Development of fluorine-18-labeled 5-HT1A antagonists
Development of fluorine-18-labeled 5-HT1A antagonists
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DOI：
10.1021/jm980456f
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发表时间：
1999-05-06
影响因子：
7.3
通讯作者：
Eckelman, WC
中科院分区：
文献类型：
--
作者：
Lang, LX;Jagoda, E;Eckelman, WC
我们已经合成了WAY 100635的五种氟化衍生物，N-{2-[4-（2-甲氧基苯基）哌嗪基]乙基）-N-（2-吡啶基）环己烷甲酰胺（4a），使用各种酸代替反应方案中的环己烷羧酸（CHCA，2a）。这五种酸是4-氟苯甲酸（FB，2b）、4-氟-3-甲基苯甲酸（MeFB，2c）、反式-4-氟环己烷甲酸（FC，2d）、4-（氟甲基）苯甲酸（FMeB，2 e）和3-硝基-4-（氟甲基）苯甲酸（NFMeB，2f）（参见方案1）。用氟-18对这些化合物进行了放射性标记，并在大鼠中评价了它们的生物学性质，并与[C-11]羰基WAY 100635的生物学性质进行了比较（[羰基-C-11]4a），[Carbonyl-C-11]4a清除大脑，生物半衰期平均为41分钟。代谢物校正的血液放射性半衰期为29分钟。[F-18]FCWAY（[F-18]4d）在大脑中的半衰期和拦截量与[羰基-C-11]4a相当，但血液清除更快。[F-18]FBWAY（[F-18] 4 b）显示全脑早期快速净流出，生物半衰期为35 min。代谢物校正的血液半衰期为41 min。Me[F-18]FBWAY（[F-18]4c）的可比全脑和血液半衰期分别为16 min和18 min。对于每种化合物，相应的羧酸被鉴定为血液中的主要代谢物。注射[F-18]4d后也发现氟。然而，对于所有化合物，在注射后30分钟，在单个大鼠脑区域中的差异摄取比（DUR，（%ID/g）×体重（g）/100）与通过大鼠体外定量放射自显影术测定的受体浓度之间存在良好的相关性（R > 0.97）。在皮质（Ctx）和海马（H）对照研究中，[羰基-C-11]4a和[F-18]4d的特异性结合率[感兴趣区域（ROI）/小脑-1]高于[F-18] 4 b和[F-18]4c。[F-18]4d与[羰基-11 C]4a具有相似的药代动力学特性和相当的特异性结合率。50 nmol的4a仅阻断了30%的[F-18]4d特异性结合，而200 nmol的4a（H/Cb-1从17.2到0.6）的共注射获得了完全阻断。[F-18] 4 b和[F-18]4c的特异性结合率低于[羰基-C-11]4a和[F-18]4d。[F-18]4c上级于[F-18] 4 b，因为其特异性结合更容易被4a阻断。这些研究表明，[F-18]4c应该是一个有用的化合物，以评估动态变化的血清素水平，而[F-18]4d，其高对比度和F-18标记，应该提供更好的统计和定量的静态测量5-HT 1A受体分布。
We have synthesized five fluorinated derivatives of WAY 100635, N-{2-[4-(2-methoxyphenyl)piperazino]ethyl)-N-(2-pyridyl)cyclohexanecarboxamide (4a), using various acids in place of the cyclohexanecarboxylic acid (CHCA, 2a) in the reaction scheme. The five acids are 4-fluorobenzoic acid (FB, 2b), 4-fluoro-3-methylbenzoic acid (MeFB, 2c), trans-4-fluorocyclohexanecarboxylic acid (FC, 2d), 4-(fluoromethyl)benzoic acid (FMeB, 2e), and 3-nitro-4-(fluoromethyl)benzoic acid (NFMeB, 2f) (see Scheme 1). These compounds were radiolabeled with fluorine-18, and their biological properties were evaluated in rats and compared with those of [C-11]carbonyl WAY 100635 ([carbonyl-C-11]4a), [Carbonyl-C-11]4a cleared the brain with a biological half-life averaging 41 min. The metabolite-corrected blood radioactivity had a half-life of 29 min. [F-18]FCWAY ([F-18]4d) gave half-lives and intercepts comparable to [carbonyl-C-11]4a in the brain, but the blood clearance was faster. [F-18]FBWAY ([F-18]4b) showed an early rapid net efflux from the whole brain, clearing with a biological half-life of 35 min. The metabolite-corrected blood half-life was 41 min. The comparable whole brain and blood half-lives for Me[F-18]FBWAY ([F-18]4c) were 16 and 18 min, respectively. For each compound, the corresponding carboxylic acid was identified as a major metabolite in blood. Fluoride was also found after injection of [F-18]4d. However, for all compounds there was a good correlation (R > 0.97) between the differential uptake ratio (DUR, (%ID/g) x body weight (g)/100) in individual rat brain regions at 30 min after injection and the concentration of receptors as determined by in vitro quantitative autoradiography in rat. Specific binding ratios [region of interest (ROI)/ cerebellum-1] in control studies for cortex (Ctx) and hippocampus (H) were higher for [carbonyl-C-11]4a and [F-18]4d compared to [F-18]4b and [F-18]4c. [F-18]4d has similar pharmacokinetic properties and comparable specific binding ratios to [carbonyl-11C]4a. Fifty nanomoles of 4a blocked only 30% of the specific binding of [F-18]4d, while complete blockade was obtained from co-injection of 200 nmol of 4a (H/Cb-1 from 17.2 to 0.6). [F-18]4b and [F-18]4c showed lower specific binding ratios than [carbonyl-C-11]4a and [F-18]4d. [F-18]4c was superior to [F-18]4b since its specific binding was more readily blocked by 4a. These studies suggest that [F-18]4c should be a useful compound to assess dynamic changes in serotonin levels while [F-18]4d, with its high contrast and F-18 label, should provide better statistics and quantification for static measurement of 5-HT1A receptor distribution.