Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors
Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors
复制标题
DOI：
10.1016/j.nucmedbio.2007.12.009
复制
发表时间：
2008-04-01
影响因子：
3.1
通讯作者：
Vasdev, Neil
中科院分区：
文献类型：
--
作者：
Wilson, Alan A.;Garcia, Armando;Vasdev, Neil
简介：合成了一种新型的[F-18]-放射性标记的苯氧基苯胺，[F-18]-FEPPA，并在体外和离体进行了评价，作为外周苯二氮卓受体（PBR）的潜在正电子发射断层扫描成像剂。[F-18]-FEPPA和两种用于PBR成像的其他放射性示踪剂，即[C-11]-PBR 28和[C-11]-PBR 28-d3，结果：[F-18]-FEPPA是由[F-18]-氟化物和其甲苯磺酸盐前体一步合成的，具有较高的放化产率和高的比活度。在大鼠线粒体膜制备物中，FEPPA对PBR显示出0.07 nM的Ki，并且对脑渗透显示出合适的亲脂性（在pH 7.4下log P为2.99）。静脉注射到大鼠体内后，[F-18]-FEPPA显示中等脑摄取[5分钟时标准摄取值（SUV）为0.6]和缓慢洗脱（60分钟后SUV为0.35）。在下丘脑和嗅球中观察到最高的放射性摄取，这些区域先前报告在大鼠大脑中富集PBR。血浆和脑提取物的分析表明，[F-18]-FEPPA被快速代谢，但在两种制剂中均未观察到亲脂性代谢物，脑组织提取物中仅存在5%的放射性代谢物。阻断研究，以确定在大鼠大脑中的[F-18]-FEPPA的特异性结合的程度是有问题的，由于在循环放射性示踪剂和缺乏一个参考regions.Conclusions的大扰动：[F-18]-FEPPA的潜力的进一步评估将需要采用严格的动力学模型和/或适当的动物模型。(C)2008年爱思唯尔公司All rights reserved.
Introduction: A novel [F-18]-radiolabelled phenoxyanilide, [F-18]-FEPPA, has been synthesized and evaluated, in vitro and ex vivo, as a potential positron emission tomography imaging agent for the peripheral benzodiazepine receptor (PBR).Methods: [F-18]-FEPPA and two other radiotracers for imaging PBR, namely [C-11]-PBR28 and [C-11]-PBR28-d3, were synthesised and evaluated in vitro and ex vivo as potential PBR imaging agents.Results: [F-18]-FEPPA is efficiently prepared in one step from its tosylate precursor and [F-18]-fluoride in high radiochemical yields and at high specific activity. FEPPA displayed a K-i of 0.07 nM for PBR in rat mitochondrial membrane preparations and a suitable lipophilicity for brain penetration (log P of 2.99 at pH 7.4). Upon intravenous injection into rats, [F-18]-FEPPA showed moderate brain uptake [standard uptake value (SUV) of 0.6 at 5 min] and a slow washout (SUV of 0.35 after 60 min). Highest uptake of radioactivity was seen in the hypothalamus and olfactory bulb, regions previously reported to be enriched in PBR in rat brain. Analysis of plasma and brain extracts demonstrated that [F-18]-FEPPA was rapidly metabolized, but no lipophilic metabolites were observed in either preparation and only 5% radioactive metabolites were present in brain tissue extracts. Blocking studies to determine the extent of specific binding of [F-18]-FEPPA in rat brain were problematic due to large perturbations in circulating radiotracer and the lack of a reference region.Conclusions: Further evaluation of the potential of [F-18]-FEPPA will require the employment of rigorous kinetic models and/or appropriate animal models. (C) 2008 Elsevier Inc. All rights reserved.