[18F]-16alpha-Fluoroestradiol | 94153-53-4

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: [18F]-16alpha-Fluoroestradiol
• 英文别名: 16α-[¹⁸F]fluoro-17β-estradiol；16α-[¹⁸F]fluoroestradiol；16α-(18)F-fluoroestradiol；16α-[18F]fluoroestradiol；18F-fluoroestradiol；[18F]fluoroestradiol；Fluoroestradiol F-18；(8R,9S,13S,14S,16R,17R)-16-(18F)fluoranyl-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol
• CAS: 94153-53-4
• 化学式: C₁₈H₂₃FO₂
• 分子量: 289.379
• InChiKey: KDLLNMRYZGUVMA-ZYMZXAKXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  21
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  40.5
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

氟代雌二醇 F-18 被肝脏高度提取和代谢 - 在给药后2小时，仅有10%的总活性归因于未代谢的母药。生成的代谢物大多数是葡萄糖醛酸或硫酸盐结合的产物。

Fluoroestradiol F-18 is highly extracted and metabolized by the liver - at 2 hours post-administration, only 10% of the total activity is attributable to unmetabolized parent drug. The majority of generated metabolites are products of glucuronide or sulfate conjugation.

来源:DrugBank

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：本记录中的信息是指氟雌二醇F18（18F-FES）作为一种诊断剂的使用。目前没有关于氟雌二醇F18在哺乳期间临床使用的信息。制造商建议母亲在注射氟雌二醇F18后避免哺乳4小时。哺乳期母亲不应在其工作场所处理用于PET扫描的放射性物质。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:Information in this record refers to the use of fluoroestradiol F18 (18F-FES) as a diagnostic agent. No information is available on the clinical use of fluoroestradiol F18 during breastfeeding. The manufacturer recommends that mothers avoid breastfeeding for 4 hours after administration of fluoroestradiol F18. Nursing mothers should not work with radioactive substances used in PET scans in their workplace. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

静脉给药后，大约95%的氟代雌二醇F-18与白蛋白和性激素结合球蛋白结合。

Following intravenous administration, approximately 95% of fluoroestradiol F-18 is protein-bound to both albumin and sex hormone-binding globulin.

来源:DrugBank

吸收、分配和排泄

• 消除途径

消除主要是通过尿液和胆汁排泄。未结合的代谢物主要是葡萄糖醛酸和硫酸结合物，这些代谢物通过胆汁分泌，经肠肝循环再吸收，然后通过肾脏排泄。

Elimination is primarily via urinary and biliary excretion. Unbound metabolites comprising mainly glucuronide and sulfate conjugates are secreted in the bile, reabsorbed via enterohepatic circulation, and then renally excreted.

来源:DrugBank

吸收、分配和排泄

• 分布容积

由于氟代雌二醇及其代谢物经历肠肝循环，它主要分布在肝胆系统中。它还分布到肠道、心肌壁、血液、肾脏、子宫和膀胱。

As fluoroestradiol and its metabolites undergo enterohepatic circulation, it is found primarily distributed within the hepatobiliary system. It also distributes to the intestines, heart wall, blood, kidney, uterus, and bladder.

来源:DrugBank

吸收、分配和排泄

• 清除

氟代雌二醇 F-18 能被肝脏迅速从血液中清除。

Fluoroestradiol F-18 is rapidly cleared from the blood by the liver.

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  [18F]-16alpha-Fluoroestradiol 在 alkali carbonate 、 氨基磺酰氯 作用下， 以 乙腈 为溶剂， 以50%的产率得到16α-[18F]fluoroestradiol-3,17β-disulphamate
  参考文献：
  名称：

  Romer; Fuchtner; Steinbach, Journal of labelled compounds and radiopharmaceuticals, 1999, vol. 42, # SUPPL. 1, p. S715-S716

  摘要：

  DOI：
• 作为产物：
  描述：

  在 硫酸 作用下， 以 甲醇 为溶剂， 反应 0.33h， 生成 [18F]-16alpha-Fluoroestradiol
  参考文献：
  名称：

  16α-[18F]氟-17β-雌二醇的自动化合成方法

  摘要：

  本发明提供了一种16α‑[ 18 F]氟‑17β‑雌二醇（ 18 F‑FES）的自动化合成方法，包括在自动化合成模块的同一反应瓶中进行的前体3‑O‑(甲氧甲基)‑16,17‑O‑磺酰基‑16‑表雌二醇（MMSE）的[ 18 F]亲核氟化反应、不经过分离的[ 18 F]氟化中间体与含醇酸性溶液发生水解反应、以及通过固相柱代替制备液相分离纯化后得到产品 18 F‑FES。该自动化合成方法，采用常规的FDG合成模块即可实现16α‑[ 18 F]氟‑17β‑雌二醇的自动化生产，总合成时间短，放射化学产率高。

