First-in-Human Study of [11C]NCGG401 for Imaging Colony-Stimulating Factor 1 Receptors in the Brain

Aya Ogata, Hiroshi Ikenuma, Fumihiko Yasuno, Takashi Nihashi, Saori Hattori, Yayoi Sato, Masanori Ichise, Kengo Ito, Takashi Kato, Yasuyuki Kimura
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Abstract

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.

[11C]NCGG401在脑成像集落刺激因子1受体中的首次人体研究
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,2R)-2-羟基环己基)(甲基)氨基]苯并噻唑-6-基氧基}- n -甲基吡啶酰胺,NCGG401),靶向集落刺激因子1受体(CSF1R)。在这项研究中,我们首次对[11C]NCGG401进行了人体评估,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名健康男性进行头部至大腿上部PET扫描,估计[11C]NCGG401的有效剂量。对6名健康男性进行了脑PET扫描,并结合动脉血液采样和代谢物分析。采用区室模型和图形模型量化人脑中的CSF1R。[11C]NCGG401 PET数据间接比较了一项蛋白质组学研究中报道的死亡后区域CSF1R蛋白水平。此外,使用[11C]DPA-713 (N,N-二乙基-2-[2-(4-甲氧基苯基)-5,7-二甲基吡唑罗[1,5-a]嘧啶-3-基]乙酰胺,DPA-713)直接将本研究结果与18-kDa转运蛋白的PET成像进行比较。结果:给药[11C]NCGG401未发生严重不良事件。男性每次注射有效剂量为5.1±0.2µSv/MBq,女性为6.1±0.3µSv/MBq。[11C]NCGG401表现出良好的脑通透性,峰值摄取达到SUV的3。使用2组织室模型和Logan图与60分钟的扫描数据可靠地量化区域总分布体积。所得到的参数化图像反映了CSF1R在大脑中的已知分布。此外,[11C]NCGG401的区域总分布容积值与区域CSF1R蛋白水平具有良好的相关性。[11C]NCGG401图像显示出与[11C]DPA-713不同的区域分布。结论:[11C]NCGG401图像似乎反映了CSF1R在脑内的区域小胶质细胞特异性分布,与其他CSF1R蛋白质组学研究的结果一致。然而,最终确认特异性的CSF1R结合应该通过评估,在适当的临床前或人体实验中,在体内的大脑中对其结合的药物阻断来验证。
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