Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA.
Nucl Med Biol. 2013 Oct;40(7):901-5. doi: 10.1016/j.nucmedbio.2013.06.004. Epub 2013 Jul 23.
Two 7-fluoroimidazobenzodiazepines (AH114726 and GEH120348), analogs of flumazenil, were labeled with fluorine-18 and evaluated as alternative radioligands for in vivo imaging of the GABAA/benzodiazepine receptor by comparing them to [(11)C]flumazenil in rhesus monkey.
Radiotracers were prepared from the corresponding nitro-precursors in an automated synthesis module, and primate imaging studies were conducted on a Concorde MicroPET P4 scanner. The brain was imaged for 60 (12 × 5 min frames) or 90 min (18 × 5 min frames), and data was reconstructed using the 3D MAP algorithm. Specificity of [(18)F]AH114726 and [(18)F]GEH120348 was confirmed by displacement studies using unlabeled flumazenil.
[(18)F]GEH120348 and [(18)F]AH114726 were obtained in 13-24% yields (end of synthesis) with high chemical (>95%) and radiochemical (>99%) purities, and high specific activities (2061 ± 985 Ci/mmol). The in vivo pharmacokinetics of [(18)F]AH114726 and [(18)F]GEH120348 were determined in a non-human primate and directly compared with [(11)C]flumazenil. Both fluorine-18 radioligands showed time-dependent regional brain distributions that correlated with the distribution of [(11)C]flumazenil and the known concentrations of GABAA/benzodiazepine receptors in the monkey brain. [(18)F]AH114726 exhibited maximal brain uptake and tissue time-radioactivity curves that were most similar to [(11)C]flumazenil. In contrast, [(18)F]GEH120348 showed higher initial brain uptake but very different pharmacokinetics with continued accumulation of radioactivity into the cortical regions of high GABA/benzodiazepine receptor concentrations and very little clearance from the regions of low receptor densities. Rapid washout of both radiotracers occurred upon treatment with unlabeled flumazenil.
The ease of the radiochemical synthesis, together with in vivo brain pharmacokinetics most similar to [(11)C]flumazenil, support that [(18)F]AH114726 is a suitable option for imaging the GABAA receptor.
两种 7-氟咪唑并苯并二氮杂䓬（AH114726 和 GEH120348）是氟马西尼的类似物，被标记为氟-18，并与 [(11)C]氟马西尼进行比较，以评估其作为体内 GABA A/苯二氮䓬受体成像的替代放射性配体在恒河猴中。
放射性示踪剂由相应的硝基前体在自动化合成模块中制备，并在 Concorde MicroPET P4 扫描仪上进行灵长类动物成像研究。大脑以 60 分钟（12 × 5 分钟帧）或 90 分钟（18 × 5 分钟帧）进行成像，使用 3D MAP 算法重建数据。使用未标记的氟马西尼进行的置换研究证实了 [(18)F]AH114726 和 [(18)F]GEH120348 的特异性。
[(18)F]GEH120348 和 [(18)F]AH114726 的产率分别为 13-24%（合成结束时），具有高化学（>95%）和放射化学（>99%）纯度以及高比活度（2061 ± 985 Ci/mmol）。在非人类灵长类动物中确定了 [(18)F]AH114726 和 [(18)F]GEH120348 的体内药代动力学，并直接与 [(11)C]氟马西尼进行了比较。两种氟-18 放射性配体均显示出与 [(11)C]氟马西尼和猴脑中已知 GABA A/苯二氮䓬受体浓度分布相关的时间依赖性区域性脑分布。[(18)F]AH114726 表现出与 [(11)C]氟马西尼最相似的最大脑摄取和组织时间放射性曲线。相比之下，[(18)F]GEH120348 显示出更高的初始脑摄取，但药代动力学非常不同，放射性物质持续积聚在高 GABA/苯二氮䓬受体浓度的皮质区域，并且很少从受体密度低的区域清除。用未标记的氟马西尼处理后，两种放射性示踪剂均迅速洗脱。
放射化学合成的简便性，以及与 [(11)C]氟马西尼最相似的体内脑药代动力学，支持 [(18)F]AH114726 是一种适合成像 GABA A 受体的选择。
