European Institute for Molecular Imaging, University of Münster, Münster, Germany;
PET Imaging in Drug Design and Development, Münster, Germany.
J Nucl Med. 2022 Sep;63(9):1386-1393. doi: 10.2967/jnumed.121.263318. Epub 2022 Feb 3.
Glioma-associated microglia and macrophages (GAMMs) are key players in creating an immunosuppressive microenvironment. They can be efficiently targeted by inhibiting the colony-stimulating factor 1 receptor (CSF-1R). We applied noninvasive PET/CT and PET/MRI using F-fluoroethyltyrosine (F-FET) (amino acid metabolism) and -diethyl-2-[4-(2-F-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-]pyrimidine-3-acetamide (F-DPA-714) (translocator protein) to understand the role of GAMMs in glioma initiation, monitor in vivo therapy-induced GAMM depletion, and observe GAMM repopulation after drug withdrawal. C57BL/6 mice ( = 44) orthotopically implanted with syngeneic mouse GL261 glioma cells were treated with different regimens using the CSF-1R inhibitor PLX5622 (6-fluoro--((5-fluoro-2-methoxypyridin-3-yl)methyl)-5-((5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-amine) or vehicle, establishing a preconditioning model and a repopulation model, respectively. The mice underwent longitudinal PET/CT and PET/MRI. The preconditioning model indicated similar tumor growth based on MRI (44.5% ± 24.8%), F-FET PET (18.3% ± 11.3%), and F-DPA-714 PET (16% ± 19.04%) volume dynamics in all groups, suggesting that GAMMs are not involved in glioma initiation. The repopulation model showed significantly reduced F-DPA-714 uptake (-45.6% ± 18.4%), significantly reduced GAMM infiltration even after repopulation, and a significantly decreased tumor volume (-54.29% ± 8.6%) with repopulation as measured by MRI, supported by a significant reduction in F-FET uptake (-50.2% ± 5.3%). F-FET and F-DPA-714 PET/MRI allow noninvasive assessment of glioma growth under various regimens of CSF-1R therapy. CSF-1R-mediated modulation of GAMMs may be of high interest as therapy or cotherapy against glioma.
胶质细胞瘤相关的小胶质细胞和巨噬细胞（GAMMs）是形成免疫抑制微环境的关键因素。通过抑制集落刺激因子 1 受体（CSF-1R），可以有效地靶向这些细胞。我们应用非侵入性的正电子发射断层扫描/计算机断层扫描（PET/CT）和正电子发射断层扫描/磁共振成像（PET/MRI），使用 F-氟乙基酪氨酸（F-FET）（氨基酸代谢）和 -二乙基-2-[4-（2-F-氟乙氧基）苯基]-5,7-二甲基吡唑并[1,5-a]嘧啶-3-乙酰胺（F-DPA-714）（转位蛋白），来了解 GAMMs 在胶质瘤起始中的作用，监测体内治疗诱导的 GAMM 耗竭，并观察停药后的 GAMM 再填充。将同源的 GL261 胶质细胞瘤细胞原位植入 C57BL/6 小鼠（=44）中，使用 CSF-1R 抑制剂 PLX5622（6-氟--（5-氟-2-甲氧基吡啶-3-基）甲基）-5-（5-甲基-1H-吡咯并[2,3-b]吡啶-3-基）甲基）吡啶-2-甲酰胺）或载体进行不同方案的治疗，分别建立预处理模型和再填充模型。小鼠进行了纵向 PET/CT 和 PET/MRI 检查。预处理模型显示基于 MRI（44.5%±24.8%）、F-FET PET（18.3%±11.3%）和 F-DPA-714 PET（16%±19.04%）的肿瘤生长具有相似的体积动力学，表明 GAMMs 不参与胶质瘤的起始。再填充模型显示 F-DPA-714 摄取显著减少（-45.6%±18.4%），即使在再填充后 GAMM 浸润也显著减少，肿瘤体积显著缩小（-54.29%±8.6%），MRI 测量的结果得到 F-FET 摄取减少（-50.2%±5.3%）的支持。F-FET 和 F-DPA-714 PET/MRI 允许对各种 CSF-1R 治疗方案下的胶质瘤生长进行非侵入性评估。CSF-1R 介导的 GAMM 调节可能作为治疗或联合治疗胶质细胞瘤的方法具有重要意义。
