PET imaging of colony-stimulating factor 1 receptor: A head-to-head comparison of a novel radioligand, 11C-GW2580, and 11C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey
PET imaging of colony-stimulating factor 1 receptor: A head-to-head comparison of a novel radioligand, 11C-GW2580, and 11C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey
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DOI：
10.1177/0271678x211004146
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发表时间：
2021-03-24
影响因子：
6.3
通讯作者：
Higuchi, Makoto
中科院分区：
文献类型：
--
作者：
Zhou, Xiaoyun;Ji, Bin;Higuchi, Makoto
集落刺激因子1受体（CSF 1 R）是小胶质细胞的特异性生物标志物。在这项研究中，我们开发了一种新的PET放射性配体CSF 1 R，C-11-GW 2580，并将其与报道的CSF 1 R示踪剂C-11-CPPC在急性和慢性神经炎症小鼠模型和恒河猴中进行了比较。动态C-11-GW 2580-和C-11-CPPC-PET图像通过基于参考组织的模型和标准化摄取值比率进行定量。两种示踪剂在脂多糖注射小鼠的损伤纹状体和App（NL-G-F/NL-G-F）敲入小鼠的前脑中均表现出增加的摄取，在空间上与增加的18 kDa转运蛋白放射性配体保留一致。此外，在这些模型动物中，C-11-GW 2580比C-11-CPPC更敏感地捕获CSF 1 R可用性的变化，具有更大的动态范围和更小的个体间变异性。恒河猴中CSF 1 R的PET成像显示基线时大脑中的中度至高度示踪剂保留。Homopolymer blocker（i. e.未标记的示踪剂）处理在除半卵圆中心白色物质外的所有检查的脑区域中使C-11-GW 2580的摄取减少了约30%，但不影响C-11-CPPC的保留。总之，我们的结果表明，C-11-GW 2580-PET捕获小鼠脑中的炎性小胶质细胞增生的灵敏度高于报道的放射性配体，并在猴脑中显示可饱和结合，可能为反应性小胶质细胞增生提供基于成像的定量生物标志物。
Colony-stimulating factor 1 receptor (CSF1R) is a specific biomarker for microglia. In this study, we developed a novel PET radioligand for CSF1R, C-11-GW2580, and compared it to a reported CSF1R tracer, C-11-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. Dynamic C-11-GW2580- and C-11-CPPC-PET images were quantified by reference tissue-based models and standardized uptake value ratio. Both tracers exhibited increased uptake in the lesioned striata of lipopolysaccharide-injected mice and in the forebrains of App(NL-G-F/NL-G-F)-knock-in mice, spatially in agreement with an increased 18-kDa translocator protein radioligand retention. Moreover, C-11-GW2580 captured changes in CSF1R availability more sensitively than C-11-CPPC, with a larger dynamic range and a smaller inter-individual variability, in these model animals. PET imaging of CSF1R in a rhesus monkey displayed moderate-to-high tracer retention in the brain at baseline. Homologous blocker (i. e. unlabeled tracer) treatment reduced the uptake of C-11-GW2580 by similar to 30% in all examined brain regions except for centrum semi-ovale white matter, but did not affect the retention of C-11-CPPC. In summary, our results demonstrated that C-11-GW2580-PET captured inflammatory microgliosis in the mouse brain with higher sensitivity than a reported radioligand, and displayed saturable binding in the monkey brain, potentially providing an imaging-based quantitative biomarker for reactive microgliosis.