Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Shanghai Institute of Medical Imaging, Shanghai, China; and.
J Nucl Med. 2019 Jul;60(7):930-936. doi: 10.2967/jnumed.118.222547. Epub 2019 Jan 17.
Site-specific imaging agents play a key role in tumor targeting, but only a few agents are currently available for inflammation targeting. Since the P2X7 receptor (P2X7R) is a promising molecular target for inflammation, we evaluated the potential value of the F-labeled tracer F-PTTP (5-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-pyrimidin-2-yl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridin) for targeting P2X7Rs and thus differentiating inflammation from tumors. The radioligand F-PTTP was achieved by a 1-step F-trifluoromethylation reaction. The binding affinity of the ligand for P2X7R and its stability were evaluated in vitro. Blood pharmacokinetics tests and biodistribution studies were performed in vivo. Dynamic F-PTTP small-animal PET/CT imaging was performed for 60 min on A549 tumor-bearing mice and inflammation-model mice for targeting differentiation. F-PTTP was afforded with decay-corrected radiochemical yields of 2.5%-7.0%, specific activity of 296-370 MBq/μmol, and radiochemical purity over 95%. F-PTTP showed excellent stability in 0.9% NaCl and 0.1% bovine serum albumin, good affinity to RAW264.7 cells, and rapid blood clearance in mice. In inflammation-model mice, uptake of F-PTTP peaked at 5 min after injection and kept at an imageable level till 30 min, whereas no significant radioactivity uptake was found in tumor grafts till 1 h after injection. The specificity of F-PTTP was verified by blocking studies and histologic analysis. The current study provides compelling data that F-PTTP is a novel radioligand targeting P2X7R and has potential to screen new drugs, quantify peripheral inflammation, and distinguish inflammation from certain solid tumors.
靶向特定部位的成像剂在肿瘤靶向中起着关键作用，但目前可用的炎症靶向剂却寥寥无几。由于 P2X7 受体（P2X7R）是炎症的一个很有前途的分子靶点，我们评估了 F 标记示踪剂 F-PTTP（5-[[2-氯-3-（三氟甲基）苯基]羰基]-1-嘧啶-2-基-4,5,6,7-四氢-1H-[1,2,3]三唑[4,5-c]吡啶）作为靶向 P2X7R 的潜在价值，从而区分炎症与肿瘤。该放射性配体 F-PTTP 通过一步 F-三氟甲基化反应获得。在体外评估了配体对 P2X7R 的结合亲和力及其稳定性。在体内进行了血液药代动力学测试和生物分布研究。对荷 A549 肿瘤和炎症模型小鼠进行了 60 分钟的 F-PTTP 小动物 PET/CT 动态成像，以进行靶向区分。F-PTTP 的放射性化学产率校正衰减为 2.5%-7.0%，比活度为 296-370MBq/μmol，放射性纯度大于 95%。F-PTTP 在 0.9%NaCl 和 0.1%牛血清白蛋白中具有极好的稳定性，对 RAW264.7 细胞具有良好的亲和力，在小鼠体内具有快速的血液清除率。在炎症模型小鼠中，F-PTTP 的摄取在注射后 5 分钟达到峰值，并在 30 分钟内保持可成像水平，而在注射后 1 小时，肿瘤移植物中未发现明显的放射性摄取。阻断研究和组织学分析验证了 F-PTTP 的特异性。本研究提供了令人信服的证据，表明 F-PTTP 是一种新型靶向 P2X7R 的放射性配体，具有筛选新药、定量外周炎症和区分炎症与某些实体瘤的潜力。
