[¹⁸F]-N,N-diethyl-2-(2-(4-(5-fluoropent-1-yn-1-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide | 1580494-77-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: [¹⁸F]-N,N-diethyl-2-(2-(4-(5-fluoropent-1-yn-1-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide
• 英文别名: N,N-diethyl-2-(2-(4-(5-[¹⁸F]fluoropent-1-yn-1-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide；[¹⁸F]DPA-C5yne；N,N-diethyl-2-[2-[4-(5-(18F)fluoranylpent-1-ynyl)phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl]acetamide
• CAS: 1580494-77-4
• 化学式: C₂₅H₂₉FN₄O
• 分子量: 419.531
• InChiKey: CLVOYKWKTAVRQM-KPVNRNJOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  50.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-碘苯甲酰乙腈 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 Kryptofix222[18F]钾盐 、 potassium carbonate 、 一水合肼 、 溶剂黄146 、 三乙胺 、 sodium hydroxide 作用下， 以 乙醇 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 106.42h， 生成 [¹⁸F]-N,N-diethyl-2-(2-(4-(5-fluoropent-1-yn-1-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide
  参考文献：
  名称：

  新型吡唑并[1,5- a ]嘧啶作为转运蛋白18 kDa（TSPO）配体：合成，体外生物学评估，[ 18 F]标签和体内神经炎症PET图像

  摘要：

  一系列新的吡唑的[1,5-一个]嘧啶，密切相关的Ñ，ñ -二乙基- 2-（2-（4-（2-氟乙氧基）苯基）-5,7-二甲基[1,5-一个合成]嘧啶-3-基）乙酰胺（2，DPA-714），并在生物学上体外评估其结合转运蛋白18 kDa（TSPO）的潜力，该蛋白今天被认为是神经炎症过程的早期生物标记。该系列由氟烷基-和氟炔基-类似物组成，它们是通过Sonogashira偶联反应从常见的碘化中间体制得的。所有衍生物均表现出对TSPO的亚纳摩尔亲和力（0.37至0.86 nM），与2的亲和力相当（0.91 nM）。其中两个被氟18放射性标记，并通过体外放射自显影和正电子发射断层扫描（PET）成像在啮齿类神经炎模型上研究了它们的生物分布。两种化合物在AMPA介导的病变中的大脑摄取和局部蓄积证实了它们作为体内PET放射治疗者的潜力。特别地，[ 18 F] 23在体内显示出比母体分子[ 18 F] 2在60分钟时显着更高的ipsi-对侧比。

  DOI：

  10.1021/acs.jmedchem.5b00932

文献信息

• [¹⁸F]DPA-C5yne, a novel fluorine-18-labelled analogue of DPA-714: radiosynthesis and preliminary evaluation as a radiotracer for imaging neuroinflammation with PET
  作者：Vincent Médran-Navarrete、Nicholas Bernards、Bertrand Kuhnast、Annelaure Damont、Géraldine Pottier、Marie-Anne Peyronneau、Michael Kassiou、Frank Marguet、Frédéric Puech、Raphaël Boisgard、Frédéric Dollé

  DOI：10.1002/jlcr.3199

  日期：2014.5.30

  DPA-C5yne, the lead compound of a novel series of DPA-714 derivatives in which the fluoroethoxy chain linked to the phenylpyrazolopyrimidine scaffold has been replaced by a fluoroalkyn-1-yl moiety, is a high affinity (Ki: 0.35 nM) and selective ligand targeting the translocator protein 18 kDa. In the present work, DPA-C5yne was labelled with no-carrier-added [18F]fluoride based on a one-step tosyloxy-for-fluorine nucleophilic substitution reaction, purified by cartridge and HPLC, and formulated as an i.v. injectable solution using a TRACERLab FX N Pro synthesizer. Typically, 4.3–5.2 GBq of [18F]DPA-C5yne, ready-to-use, chemically and radiochemically pure (> 95%), was obtained with specific radioactivities ranging from 55 to 110 GBq/µmol within 50–60 min, starting from a 30 GBq [18F]fluoride batch (14–17%). LogP and LogD of [18F]DPA-C5yne were measured using the shake-flask method and values of 2.39 and 2.51 were found, respectively. Autoradiography studies performed on slices of ((R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolopropionique (AMPA)-lesioned rat brains showed a high target-to-background ratio (1.9 ± 0.3). Selectivity and specificity of the binding for the translocator protein was demonstrated using DPA-C5yne (unlabelled), PK11195 and Flumazenil (central benzodiazepine receptor ligand) as competitors. Furthermore, DPA-C5yne proved to be stable in plasma at 37°C for at least 90 min.

