Zhang Ming-Rong, Ogawa Masanao, Maeda Jun, Ito Takehito, Noguchi Junko, Kumata Katsushi, Okauchi Takashi, Suhara Tetsuya, Suzuki Kazutoshi
Department of Medical Imaging, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan.
J Med Chem. 2006 May 4;49(9):2735-42. doi: 10.1021/jm060006k.
The peripheral benzodiazepine receptor (PBR) is widely expressed in peripheral tissues, blood cells, and in glia cells in the brain. We have previously developed two positron emission tomography (PET) ligands, N-(2-[(11)C],5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide ([(11)C]2) and its [(18)F]fluoroethyl analogue ([(18)F]6), for the current investigation of PBR in the human brain. The aim of this study was to label the potent PBR agonist N-(4-chloro-2-phenoxyphenyl)-N-(isopropoxybenzyl)acetamide (3) and its ethyl (7) and methyl (8) homologues with (11)C and to evaluate them as PET ligands for PBR with mice, rats, and monkeys. Ligands [(11)C]3, [(11)C]7, and [(11)C]8 were synthesized by alkylation of phenol precursor 9 with 2-[2-(11)C]iodopropane ([(11)C]10), [1-(11)C]iodoethane ([(11)C]11), and [(11)C]iodomethane ([(11)C]12), respectively. The alkylating agent [(11)C]10 or [(11)C]11 was prepared by reacting CH(3)MgBr with [(11)C]CO(2), followed by reduction with LiAlH(4) and iodination with HI. In vitro quantitative autoradiography determined that 3, 7, and 8 had potent binding affinities (K(i) = 0.07-0.19 nM) for PBR in the rat brain. These [(11)C]ligands could pass across the blood-brain barrier and enter the rat brain (0.17-0.32% of injected dose per gram wet tissue). Ex vivo autoradiography showed that the [(11)C]ligands preferably distributed in the olfactory bulb and cerebellum, two regions with richer PBR density in the rat brain. The co-injection of PBR-selective 2 reduced the [(11)C]ligand binding in the two regions, suggesting that binding in the rat brain was specific to PBR. PET study determined that the [(11)C]ligands preferably accumulate in the occipital cortex of the monkey brain, a region with a high density of PBR in the primate brain. Moreover, in vivo binding of the methyl homologue [(11)C]8 in the monkey brain could be inhibited by PBR-selective 2 or 1, indicating that some of the [(11)C]8 binding was due to PBR. Metabolite analysis demonstrated that these [(11)C]ligands were metabolized by debenzylation to polar products mainly in the plasma.
外周苯二氮䓬受体（PBR）广泛表达于外周组织、血细胞以及大脑中的神经胶质细胞。我们之前已开发出两种正电子发射断层扫描（PET）配体，即N-(2-[(11)C],5-二甲氧基苄基)-N-(5-氟-2-苯氧基苯基)乙酰胺（[(11)C]2）及其[(18)F]氟乙基类似物（[(18)F]6），用于当前对人脑中PBR的研究。本研究的目的是用(11)C标记强效PBR激动剂N-(4-氯-2-苯氧基苯基)-N-(异丙氧基苄基)乙酰胺（3）及其乙基（7）和甲基（8）同系物，并在小鼠、大鼠和猴子身上评估它们作为PBR的PET配体的性能。配体[(11)C]3、[(11)C]7和[(11)C]8分别通过酚前体9与2-[2-(11)C]碘丙烷（[(11)C]10）、[1-(11)C]碘乙烷（[(11)C]11）和[(11)C]碘甲烷（[(11)C]12）的烷基化反应合成。烷基化剂[(11)C]10或[(11)C]11是通过使CH(3)MgBr与[(11)C]CO(2)反应，然后用LiAlH(4)还原并用HI碘化制备的。体外定量放射自显影测定3、7和8对大鼠脑中的PBR具有强效结合亲和力（K(i)=0.07 - 0.19 nM）。这些[(11)C]配体能够穿过血脑屏障并进入大鼠脑（每克湿组织注射剂量的0.17 - 0.32%）。离体放射自显影显示[(11)C]配体优先分布于嗅球和小脑，这是大鼠脑中PBR密度较高的两个区域。PBR选择性配体2的共同注射降低了这两个区域中[(11)C]配体的结合，表明在大鼠脑中的结合是PBR特异性的。PET研究确定[(11)C]配体优先聚集在猴脑的枕叶皮质，这是灵长类动物脑中PBR密度较高的区域。此外，甲基同系物[(11)C]8在猴脑中的体内结合可被PBR选择性配体2或1抑制，表明[(11)C]8的部分结合归因于PBR。代谢物分析表明这些[(11)C]配体主要在血浆中通过脱苄基作用代谢为极性产物。
