Abstract：
Colony-stimulating factor 1 receptor (CSF1R) is a type III receptor tyrosine kinase that is crucial for immune cell activation, survival, proliferation, and differentiation. Its expression significantly increases in macrophages during inflammation, playing a crucial role in regulating inflammation resolution and termination. Consequently, CSF1R has emerged as a critical target for both therapeutic intervention and imaging of inflammatory diseases. Herein, we have developed a radiotracer, 1-[4-((7-(dimethylamino)quinazolin-4-yl)oxy)phenyl]-3-(4-[18F]fluorophenyl)urea ([18F]17), for in vivo positron emission tomography (PET) imaging of CSF1R. Compound 17 exhibits a comparable inhibitory potency against CSF1R as the well-known CSF1R inhibitor PLX647. The radiosynthesis of [18F]17 was successfully performed by radiofluorination of aryltrimethyltin precursor with a yield of approximately 12% at the end of synthesis, maintaining a purity exceeding 98%. In vivo stability and biodistribution studies demonstrate that [18F]17 remains >90% intact at 30 min postinjection, with no defluorination observed even at 60 min postinjection. The PET/CT imaging study in lipopolysaccharide-induced pulmonary inflammation mice indicates that [18F]17 offers a more sensitive characterization of pulmonary inflammation compared to traditional [18F]FDG. Notably, [18F]17 shows a higher discrepancy in uptake ratio between mice with pulmonary inflammation and the sham group. Furthermore, the variations in [18F]17 uptake ratio observed on day 7 and day 14 correspond to lung density changes observed in CT imaging. Moreover, the expression levels of CSF1R on day 7 and day 14 follow a trend similar to the uptake pattern of [18F]17, indicating its potential for accurately characterizing CSF1R expression levels and effectively monitoring the pulmonary inflammation progression. These results strongly suggest that [18F]17 has promising prospects as a CSF1R PET tracer, providing diagnostic opportunities for pulmonary inflammatory diseases.
摘要：
集落刺激因子1受体（CSF1R）是一种III型受体酪氨酸激酶，对免疫细胞活化至关重要。生存,扩散,和差异化。它在炎症期间在巨噬细胞中的表达显着增加，在调节炎症消退和终止中起着至关重要的作用。因此,CSF1R已成为炎症性疾病的治疗干预和成像的关键靶标。在这里，我们开发了一种放射性示踪剂，1-[4-((7-(二甲基氨基)喹唑啉-4-基)氧基)苯基]-3-(4-[18F]氟苯基)脲([18F]17),用于CSF1R的体内正电子发射断层扫描（PET）成像。化合物17对CSF1R表现出与众所周知的CSF1R抑制剂PLX647相当的抑制效力。[18F]17的放射性合成是通过芳基三甲基锡前体的放射性氟化成功进行的，在合成结束时收率约为12％，保持纯度超过98%。体内稳定性和生物分布研究表明，[18F]17在注射后30分钟保持>90%完整，即使在注射后60分钟也没有观察到脱氟。在脂多糖诱导的肺部炎症小鼠中的PET/CT成像研究表明，与传统的[18F]FDG相比，[18F]17提供了更敏感的肺部炎症表征。值得注意的是,[18F]17显示具有肺部炎症的小鼠和假手术组之间的摄取比率的较高差异。此外，在第7天和第14天观察到的[18F]17摄取比的变化对应于CT成像中观察到的肺密度变化。此外，CSF1R在第7天和第14天的表达水平遵循与[18F]17的摄取模式相似的趋势,表明其具有准确表征CSF1R表达水平和有效监测肺部炎症进展的潜力.这些结果强烈表明[18F]17具有作为CSF1RPET示踪剂的前景，为肺部炎症性疾病提供诊断机会。
