1-(3-fluoro-4-(3-fluoropropoxy)phenethyl)guanidine | 2452164-25-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 1-(3-fluoro-4-(3-fluoropropoxy)phenethyl)guanidine
• 英文别名: [¹⁸F]AF78；[¹⁸F]AF78(F)；Z8L8Dwv2EK；2-[2-[4-(3-(18F)fluoranylpropoxy)-3-fluorophenyl]ethyl]guanidine
• CAS: 2452164-25-7
• 化学式: C₁₂H₁₇F₂N₃O
• 分子量: 256.285
• InChiKey: RBHDCVHMNCYKJZ-HSGWXFLFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.59
• 重原子数：
  18.0
• 可旋转键数：
  7.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  71.13
• 氢给体数：
  3.0
• 氢受体数：
  2.0

反应信息

• 作为产物：
  描述：

  在 盐酸 作用下， 以 乙腈 为溶剂， 反应 0.33h， 生成 1-(3-fluoro-4-(3-fluoropropoxy)phenethyl)guanidine
  参考文献：
  名称：

  Molecular Imaging-Derived Biomarker of Cardiac Nerve Integrity — Introducing High NET Affinity PET Probe ¹⁸F-AF78

  摘要：

  背景：作为去甲肾上腺素转运体（NET）底物的放射性标记剂可用于量化心脏交感神经状况，并已被证明可用于识别易发生心律失常的高危充血性心力衰竭（HF）患者。我们的目标是充分描述新型18F标记NET探针AF78的动力学特征，用于对不同物种的心脏交感神经系统（SNS）进行PET成像。

  DOI：

  10.7150/thno.63205

文献信息

• [EN] COMPOUND TARGETING NOREPINEPHRINE TRANSPORTER<br/>[FR] COMPOSÉ CIBLANT UN TRANSPORTEUR DE NORÉPINÉPHRINE
  申请人：UNIV WUERZBURG J MAXIMILIANS

  公开号：WO2020148154A1

  公开（公告）日：2020-07-23

  The invention concerns a compound according to following formula, wherein R1 is an F or an I residue.

  这项发明涉及一种化合物，其化学式如下，其中R1是F或I残基。
• Rationalizing the Binding Modes of PET Radiotracers Targeting the Norepinephrine Transporter
  作者：Anna Tutov、Xinyu Chen、Rudolf A. Werner、Saskia Mühlig、Thomas Zimmermann、Naoko Nose、Kazuhiro Koshino、Constantin Lapa、Michael Decker、Takahiro Higuchi

  DOI：10.3390/pharmaceutics15020690

  日期：——

  Purpose: A new PET radiotracer 18F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations of the structure–activity relationships (SARs) of NET-targeting radiotracers have rarely been performed. Methods: Without changing the phenethylguanidine pharmacophore and 3-fluoropropyl moiety that is crucial for easy labeling, six new analogs of 18F-AF78 with different meta-substituents on the benzene-ring were synthesized and evaluated in a competitive cellular uptake assay and in in vivo animal experiments in rats. Computational modeling of these tracers was established to quantitatively rationalize the interaction between the radiotracers and NET. Results: Using non-radiolabeled reference compounds, a competitive cellular uptake assay showed a decrease in NET-transporting affinity from meta-fluorine to iodine (0.42 and 6.51 µM, respectively), with meta-OH being the least active (22.67 µM). Furthermore, in vivo animal studies with radioisotopes showed that heart-to-blood ratios agreed with the cellular experiments, with AF78(F) exhibiting the highest cardiac uptake. This result correlates positively with the electronegativity rather than the atomic radius of the meta-substituent. Computational modeling studies revealed a crucial influence of halogen substituents on the radiotracer–NET interaction, whereby a T-shaped π–π stacking interaction between the benzene-ring of the tracer and the amino acid residues surrounding the NET binding site made major contributions to the different affinities, in accordance with the pharmacological data. Conclusion: The SARs were characterized by in vitro and in vivo evaluation, and computational modeling quantitatively rationalized the interaction between radiotracers and the NET binding site. These findings pave the way for further evaluation in different species and underline the potential of AF78(F) for clinical application, e.g., cardiac innervation imaging or molecular imaging of neuroendocrine tumors.

  目的：最近报道了一种新的 PET 放射性示踪剂 18F-AF78，显示出巨大的临床应用潜力。它属于新一代基于苯乙胍的去甲肾上腺素转运体（NET）靶向放射性示踪剂。尽管人们一直在努力开发作为抗抑郁药物的NET抑制剂，但很少对NET靶向放射性核素的结构-活性关系（SAR）进行系统研究。研究方法在不改变苯乙胍药理结构和对易于标记至关重要的 3-氟丙基的情况下，合成了苯环上具有不同元取代基的 18F-AF78 的六种新类似物，并在竞争性细胞摄取试验和大鼠体内动物实验中进行了评估。建立了这些示踪剂的计算模型，以定量合理地解释放射性示踪剂与 NET 之间的相互作用。结果：使用非放射性标记的参考化合物进行的竞争性细胞摄取试验表明，NET的转运亲和力从偏氟下降到碘（分别为0.42和6.51 µM），其中偏OH的活性最低（22.67 µM）。此外，利用放射性同位素进行的体内动物实验表明，心脏对血液的吸收比与细胞实验结果一致，AF78(F) 的心脏吸收率最高。这一结果与元取代基的电负性而非原子半径呈正相关。计算模型研究显示，卤素取代基对放射性示踪剂与 NET 的相互作用有重要影响，示踪剂的苯环与围绕 NET 结合位点的氨基酸残基之间的 T 型 π-π 堆积相互作用对不同的亲和力有重大贡献，这与药理学数据一致。结论通过体外和体内评估确定了 SARs 的特征，计算模型定量合理地解释了放射性示踪剂与 NET 结合位点之间的相互作用。这些发现为在不同物种中进行进一步评估铺平了道路，并凸显了 AF78(F) 在临床应用（如心脏神经支配成像或神经内分泌肿瘤的分子成像）方面的潜力。