  公开号：

  CN108250260B

文献信息

• Fast and reliable generation of [¹⁸F]triflyl fluoride, a gaseous [¹⁸F]fluoride source
  作者：A. Pees、C. Sewing、M. J. W. D. Vosjan、V. Tadino、J. D. M. Herscheid、A. D. Windhorst、D. J. Vugts

  DOI：10.1039/c8cc03206h

  日期：——

  [18F]fluoride has been developed, omitting time consuming azeotropic drying procedures. Gaseous [18F]triflyl fluoride is formed instantaneously at room temperature from hydrated [18F]fluoride, followed by distillation in less than 5 minutes into a dry aprotic solvent, in which dry [18F]fluoride is released in presence of base with >90% radiochemical yield. The reactivity of the [18F]fluoride has been

  已经开发了一种生产反应性[ 18 F]氟化物的新方法，省却了耗时的共沸干燥程序。在室温下由水合的[ 18 F]氟化物瞬时形成气态[ 18 F]三氟氟化物，然后在不到5分钟的时间内蒸馏至干燥的非质子溶剂中，在碱的存在下在其中释放出干燥的[ 18 F]氟化物。 > 90％的放射化学收率。的反应性[ 18 F]氟化物已经证实通过用几个模型化合物反应，并通过在PET示踪剂[合成18 F]氟雌二醇（[ 18 F] FES）和ö -2- [ 18 F] fluoroethyl-L-酪氨酸（[ 18 F] FET），具有良好的分离放射化学产率和高达123 GBqμmol -1的摩尔活性。
• Alternative synthesis for the preparation of 16<i>α</i>-[¹⁸F]fluoroestradiol
  作者：Hee Seup Kil、Han Yang Cho、Sang Ju Lee、Seung Jun Oh、Dae Yoon Chi

  DOI：10.1002/jlcr.3076

  日期：2013.10

  We have developed a new precursor, 3,17β-O-bis(methoxymethyl)-16β-O-p-nitrobenzenesulfonylestriol (14c) of 16α-[18F]fluoroestradiol ([18F]FES). Although we could not selectively protect the C17 alcohol in the presence of the C16 alcohol, we were able to prepare and chromatographically isolate the desired C16 TBDMS, C17,C3-dimethoxymethyl (diMOM) protected estriol derivative and convert into the ultimate fluorination precursor. The MOM protective group proved to be more quickly removed than the cyclic sulfate group. The di-MOM protective precursor at the C3 and C17 alcohols instead of a cyclic sulfate group shortened hydrolysis time. We prepared three different sulfonate precursors at C16 alcohol. After checking their reactivity in the [18F]fluorination step and considering the stability of the precursors, we obtained the best results with nosylate precursor 14c.

  我们开发了一种新的前体，16α-[18F]氟雌二醇（[18F]FES）的3,17β-O-双（甲氧基甲基）-16β-O-对硝基苯磺酰雌三醇（14c）。尽管我们无法在 C16 醇存在的情况下选择性地保护 C17 醇，但我们能够制备并通过色谱分离所需的 C16 TBDMS、C17,C3-二甲氧基甲基 (diMOM) 保护的雌三醇衍生物，并将其转化为最终的氟化前体。 MOM 保护基团被证明比环状硫酸基团更容易被去除。 C3和C17醇上的二-MOM保护前体代替环状硫酸基团缩短了水解时间。我们在 C16 醇中制备了三种不同的磺酸盐前体。在检查了它们在[18F]氟化步骤中的反应性并考虑了前体的稳定性后，我们用苯磺酸盐前体14c获得了最好的结果。
• Simplified and automatic one-pot synthesis of 16α-[18F]fluoroestradiol without high-performance liquid chromatography purification
  作者：K. E. Knott、D. Grätz、S. Hübner、S. Jüttler、C. Zankl、M. Müller

