[2-11C]isopropyl-, [1-11C]ethyl-, and [11C]methyl-labeled phenoxyphenyl acetamide derivatives as positron emission tomography ligands for the peripheral benzodiazepine receptor: radiosynthesis, uptake, and in vivo binding in brain.
[2-11C]isopropyl-, [1-11C]ethyl-, and [11C]methyl-labeled phenoxyphenyl acetamide derivatives as positron emission tomography ligands for the peripheral benzodiazepine receptor: radiosynthesis, uptake, and in vivo binding in brain.
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[2-11C]异丙基、[1-11C]乙基和[11C]甲基标记的苯氧基苯基乙酰胺衍生物作为外周苯二氮卓受体的正电子发射断层扫描配体：放射合成、摄取和脑内体内结合。
DOI：
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发表时间：
2006
影响因子：
7.3
通讯作者：
Kazutoshi Suzuki
中科院分区：
文献类型：
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作者：
Ming;M. Ogawa;J. Maeda;Takehito Ito;J. Noguchi;K. Kumata;T. Okauchi;T. Suhara;Kazutoshi Suzuki
外周苯二氮卓类受体(PBR)广泛表达于外周组织、血细胞和脑内神经胶质细胞。我们以前已经开发了两个正电子发射断层扫描配体，N-(2-[(11)C]，5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide([(11)C]2)和它的[(18)F]氟乙基类似物([(18)F]6)，用于目前对人脑中的PBR的研究。本研究的目的是标记有效的PBR激动剂N-(4-chloro-2-phenoxyphenyl)-N-(isopropoxybenzyl)acetamide(3)及其乙基(7)和甲基(8)同系物与(11)C，并评价它们作为PET配体用于小鼠、大鼠和猴子的PBR。苯酚前体9分别与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)通过烷基化反应合成了配体[(11)C]3、[(11)C]7和[(11)C]8。烷化剂[(11)C]10或[(11)C]11是由甲基溴化镁与[(11)C]CO(2)反应，然后用LiAlH(4)还原，再用HI碘化而成。体外定量放射自显影测定表明，3、7和8与大鼠脑内的PBR有很强的结合亲和力(K(I)=0.07-0.19 nM)。这些[(11)C]配体可以通过血脑屏障进入大鼠脑内(每克湿组织注射剂量的0.17-0.32%)。体外放射自显影显示[(11)C]配体较好地分布在嗅球和小脑，这两个区域是大鼠脑内PBR密度较高的区域。联合注射PBR选择性2减少了这两个区域的[(11)C]配体结合，表明大鼠脑内的结合是PBR所特有的。PET研究确定，[(11)C]配体最好聚集在猴子大脑的枕叶皮质，这是灵长类动物大脑中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选择性的2或1抑制，表明[(11)C]8的部分结合是由于PBR。代谢物分析表明，这些[(11)C]配体主要在血浆中通过脱苄反应代谢成极性产物。
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.