Microglia, the immune cells in the brain, play a significant role in the pathophysiology of neurodegenerative diseases. To visualize these cells in the living brain, we developed a PET ligand, [¹¹C]NCGG401 (4-{2-[((1R,2R)-2-hydroxycyclohexyl)(methyl)amino]benzothiazol-6-yloxy}-N-methylpicolinamide, NCGG401), that targets colony-stimulating factor 1 receptor (CSF1R). In this study, we present the first-in-human evaluation of [¹¹C]NCGG401 to assess its safety profile and then to evaluate its kinetics to quantify CSF1R in the human brain. Methods: Head to upper thigh PET scans were conducted in 3 healthy men to estimate the effective dose of [¹¹C]NCGG401. Brain PET scans were performed on 6 healthy men, combined with arterial blood sampling and metabolite analyses. Compartmental and graphical models were used to quantify CSF1R in the human brain. [¹¹C]NCGG401 PET data were indirectly compared with regional CSF1R protein levels after death that were reported in a proteomics study. In addition, the results of this study were directly compared with the PET imaging of 18-kDa translocator protein using [¹¹C]DPA-713 (N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl]acetamide, DPA-713). Results: The administration of [¹¹C]NCGG401 did not result in severe adverse events. The effective doses per injected activity were 5.1 ± 0.2 µSv/MBq for men and 6.1 ± 0.3 µSv/MBq for women. [¹¹C]NCGG401 demonstrated good brain permeability, with peak uptake reaching an SUV of 3. Regional total distribution volumes were reliably quantified using the 2-tissue compartment model and a Logan plot with 60 min of scan data. The resulting parametric images reflected the known distribution of CSF1R in the brain. Furthermore, regional total distribution volume values of [¹¹C]NCGG401 showed good correlation with regional CSF1R protein levels. The [¹¹C]NCGG401 images showed regional distributions different from those of [¹¹C]DPA-713. Conclusion: [¹¹C]NCGG401 images appear to reflect regional microglia-specific distributions of CSF1R in the brain, consistent with the findings of a CSF1R proteomics study by others. However, ultimate confirmation of specific CSF1R binding should be validated by evaluating, in suitable preclinical or human experiments, pharmacologic blockade of its binding in the brain in vivo.

小胶质细胞是大脑中的免疫细胞，在神经退行性疾病的病理生理学中起着重要作用。为了在活体大脑中可视化这些细胞，我们开发了一种 PET 配体 [¹¹C]NCGG401 （4-{2-[（（1R，2 R）-2-羟基环己基）（甲基）氨基]苯并噻唑-6-基氧基}-N-甲基吡啶甲酰胺，NCGG401），靶向集落刺激因子 1 受体 （CSF1R）。在这项研究中，我们提出了 [¹¹C]NCGG401 的首次人体评估，以评估其安全性，然后评估其动力学以量化人脑中的 CSF1R。方法：对 3 名健康男性进行了头部到大腿上部的 PET 扫描，以估计 [¹¹C]NCGG401 的有效剂量。对 6 名健康男性进行脑部 PET 扫描，结合动脉血取样和代谢物分析。房室和图形模型用于量化人脑中的 CSF1R。[¹¹个分类]NCGG401 PET 数据与蛋白质组学研究中报道的死后区域 CSF1R 蛋白水平间接进行比较。此外，本研究的结果与使用 [¹¹C]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，DPA-713）对 18-kDa 易位蛋白的 PET 成像进行了直接比较。结果：[¹¹C]NCGG401 的给药未导致严重的不良事件。男性每次注射活性的有效剂量为 5.1 ± 0.2 μSv/MBq，女性为 6.1 ± 0.3 μSv/MBq。[¹¹个分类]NCGG401 表现出良好的脑通透性，SUV 的峰值摄取达到 3。使用 2 组织隔室模型和具有 60 分钟扫描数据的 Logan 图可靠地量化区域总分布体积。 由此产生的参数图像反映了 CSF1R 在大脑中的已知分布。此外，[¹¹C]NCGG401 的区域总分布体积值与区域 CSF1R 蛋白水平具有良好的相关性。[¹¹C]NCGG401 图像显示的区域分布与 [¹¹C]DPA-713 不同。结论：[¹¹C]NCGG401 图像似乎反映了 CSF1R 在大脑中的区域小胶质细胞特异性分布，这与其他人的 CSF1R 蛋白质组学研究结果一致。然而，特异性 CSF1R 结合的最终确认应通过在适当的临床前或人体实验中评估其在体内结合的药物阻断来验证。