  DOI：10.1002/jlcr.1916

  日期：2011.10

  16α-[18F]Fluoroestradiol (16α-[18F]FES, 1) is known as a valuable tracer in molecular imaging as estrogen receptor (ER) ligand for investigation of primary and metastatic breast cancer. ER concentration in human breast tumor cells is a significant indicator for the degree of disease and is often monitored by immunoassays or in vitro ligand binding of a tumor biopsy sample. More preferable non-invasive diagnosis is accessible using 16α-[18F]FES (1) as PET tracer. Our aim was to develop a reliable, easy-to-use, remotely controlled synthesis for non carrier added (n.c.a.) 16α-[18F]FES (1) by nucleophilic substitution using a disposable cassette for GE TRACERlab® MXFDG. Purification of the crude product using solid phase extraction (SPE) cartridges, Oasis® WAX, HLB Plus, Sep-Pak® C18 and Light Alumina N, allows abandonment of an HPLC purifying system. Formulation of the final product is included in the automatic synthesis. The experimental conditions for this easy-to-use synthesis for routine production of 16α-[18F]FES (1) are given in detail. Within 75 min 16α-[18F]FES (1) is produced in typically 20% n.c.a., radiochemical yield (non decay corrected). Chemical and radiochemical purity is >95% and >99%, respectively. Copyright © 2011 John Wiley & Sons, Ltd.

  16α-[18F]氟雌二醇 (16α-[18F]FES, 1) 被认为是分子成像中有价值的示踪剂，作为雌激素受体 (ER) 配体，用于研究原发性和转移性乳腺癌。人类乳腺肿瘤细胞中的 ER 浓度是疾病程度的重要指标，通常通过免疫测定或肿瘤活检样品的体外配体结合来监测。使用 16α-[18F]FES (1) 作为 PET 示踪剂可以实现更优选的非侵入性诊断。我们的目标是使用 GE TRACERlab® MXFDG 的一次性盒通过亲核取代来开发一种可靠、易于使用、远程控制的无载体添加 (n.c.a.) 16α-[18F]FES (1) 合成方法。使用固相萃取 (SPE) 柱、Oasis® WAX、HLB Plus、Sep-Pak® C18 和 Light Alumina N 纯化粗产物，可以放弃 HPLC 纯化系统。最终产品的配方包含在自动合成中。详细给出了这种用于常规生产 16α-[18F]FES (1) 的易于使用的合成的实验条件。 75 分钟内，16α-[18F]FES (1) 的放射化学产率通常为 20% n.c.a.（未衰减校正）。化学纯度和放射化学纯度分别>95% 和>99%。版权所有 © 2011 约翰·威利父子有限公司
• Optimization of the preparation of fluorine-18-labeled steroid receptor ligands 16alpha-[¹⁸ F]fluoroestradiol (FES), [¹⁸ F]fluoro furanyl norprogesterone (FFNP), and 16beta-[¹⁸ F]fluoro-5alpha-dihydrotestosterone (FDHT) as radiopharmaceuticals
  作者：Dong Zhou、Mai Lin、Norio Yasui、Mohammed H. Al-Qahtani、Carmen S. Dence、Sally Schwarz、John A. Katzenellenbogen

  DOI：10.1002/jlcr.3191

  日期：2014.5.15

  Fluorine-18-labeled steroid receptor tracers, 16α-[18F]fluoroestradiol (FES), [18F]fluoro furanyl norprogesterone (FFNP), and 16β-[18F]fluoro-5α-dihydrotestosterone (FDHT), are important imaging tools for studies of breast and prostate cancers using positron emission tomography (PET). The automated production of these ligands with high specific activity (SA) as radiopharmaceuticals requires modification and optimization of the currently reported methods. [18F]FES with high SA was synthesized in over 60% radiochemical yield (RCY) at the end of synthesis (EOS) using a small amount of precursor (1) (as low as 0.3 mg) and 1 M H2SO4 for deprotection of the intermediate (2). [18F]FFNP was synthesized in up to 77% RCY at EOS using the triflate precursor (4) at room temperature or in 25% RCY using the mesylate precursor (6) at 65°C. Both methods are highly reproducible and afford high SA. [18F]FDHT was synthesized by radiofluoride incorporation at room temperature, reduction with NaBH4, and deprotection with HCl/acetone, giving [18F]FDHT in up to 75% yield (RCY). All of these methods can be easily translated to automated production. The information provided here will aid in the development of automated production of these steroid receptor tracers with high or improved yields, optimal SA, and ease of processing for research and clinical use. Copyright © 2014 John Wiley & Sons, Ltd.

