Synthesis and evaluation of N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide: a deuterium-substituted radioligand for peripheral benzodiazepine receptor.
Synthesis and evaluation of N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide: a deuterium-substituted radioligand for peripheral benzodiazepine receptor.
复制标题
DOI：
10.1016/j.bmc.2004.11.058
复制
发表时间：
2005-03
影响因子：
3.5
通讯作者：
Ming-Rong Zhang;J. Maeda;Takehito Ito;T. Okauchi;M. Ogawa;J. Noguchi;T. Suhara;C. Halldin;Kazutoshi Suzuki
中科院分区：
文献类型：
--
作者：
Ming-Rong Zhang;J. Maeda;Takehito Ito;T. Okauchi;M. Ogawa;J. Noguchi;T. Suhara;C. Halldin;Kazutoshi Suzuki
N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoromethoxy-d2-5-methoxybenzyl)acetamide([18F]2)是外周苯二氮卓类受体的有效配体(IC_(50)：1.71 nM)。然而，在啮齿动物和灵长类动物体内的评估表明，该配体是不稳定的，并通过[18F]氟甲基部分的脱氟迅速代谢为[18F]F−。在这项研究中，我们设计了一个氢取代类似物N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoromethoxy-d2-5-methoxybenzyl)acetamide([18F]5)作为PBR的放射性配体来降低非氚[18F]2的体内代谢率。设计原理是基于这样的假设：在不改变与PBR的结合亲和力的情况下，氢取代可以降低由于C-H键断裂而引发的脱氟速率。非放射性的5是通过二碘甲烷-D2(CD2I2，6)与苯酚前体7反应，然后用四丁基氟化铵处理得到的。通过7与[18F]氟甲基碘D2([18F]FCD2I，[18F]9)的烷基化反应合成了配体[18F]5。化合物5与2具有相似的体外亲和力(IC_(50)：1.90 nm)。体内评价表明，[18F]5在小鼠脑内通过脱氟代谢为主要放射性成分[18F]F-−，但其代谢速度慢于[18F]-2。用体外放射自显影测定，大鼠脑内[18F]5与PBR的特异性结合百分率增加，而[18F]5在小鼠骨骼中的放射性水平降低。然而，猴脑的[18F]5的PET图像显示，大脑和头骨中的放射性很高，这表明啮齿类动物和灵长类动物之间可能存在物种差异。
N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoromethoxy-d2-5-methoxybenzyl)acetamide ([18F]2) is a potent ligand (IC50: 1.71nM) for peripheral benzodiazepine receptor (PBR). However, in vivo evaluation on rodents and primates showed that this ligand was unstable and rapidly metabolized to [18F]F−by defluorination of the [18F]fluoromethyl moiety. In this study, we designed a deuterium-substituted analogue, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoromethoxy-d2-5-methoxybenzyl)acetamide ([18F]5) as a radioligand for PBR to reduce the in vivo metabolic rate of the non-deuterated [18F]2. The design principle was based on the hypothesis that the deuterium substitution may reduce the rate of defluorination initiated by cleavage of the C–H bond without altering the binding affinity for PBR. The non-radioactive 5 was prepared by reacting diiodomethane-d2(CD2I2, 6) with a phenol precursor 7, followed by treatment with tetrabutylammonium fluoride. The ligand [18F]5 was synthesized by the alkylation of 7 with [18F]fluoromethyl iodide-d2([18F]FCD2I, [18F]9). Compound 5 displayed a similar in vitro affinity to PBR (IC50: 1.90nM) with 2. In vivo evaluation demonstrated that [18F]5 was metabolized by defluorination to [18F]F−as a main radioactive component, but its metabolic rate was slower than that of [18F]2 in the brain of mice. The deuterium substitution decreased the radioactivity level of [18F]5 in the bone of mouse, augmented by the percentage of specific binding to PBR in the rat brain determined by ex vivo autoradiography. However, the PET image of [18F]5 for monkey brain showed high radioactivity in the brain and skull, suggesting a possible species difference between rodents and primates.