Rui Xiyan, Ding Yuzhou, Zhang Nailian, Zhao Xinran, Seki Chie, Yamasaki Tomoteru, Fujinaga Masayuki, Zhang Ming-Rong, Qian Jun, Ji Bin, Zhou Rong
Tongji University Affilliated Yangpu Hospital: Shanghai Yangpu District Central Hospital; Fudan university.
Advanced Advanced Neuroimaging Center, National Institutes for Quantum Science and Technology.
Res Sq. 2025 Mar 20:rs.3.rs-6194254. doi: 10.21203/rs.3.rs-6194254/v1.
Colony-stimulating factor 1 receptor (CSF1R) is a promising imaging biomarker for neuroinflammation or tumor-associated macrophages. However, existing positron emission tomography (PET) tracers for CSF1R imaging commonly are suffering from limited specificity or sensitivity.
We have performed C-labeled radiosynthesis of compound FJRD (3-((2-amino-5-(1-methyl-1-pyrazol-4-yl)pyridin-3-yl)ethynyl)--(4-methoxyphenyl)-4-methylbenzamide) with excellent affinity for CSF1R and evaluated its - and - binding properties. PET images of [C]FJRD show low brain uptake and specific binding in the living organs except kidneys in the normal mice and rats. - autoradiographs show high-level specific binding in all investigated organs including brain, spleen, liver, kidneys and lungs when used self-blocking. Addition of cold CPPC partially blocked - [C]FJRD binding in the various organs with blocking effects from 9 to 67%, and other two CSF1R inhibitors, GW2580 and BLZ945, showed minimal blocking effect, suggesting unignorable off-target binding in these organs. Meanwhile specific bindings of [C]CPPC and [C]GW2580 were faint in the mouse organs except [C]CPPC specific binding detectable in the spleen.
These results suggest [C]FJRD as a potential CSF1R-PET tracer for more sensitively detecting CSF1R compared to [C]CPPC and [C]GW2580. However, high-level off-target binding requires further improvement in specificity for CSF1R imaging.
集落刺激因子1受体（CSF1R）是用于神经炎症或肿瘤相关巨噬细胞的一种很有前景的成像生物标志物。然而，现有的用于CSF1R成像的正电子发射断层扫描（PET）示踪剂通常存在特异性或敏感性有限的问题。
我们进行了化合物FJRD（3-((2-氨基-5-(1-甲基-1-吡唑-4-基)吡啶-3-基)乙炔基)-α-(4-甲氧基苯基)-4-甲基苯甲酰胺）的碳-11标记放射性合成，其对CSF1R具有优异的亲和力，并评估了其体内和体外结合特性。[碳-11]FJRD的PET图像显示，在正常小鼠和大鼠中，除肾脏外，活体器官中的脑摄取和特异性结合较低。体外放射自显影片显示，当使用自身阻断时，在包括脑、脾、肝、肾和肺在内的所有研究器官中均有高水平的特异性结合。加入冷的CPPC可部分阻断碳-11-[C]FJRD在各个器官中的结合，阻断效果为9%至67%，另外两种CSF1R抑制剂GW2580和BLZ945的阻断效果最小，表明这些器官中存在不可忽视的非靶向结合。同时，[碳-11]CPPC和[碳-11]GW2580在小鼠器官中的特异性结合较弱，除了在脾脏中可检测到[碳-11]CPPC的特异性结合。
这些结果表明，与[碳-11]CPPC和[碳-11]GW2580相比，[碳-11]FJRD作为一种潜在的CSF1R-PET示踪剂，能更灵敏地检测CSF1R。然而，高水平的非靶向结合需要进一步提高CSF1R成像的特异性。