  氟-18 标记的类固醇受体示踪剂 16α-[18F]fluoroestradiol (FES)、[18F]fluoro furanyl norprogesterone (FFNP) 和 16β-[18F]fluoro-5α-dihydrotestosterone (FDHT) 是利用正电子发射断层扫描（PET）研究乳腺癌和前列腺癌的重要成像工具。要自动生产这些具有高特异性（SA）的放射性药物配体，需要对目前已报道的方法进行修改和优化。使用少量前体（1）（低至 0.3 毫克）和 1 M H2SO4 对中间体（2）进行脱保护，就能合成具有高 SA 的[18F]FES，合成结束时的放射化学收率（RCY）超过 60%。在室温下使用三late前体（4）在 EOS 下合成 [18F]FFNP 的 RCY 可高达 77%，或在 65°C 下使用甲磺酸盐前体（6）在 EOS 下合成 [18F]FFNP 的 RCY 可高达 25%。这两种方法都具有很高的重现性，并能获得较高的 SA 值。[18F]FDHT 的合成方法是在室温下加入放射性氟化物，用 NaBH4 还原，再用 HCl/ 丙酮脱保护，得到[18F]FDHT，收率高达 75%（RCY）。所有这些方法都可以很容易地转化为自动化生产。本文所提供的信息将有助于开发这些类固醇受体示踪剂的自动化生产，使其具有更高或更高的产率、最佳的 SA 和易于处理的特点，以满足研究和临床使用的需要。Copyright © 2014 John Wiley & Sons, Ltd. All Rights Reserved.
• Rapid synthesis of [¹⁸F]fluoroestradiol: remarkable advantage of microwaving over conventional heating
  作者：Jianfeng Shi、George Afari、Sibaprasad Bhattacharyya

  DOI：10.1002/jlcr.3248

  日期：2014.12

  16α-[18F]fluoroestradiol ([18F]FES) is known as a clinically important tracer in nuclear medicine as an estrogen receptor ligand for investigating primary and metastatic breast cancers. Synthesizing [18F]FES is a two-step process associated with [18F]fluoride incorporation to the precursor (3-methoxymethyl 16β,17β-epiestriol-O-cyclic sulfone) and subsequent hydrolysis of the [18F]fluorinated intermediate with 2 N HCl. The impact of microwave (MW) heating on both fluorination and hydrolysis reactions was investigated. The duration and temperatures of the fluorination reaction were varied for both MW heating and conventional heating (CH) methods. Chemical and radiochemical purity and radiochemical yields were investigated for CH and compared with MW-assisted radiosyntheses. Quality control tests of MW-assisted [18F]FES were performed following US Pharmacopeia procedures for clinical-grade positron emission tomography pharmaceuticals. The results demonstrate that microwaving not only improves the 18F-fluoride incorporation (~55% improvement at 110°C for 4 min) but also significantly reduces hydrolysis time (approximately sevenfold reduction at 120°C) in comparison with CH under similar conditions. The overall isolated radiochemical yield of purified [18F]FES was significantly higher (~90% improvement) with MW, and side products were notably fewer. Quality control test results demonstrated that [18F]FES produced by microwaving was suitable for human injection.

  众所周知，16α-[18F]氟雌二醇（[18F]FES）是核医学中一种重要的临床示踪剂，它是一种雌激素受体配体，用于研究原发性和转移性乳腺癌。[18F]FES 的合成过程分为两步：[18F]氟化物掺入前体（3-甲氧基甲基 16β,17β-epiestriol-O-环砜），然后用 2 N HCl 水解[18F]氟化中间体。研究了微波（MW）加热对氟化和水解反应的影响。微波加热法和传统加热法（CH）氟化反应的持续时间和温度各不相同。研究了 CH 的化学和放射化学纯度以及放射化学产率，并与 MW 辅助放射合成进行了比较。按照美国药典对临床级正电子发射断层扫描药物的要求，对 MW 辅助[18F]FES 进行了质量控制测试。结果表明，与类似条件下的 CH 相比，微波不仅能提高 18F 氟化物的掺入率（110°C 4 分钟时提高约 55%），还能显著缩短水解时间（120°C 时缩短约 7 倍）。纯化的[18F]FES 的总体分离放射化学收率在使用 MW 时显著提高（提高约 90%），副产物也明显减少。质量控制测试结果表明，微波炉生产的[18F]FES 适合人体注射。