Zhang Ming-Rong, Maeda Jun, Ogawa Masanao, Noguchi Junko, Ito Takehito, Yoshida Yuichiro, Okauchi Takashi, Obayashi Shigeru, Suhara Tetsuya, Suzuki Kazutoshi
Department of Medical Imaging, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
J Med Chem. 2004 Apr 22;47(9):2228-35. doi: 10.1021/jm0304919.
To develop a positron emission tomography (PET) ligand for imaging the 'peripheral benzodiazepine receptor' (PBR) in brain and elucidating the relationship between PBR and brain diseases, four analogues (4-7) of N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (2) were synthesized and evaluated as ligands for PBR. Of these compounds, fluoromethyl (4) and fluoroethyl (5) analogues had similar or higher affinities for PBR than the parent compound 2 (K(i) = 0.16 nM for PBR in rat brain sections). Iodomethyl analogue 6 displayed a moderate affinity, whereas tosyloxyethyl analogue 7 had weak affinity. Radiolabeling was performed for the fluoroalkyl analogues 4 and 5 using fluorine-18 ((18)F, beta(+); 96.7%, T(1/2) = 109.8 min). Ligands [(18)F]4 and [(18)F]5 were respectively synthesized by the alkylation of desmethyl precursor 3 with [(18)F]fluoromethyl iodide ([(18)F]8) and 2-[(18)F]fluoroethyl bromide ([(18)F]9). The distribution patterns of [(18)F]4 and [(18)F]5 in mice were consistent with the known distribution of PBR. However, compared with [(18)F]5, [(18)F]4 displayed a high uptake in the bone of mice. The PET image of [(18)F]4 for monkey brain also showed significant radioactivity in the bone, suggesting that this ligand was unstable for in vivo defluorination and was not a useful PET ligand. Ligand [(18)F]5 displayed a high uptake in monkey brain especially in the occipital cortex, a region with richer PBR than the other regions in the brain. The radioactivity level of [(18)F]5 in monkey brain was 1.5 times higher than that of [(11)C]2, and 6 times higher than that of (R)-(1-(2-chlorophenyl)-N-[(11)C]methyl,N-(1-methylpropyl)isoquinoline ([(11)C]1). Moreover, the in vivo binding of [(18)F]5 was significantly inhibited by PBR-selective 2 or 1, indicating that the binding of [(18)F]5 in the monkey brain was mainly due to PBR. Metabolite analysis revealed that [(18)F]4 was rapidly metabolized by defluorination to [(18)F]F(-) in the plasma and brain of mice, whereas [(18)F]5 was metabolized by debenzylation to a polar product [(18)F]13 only in the plasma. No radioactive metabolite of [(18)F]5 was detected in the mouse brain. The biological data indicate that [(18)F]5 is a useful PET ligand for PBR and is currently used for imaging PBR in human brain.
为开发一种用于脑内“外周苯二氮䓬受体”（PBR）成像并阐明PBR与脑部疾病之间关系的正电子发射断层扫描（PET）配体，合成了N-(2,5-二甲氧基苄基)-N-(5-氟-2-苯氧基苯基)乙酰胺（2）的四种类似物（4 - 7），并评估其作为PBR配体的性能。在这些化合物中，氟甲基（4）和氟乙基（5）类似物对PBR的亲和力与母体化合物2相似或更高（大鼠脑切片中PBR的K(i) = 0.16 nM）。碘甲基类似物6表现出中等亲和力，而对甲苯磺酰氧基乙基类似物7具有较弱的亲和力。使用氟-18（(18)F，β(+)；96.7%，T(1/2) = 109.8分钟）对氟烷基类似物4和5进行放射性标记。配体[(18)F]4和[(18)F]5分别通过去甲基前体3与[(18)F]氟甲基碘（[(18)F]8）和2-[(18)F]氟乙基溴（[(18)F]9）的烷基化反应合成。[(18)F]4和[(18)F]5在小鼠体内的分布模式与已知的PBR分布一致。然而，与[(18)F]5相比，[(18)F]4在小鼠骨骼中摄取较高。[(18)F]4对猴脑的PET图像也显示骨骼中有明显放射性，表明该配体在体内易发生脱氟反应，不是一种有用的PET配体。配体[(18)F]5在猴脑中摄取较高，尤其是在枕叶皮质，该区域的PBR比脑内其他区域更丰富。[(18)F]5在猴脑中的放射性水平比[(11)C]2高1.5倍，比(R)-(1-(2-氯苯基)-N-[(11)C]甲基，N-(1-甲基丙基)异喹啉（[(11)C]1）高6倍。此外，[(18)F]5的体内结合被PBR选择性拮抗剂2或1显著抑制，表明[(18)F]5在猴脑中的结合主要归因于PBR。代谢物分析表明，[(18)F]4在小鼠血浆和脑中通过脱氟迅速代谢为[(18)F]F(-)，而[(18)F]5仅在血浆中通过脱苄基代谢为极性产物[(18)F]13。在小鼠脑中未检测到[(18)F]5放射性代谢物。生物学数据表明[(18)F]5是一种用于PBR的有用PET配体，目前用于人脑PBR成像。