  DPA-C5yne是一个新系列DPA-714衍生物的主要化合物，其中连接到苯基吡唑并嘧啶支架的氟乙氧基链被氟炔基取代，是一种高亲和力（Ki: 0.35 nM）且选择性靶向18 kDa转位蛋白的配体。在本研究中，DPA-C5yne通过一步托辛氧取代反应与无载体添加的[18F]氟化物标记，经过 cartridge 和 HPLC 纯化，并使用 TRACERLab FX N Pro 合成仪制备成静脉注射用溶液。通常，从30 GBq [18F]氟化物批次（14-17%）出发，获得了4.3-5.2 GBq的[18F]DPA-C5yne，准备使用，化学和放射化学纯度超过95%，特定放射活性范围为55到110 GBq/µmol，反应时间为50到60分钟。使用摇瓶法测定的[18F]DPA-C5yne的LogP和LogD值分别为2.39和2.51。在用((R,S)-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）损伤的老鼠大脑切片进行的自显影研究中，显示出高目标与背景比率（1.9 ± 0.3）。通过使用未标记的DPA-C5yne、PK11195和氟马西尼（中央苯二氮平受体配体）作为竞争剂，证明了对转位蛋白的结合的选择性和特异性。此外，DPA-C5yne在37°C下在血浆中至少稳定90分钟。
• Preparation and evaluation of novel pyrazolo[1,5-a]pyrimidine acetamides, closely related to DPA-714, as potent ligands for imaging the TSPO 18kDa with PET
  作者：Vincent Médran-Navarrete、Annelaure Damont、Marie-Anne Peyronneau、Bertrand Kuhnast、Nicholas Bernards、Géraldine Pottier、Frank Marguet、Frédéric Puech、Raphaël Boisgard、Frédéric Dollé

  DOI：10.1016/j.bmcl.2014.01.080

  日期：2014.3

  A series of four novel analogues of DPA-714, bearing a fluoroalkynyl side chain (with a length ranging from three to six carbon atoms) in replacement of the fluoroethoxy motif, have been synthetized in six steps from commercially available methyl 4-iodobenzoate. The synthetic strategy for the preparation of these N,N-diethyl-2-(2-(4-(omega-fluoroalk-1-ynyl) phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl) acetamides (7a-d) consisted in derivatizing a key iodinated building block featuring the pyrazolopyrimidine acetamide backbone of DPA-714, by Sonogashira couplings with various alkynyl reagents. The resulting alkynols were subsequently fluorinated, yielding the expected target derivatives. All four analogues exhibited slightly higher affinity and selectivity towards the TSPO 18 kDa (K-i vs [H-3]PK11195: 0.35-0.79 nM; Ki vs [H-3] flunitrazepam: > 1000 nM) when compared to DPA-714 (Ki vs [H-3] PK11195: 0.91 nM; Ki vs [H-3] flunitrazepam: > 1000 nM). Lipophilicities (HPLC, logD(7.4)) increased with the chain length (from 3.6 to 4.3) and were significantly higher than the one determined for DPA-714 (2.9). Preliminary in vitro metabolism evaluation using rat microsomal incubations and LC-MS analyses showed, for all four novel analogues, the absence of defluorinated metabolites. Among them, the fluoropentynyl compound, DPA-C5yne (7c), was selected, labelled in one single step with fluorine-18 from the corresponding tosylate and in vivo evaluated with PET on our in-house-developed rat model of acute local neuroinflammation. (C) 2014 Elsevier Ltd. All rights reserved.
• Novel Pyrazolo[1,5-<i>a</i>]pyrimidines as Translocator Protein 18 kDa (TSPO) Ligands: Synthesis, <i>in Vitro</i> Biological Evaluation, [¹⁸F]-Labeling, and <i>in Vivo</i> Neuroinflammation PET Images
  作者：Annelaure Damont、Vincent Médran-Navarrete、Fanny Cacheux、Bertrand Kuhnast、Géraldine Pottier、Nicholas Bernards、Frank Marguet、Frédéric Puech、Raphaël Boisgard、Frédéric Dollé

  DOI：10.1021/acs.jmedchem.5b00932

  日期：2015.9.24

  A series of novel pyrazolo[1,5-a]pyrimidines, closely related to N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide (2, DPA-714), were synthesized and biologically in vitro evaluated for their potential to bind the translocator protein 18 kDa (TSPO), a protein today recognized as an early biomarker of neuroinflammatory processes. This series is composed

  一系列新的吡唑的[1,5-一个]嘧啶，密切相关的Ñ，ñ -二乙基- 2-（2-（4-（2-氟乙氧基）苯基）-5,7-二甲基[1,5-一个合成]嘧啶-3-基）乙酰胺（2，DPA-714），并在生物学上体外评估其结合转运蛋白18 kDa（TSPO）的潜力，该蛋白今天被认为是神经炎症过程的早期生物标记。该系列由氟烷基-和氟炔基-类似物组成，它们是通过Sonogashira偶联反应从常见的碘化中间体制得的。所有衍生物均表现出对TSPO的亚纳摩尔亲和力（0.37至0.86 nM），与2的亲和力相当（0.91 nM）。其中两个被氟18放射性标记，并通过体外放射自显影和正电子发射断层扫描（PET）成像在啮齿类神经炎模型上研究了它们的生物分布。两种化合物在AMPA介导的病变中的大脑摄取和局部蓄积证实了它们作为体内PET放射治疗者的潜力。特别地，[ 18 F] 23在体内显示出比母体分子[ 18 F] 2在60分钟时显着更高的ipsi-对侧比。