Gründer G, Siessmeier T, Lange-Asschenfeldt C, Vernaleken I, Buchholz H G, Stoeter P, Drzezga A, Lüddens H, Rösch F, Bartenstein P
Department of Psychiatry, University of Mainz, Germany.
Eur J Nucl Med. 2001 Oct;28(10):1463-70. doi: 10.1007/s002590100594.
5-(2'-[18F]Fluoroethyl)flumazenil ([18F]FEF) is a fluorine-18 labelled positron emission tomography (PET) tracer for central benzodiazepine receptors. Compared with the established [11C]flumazenil, it has the advantage of the longer half-life of the fluorine-18 label. After optimisation of its synthesis and determination of its in vitro receptor affinities, we performed first PET studies in humans. PET studies in seven healthy human volunteers were performed on a Siemens ECAT EXACT whole-body scanner after injection of 100-280 MBq [L8F]FEF. In two subjects, a second PET scan was conducted after pretreatment with unlabelled flumazenil (1 mg or 2.5 mg i.v., 3 min before tracer injection). A third subject was studied both with [18F]FEF and with [11C]flumazenil. Brain radioactivity was measured for 60-90 min p.i. and analysed with a region of interest-oriented approach and on a voxelwise basis with spectral analysis. Plasma radioactivity was determined from arterial blood samples and metabolites were determined by high-performance liquid chromatography. In human brain, maximum radioactivity accumulation was observed 4 +/- 2 min p.i., with a fast clearance kinetics resulting in 50% and 20% of maximal activities at about 10 and 30 min, respectively. [18F]FEF uptake followed the known central benzodiazepine receptor distribution in the human brain (occipital cortex >temporal cortex >cerebellum >thalamus >pons). Pretreatment with unlabelled flumazenil resulted in reduced tracer uptake in all brain areas except for receptor-free reference regions like the pons. Parametric images of distribution volume and binding potential generated on a voxelwise basis revealed two- to three-fold lower in vivo receptor binding of [18F]FEF compared with [11C]flumazenil, while relative uptake of [18F]FEF was higher in the cerebellum, most likely owing to its relatively higher affinity for benzodiazepine receptors containing the alpha6 subunit. Metabolism of [18F]FEF was very rapid. Polar metabolites represented about 50%-60% of total plasma radioactivity at 5 min and 80%-90% at 20 min p.i. Although [11C]flumazenil has some advantages over [18F]FEF (higher affinity, slower metabolism, slower kinetics), our results indicate that [18F]FEF is a suitable PET ligand for quantitative assessment of central benzodiazepine receptors, which can be used independently of an on-site cyclotron.
5-(2'-[18F]氟乙基)氟马西尼([18F]FEF)是一种用于中枢苯二氮䓬受体的氟-18标记正电子发射断层扫描(PET)示踪剂。与已有的[11C]氟马西尼相比，它具有氟-18标记半衰期更长的优势。在优化其合成并测定其体外受体亲和力后，我们对人体进行了首次PET研究。在向7名健康人类志愿者注射100 - 280 MBq [18F]FEF后，使用西门子ECAT EXACT全身扫描仪进行PET研究。在两名受试者中，在注射示踪剂前3分钟静脉注射未标记的氟马西尼(1 mg或2.5 mg)进行预处理后，进行了第二次PET扫描。第三名受试者同时接受了[18F]FEF和[11C]氟马西尼研究。注射后60 - 90分钟测量脑放射性，并采用感兴趣区域法和基于体素的光谱分析进行分析。从动脉血样本中测定血浆放射性，并通过高效液相色谱法测定代谢产物。在人脑内，注射后4±2分钟观察到最大放射性积累，清除动力学较快，分别在约10分钟和30分钟时达到最大活性的50%和20%。[18F]FEF摄取遵循人脑内已知的中枢苯二氮䓬受体分布(枕叶皮质>颞叶皮质>小脑>丘脑>脑桥)。用未标记的氟马西尼预处理导致除脑桥等无受体参考区域外，所有脑区的示踪剂摄取减少。基于体素生成的分布体积和结合潜能参数图像显示，与[11C]氟马西尼相比，[18F]FEF的体内受体结合低2至3倍，而[18F]FEF在小脑中的相对摄取较高，这很可能是由于其对含α6亚基的苯二氮䓬受体亲和力相对较高。[18F]FEF的代谢非常迅速。注射后5分钟时，极性代谢产物约占血浆总放射性的50% - 60%，20分钟时占80% - 90%。虽然[11C]氟马西尼比[18F]FEF有一些优势(亲和力更高、代谢更慢、动力学更慢)，但我们的结果表明，[18F]FEF是一种适用于定量评估中枢苯二氮䓬受体的PET配体，可独立于现场回旋加速器使用。
