Yu Ziyue, Huang Yong, Chen Hualong, Jiang Zeng, Li Chengze, Xie Yi, Li Zhongjing, Cheng Xuebo, Liu Yajing, Li Shengli, Liang Ying, Wu Zehui
Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing 100069, China.
Department of Nuclear Medicine, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China.
ACS Pharmacol Transl Sci. 2023 Oct 20;6(11):1745-1757. doi: 10.1021/acsptsci.3c00187. eCollection 2023 Nov 10.
Fibroblast activation protein (FAP) is closely related to central nervous system diseases such as stroke and brain tumors, but PET tracers that can be used for brain imaging have not been reported. Here, we designed, synthesized, and evaluated F-labeled UAMC1110 derivatives suitable for brain imaging targeting FAP. By substituting the F atom for the H atom on the aromatic ring of compound UAMC1110, - were designed and prepared. - were confirmed to have a high affinity for FAP through molecular docking and enzyme assay. were successfully prepared and confirmed to have high affinity. The stability indicates that no obvious metabolites of , were found in the plasma 1 h after injection, which is beneficial for brain imaging. cell uptake experiments showed that , and [Ga]FAPI04 exhibited similar uptake and internalization rates. PET imaging of U87MG subcutaneous tumor showed that , could penetrate the blood-brain barrier with higher uptake and longer retention time than [Ga]FAPI04 (uptake at 62.5 min, 1.06 ± 0.23, 1.09 ± 0.25% ID/g vs 0.21 ± 0.10% ID/g, respectively). The brain-to-blood ratios of , were better than [Ga]FAPI04. Biodistribution and PET imaging showed that had better uptake on tumors and a higher tumor-to-muscle ratio than and [Ga]FAPI04. Further imaging of U87MG intracranial glioma showed that outlined high-contrast gliomas in a short period of time compared to . Therefore, is expected to be useful in the diagnosis of FAP-related brain diseases.
成纤维细胞活化蛋白（FAP）与中风和脑肿瘤等中枢神经系统疾病密切相关，但尚未有可用于脑成像的正电子发射断层显像（PET）示踪剂的报道。在此，我们设计、合成并评估了适用于靶向FAP脑成像的F标记的UAMC1110衍生物。通过将F原子取代化合物UAMC1110芳环上的H原子，设计并制备了[具体衍生物]。通过分子对接和酶分析证实[具体衍生物]对FAP具有高亲和力。[具体衍生物]已成功制备并证实具有高亲和力。稳定性表明注射后1小时血浆中未发现[具体衍生物]的明显代谢产物，这有利于脑成像。细胞摄取实验表明，[具体衍生物]和[Ga]FAPI04表现出相似的摄取和内化率。U87MG皮下肿瘤的PET成像显示，[具体衍生物]能够穿透血脑屏障，与[Ga]FAPI04相比摄取更高且保留时间更长（62.5分钟时的摄取量分别为1.06±0.23、1.09±0.25% ID/g vs 0.21±0.10% ID/g）。[具体衍生物]的脑血比优于[Ga]FAPI04。生物分布和PET成像表明，[具体衍生物]在肿瘤上的摄取优于[具体对比物]和[Ga]FAPI04，且肿瘤肌肉比更高。U87MG颅内胶质瘤的进一步成像显示，与[具体对比物]相比，[具体衍生物]在短时间内勾勒出高对比度的胶质瘤。因此，[具体衍生物]有望用于FAP相关脑部疾病的诊断。
