Wilson Alan A, Garcia Armando, Parkes Jun, McCormick Patrick, Stephenson Karin A, Houle Sylvain, Vasdev Neil
PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada M5T 1R8.
Nucl Med Biol. 2008 Apr;35(3):305-14. doi: 10.1016/j.nucmedbio.2007.12.009.
A novel [18F]-radiolabelled phenoxyanilide, [18F]-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).
[18F]-FEPPA and two other radiotracers for imaging PBR, namely [11C]-PBR28 and [11C]-PBR28-d3, were synthesised and evaluated in vitro and ex vivo as potential PBR imaging agents.
[18F]-FEPPA is efficiently prepared in one step from its tosylate precursor and [18F]-fluoride in high radiochemical yields and at high specific activity. FEPPA displayed a Ki 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, [18F]-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 [18F]-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 [18F]-FEPPA in rat brain were problematic due to large perturbations in circulating radiotracer and the lack of a reference region.
Further evaluation of the potential of [18F]-FEPPA will require the employment of rigorous kinetic models and/or appropriate animal models.
一种新型的[18F]放射性标记苯氧基苯胺，即[18F]-FEPPA，已被合成并在体外和体内进行评估，作为外周苯二氮䓬受体（PBR）的潜在正电子发射断层扫描成像剂。
合成了[18F]-FEPPA以及另外两种用于PBR成像的放射性示踪剂，即[11C]-PBR28和[11C]-PBR28-d3，并在体外和体内作为潜在的PBR成像剂进行评估。
[18F]-FEPPA可由其对甲苯磺酸盐前体和[18F]氟化物一步高效制备，具有高放射化学产率和高比活度。FEPPA在大鼠线粒体膜制剂中对PBR的Ki为0.07 nM，且具有适合脑渗透的亲脂性（pH 7.4时log P为2.99）。静脉注射到大鼠体内后，[18F]-FEPPA显示出中等程度的脑摄取（5分钟时标准摄取值（SUV）为0.6）和缓慢清除（60分钟后SUV为0.35）。放射性摄取最高的部位是下丘脑和嗅球，这些区域先前报道在大鼠脑中富含PBR。血浆和脑提取物分析表明，[18F]-FEPPA迅速代谢，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。由于循环放射性示踪剂的大幅波动以及缺乏参考区域，用于确定[18F]-FEPPA在大鼠脑中特异性结合程度的阻断研究存在问题。
对[18F]-FEPPA潜力的进一步评估将需要采用严格的动力学模型和/或合适的动物模型。
