Design, synthesis and evaluation in an LPS rodent model of neuroinflammation of a novel (18)F-labelled PET tracer targeting P2X7.
Design, synthesis and evaluation in an LPS rodent model of neuroinflammation of a novel (18)F-labelled PET tracer targeting P2X7.
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DOI：
10.1186/s13550-017-0275-2
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发表时间：
2017-12
期刊：
影响因子：
3.2
通讯作者：
Gee A
中科院分区：
文献类型：
--
作者：
Fantoni ER;Dal Ben D;Falzoni S;Di Virgilio F;Lovestone S;Gee A
P2X7 受体已被证明在炎症级联的启动和维持中发挥重要作用。新型氟 18 PET 示踪剂的开发比目前可用的示踪剂更优越且半衰期更长，这是朝着利用该目标提供的治疗和诊断潜力迈出的有希望的一步。受已知拮抗剂 A-804598 的启发，本研究概述了新型 P2X7 示踪剂 [18F]EFB 的分子对接、合成和生物学评估的设计。该示踪剂通过三步程序进行放射性标记，通过钙流入测定在 P2X7 转染的 HEK293 和 B16 细胞中评估体外结合，并在注射脂多糖 (LPS) 的神经炎症大鼠模型中进行初步临床前评估。新型示踪剂 [18F]EFB 在 210 分钟内合成，衰减校正放射化学产率 (DC RCY) 为 3–5%，放射化学纯度 (RCP) >99%，放射化学纯度 >300 GBq/μmol，并得到充分表征。功能测定表明，该化合物可与 nM K i 结合至人类、大鼠和小鼠 P2X7 受体。在体内，[18F]EFB 显示出理想的分布特征，虽然其血脑屏障渗透性较低，但大脑摄取是可量化的，并且与对照大鼠中枢神经系统区域相比，发炎大鼠中枢神经系统区域的平均纵向摄取显着更高。 [18F]EFB 在体外表现出对人类和啮齿动物 P2X7 的强大亲和力以及有限但可量化的 BBB 渗透。考虑到 P2X7 表达升高的 LPS 大鼠模型中最初有希望的体内数据，这项工作构成了开发放射性示踪剂的重要一步，该示踪剂可用于诊断和监测与相关神经炎症过程相关的临床疾病。本文的在线版本 (doi:10.1186/s13550-017-0275-2) 包含补充材料，可供授权用户使用。
The P2X7 receptor has been shown to play a fundamental role in the initiation and sustenance of the inflammatory cascade. The development of a novel fluorine-18 PET tracer superior and with a longer half-life to those currently available is a promising step towards harnessing the therapeutic and diagnostic potential offered by this target. Inspired by the known antagonist A-804598, the present study outlines the design via molecular docking, synthesis and biological evaluation of the novel P2X7 tracer [18F]EFB. The tracer was radiolabelled via a three-step procedure, in vitro binding assessed in P2X7-transfected HEK293 and in B16 cells by calcium influx assays and an initial preclinical evaluation was performed in a lipopolysaccharide (LPS)-injected rat model of neuroinflammation. The novel tracer [18F]EFB was synthesised in 210 min in 3–5% decay-corrected radiochemical yield (DC RCY), >99% radiochemical purity (RCP) and >300 GBq/μmol and fully characterised. Functional assays showed that the compound binds with nM K i to human, rat and mouse P2X7 receptors. In vivo, [18F]EFB displayed a desirable distribution profile, and while it showed low blood–brain barrier penetration, brain uptake was quantifiable and displayed significantly higher mean longitudinal uptake in inflamed versus control rat CNS regions. [18F]EFB demonstrates strong in vitro affinity to human and rodent P2X7 and limited yet quantifiable BBB penetration. Considering the initial promising in vivo data in an LPS rat model with elevated P2X7 expression, this work constitutes an important step in the development of a radiotracer useful for the diagnosis and monitoring of clinical disorders with associated neuroinflammatory processes. The online version of this article (doi:10.1186/s13550-017-0275-2) contains supplementary material, which is available to authorized users.