Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Bioorg Med Chem. 2023 Apr 1;83:117233. doi: 10.1016/j.bmc.2023.117233. Epub 2023 Mar 8.
We report the design, synthesis and evaluation of five o‑aminopyridyl alkynyl derivatives as colony-stimulating factor 1 receptor (CSF-1R) ligands. Compounds 4 and 5 with the fluoroethoxy group at the meta- or para-position of the phenyl ring possessed nanomolar inhibitory potency against CSF-1R with IC values of 7.6 nM and 2.3 nM, respectively. Radioligands [F]4 and [F]5 were obtained in radiochemical yields of 17.2 ± 5.3% (n = 5, decay-corrected) and 14.0 ± 4.3% (n = 4, decay-corrected), with radiochemical purity of > 99% and molar activity of 9-12 GBq/μmol (n = 5) and 6-8 GBq/μmol (n = 4), respectively. In biodistribution studies, radioligands [F]4 and [F]5 showed moderate brain uptake in male ICR mice with 1.52 ± 0.15 and 0.91 ± 0.07% ID/g, respectively, at 15 min. Metabolic stability studies in mouse brain revealed that [F]4 exhibited high stability while [F]5 suffered from low stability. Higher accumulation of [F]4 in the brain of lipopolysaccharide (LPS)-treated mice was observed, and further pretreatment of BLZ945 or CPPC led to remarkable reduction, indicating specific binding of [F]4 to CSF-1R.
我们报告了五个邻氨基吡啶基炔基衍生物作为集落刺激因子 1 受体（CSF-1R）配体的设计、合成和评价。在苯环的间位或对位带有氟乙氧基的化合物 4 和 5 对 CSF-1R 具有纳摩尔抑制活性，IC 值分别为 7.6 nM 和 2.3 nM。放射性配体 [F]4 和 [F]5 的放射化学产率分别为 17.2±5.3%（n=5，衰变校正）和 14.0±4.3%（n=4，衰变校正），放射化学纯度>99%，摩尔活度分别为 9-12 GBq/μmol（n=5）和 6-8 GBq/μmol（n=4）。在雄性 ICR 小鼠的生物分布研究中，放射性配体 [F]4 和 [F]5 在 15 分钟时分别显示出 1.52±0.15%和 0.91±0.07%ID/g 的中等脑摄取。在小鼠脑的代谢稳定性研究中，[F]4 表现出高稳定性，而 [F]5 则稳定性较低。在脂多糖（LPS）处理的小鼠的大脑中观察到 [F]4 的积累增加，并且进一步的 BLZ945 或 CPPC 预处理导致显著减少，表明 [F]4 与 CSF-1R 的特异性结合。
