Lee Hyeokjin, Park Ji-Hun, Kim Hyunjung, Woo Sang-Keun, Choi Joon Young, Lee Kyung-Han, Choe Yearn Seong
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea.
Pharmaceuticals (Basel). 2022 Feb 23;15(3):276. doi: 10.3390/ph15030276.
Neuroinflammation involves activation of glial cells in the brain, and activated microglia play a particularly important role in neurodegenerative diseases such as Alzheimer's disease (AD). In this study, we developed 5-cyano--(4-(4-(2-[F]fluoroethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([F]) for PET imaging of colony-stimulating factor 1 receptor (CSF1R), an emerging target for neuroinflammation imaging. Non-radioactive ligand exhibited binding affinity comparable to that of a known CSF1R inhibitor, 5-cyano--(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide (CPPC). Therefore, we synthesized radioligand [F] by radiofluorination of chlorine-substituted precursor in 13-15% decay-corrected radiochemical yield. Dynamic PET/CT images showed higher uptake in the lipopolysaccharide (LPS)-treated mouse brain than in control mouse brain. Ex vivo biodistribution study conducted at 45 min after radioligand injection showed that the brain uptake in LPS mice increased by 78% compared to that of control mice and was inhibited by 22% in LPS mice pretreated with CPPC, indicating specificity of [F] for CSF1R. A metabolism study demonstrated that the radioligand underwent little metabolism in the mouse brain. Taken together, these results suggest that [F] may hold promise as a radioligand for CSF1R imaging.
神经炎症涉及大脑中胶质细胞的激活，而活化的小胶质细胞在诸如阿尔茨海默病（AD）等神经退行性疾病中发挥着尤为重要的作用。在本研究中，我们开发了5-氰基-（4-（4-（2-[F]氟乙基）哌嗪-1-基）-2-（哌啶-1-基）苯基）呋喃-2-甲酰胺（[F]），用于集落刺激因子1受体（CSF1R）的正电子发射断层扫描（PET）成像，CSF1R是神经炎症成像的一个新兴靶点。非放射性配体表现出与已知的CSF1R抑制剂5-氰基-（4-（4-甲基哌嗪-1-基）-2-（哌啶-1-基）苯基）呋喃-2-甲酰胺（CPPC）相当的结合亲和力。因此，我们通过对氯取代前体进行放射性氟化，以13 - 15%的衰变校正放射化学产率合成了放射性配体[F]。动态PET/CT图像显示，脂多糖（LPS）处理的小鼠大脑中的摄取量高于对照小鼠大脑。在注射放射性配体后45分钟进行的离体生物分布研究表明LPS小鼠大脑摄取量与对照小鼠相比增加了78%，并且在用CPPC预处理的LPS小鼠中被抑制了22%，这表明[F]对CSF1R具有特异性。代谢研究表明该放射性配体在小鼠大脑中几乎不发生代谢。综上所述，这些结果表明[F]有望作为一种用于CSF1R成像的放射性配体。
