的脑非炎症部分的摄取低于[(11)C]PK11195，而两种示踪剂在病变中的摄取水平相似。示踪剂定位与活化小胶质细胞的定位良好相关，免疫组织化学和放射自显影检测到的PBR表达证明了这一点。使用简化组织参考模型进行的建模表明，两种配体的R(1)相似（R(1)约为1），[(11)C]CLINME的结合潜力高于[(11)C]PK11195（1.07±0.30对0.66±0.15）。结果表明，在该模型中[(11)C]CLINME比[(11)C]PK11195表现更好。应进一步研究这种新化合物，以更好地确定其克服[(11)C]PK11195在PBR PET成像方面局限性的能力。
