(S)-Fluorocarazolol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (S)-Fluorocarazolol
• 英文别名: (S)-flurocarazolol；(2S)-1-(9H-carbazol-4-yloxy)-3-(1-fluoropropan-2-ylamino)propan-2-ol
• 化学式: C₁₈H₂₁FN₂O₂
• 分子量: 316.375
• InChiKey: QHLGXPUIUKSADT-ABLWVSNPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  57.3
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  氟代丙酮 、 (2S)-3-(9H-carbazol-4-yloxy)-2-hydroxy-propylamine 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以62%的产率得到(S)-Fluorocarazolol
  参考文献：
  名称：

  Synthesis, Binding Properties, and 18F Labeling of Fluorocarazolol, a High-Affinity .beta.-Adrenergic Receptor Antagonist

  摘要：

  New beta-adrenergic receptor antagonists, 2-(R)-(+)- and 2-(S)-(-)-1-(9H-earbazol-4-yl-oxy)-3-[[1-(fluoromethyl)ethyl]amino]-2-propanol ((S)- and (R)-fluorocarazolols), were labeled with fluorine-18 at the no-carrier-added level by reductive alkylation of desisopropylcarazolol (4-(2-hydroxy-3-amino-1-propoxy)carbazole) with [F-18]fluoroacetone. The latter was prepared by nucleophilic substitution of fluoride on acetol tosylate and may serve as a useful synthetic precursor for other radiotracers. The radiochemical yield of [F-18]fluorocarazolol (500-1200 Ci/mmol) from [F-18]fluoride was 40 +/- 10% at the end of the 45 min synthesis. Chiral HPLC showed >99% enantiomeric purity of 2-(S)- and 2-(R)- [F-18] fluorocarazolols. The log P of fluorocarazolol was 2.2 at pH 7.4. The in vitro K-D values of(S)- and (R)-fluorocarazolol for the beta-adrenergic receptor were measured in a rat heart preparation to be K-D= 68 and 1128 pM, respectively. Biodistribution experiments in mice demonstrated specific beta-adrenergic receptor binding of (S)-[F-18]fluorocarazolol. (R)-[F-18]fluorocarazolol showed no observable specific binding to beta-receptors in vivo. The uptake of (R)-[F-18]fluorocarazolol may therefore be used as an estimation of nonspecific binding. Positron emission tomography images of pigs showed receptor-specific uptake of(S)-[F-18]fluorocarazolol in the heart and lung. Washout of dissociated ligand from the tissue was observed only after 70 min postinjection. The maximum ratio of specific to nonspecific uptake in pig heart and lung was ca. 10 at 150 min postinjection. Observed levels of fluorocarazolol metabolites in mouse and pig blood were relatively low and remained fairly constant during the period from 10 to 180 min postinjection. These results indicate that (S)-(-)-[F-18]fluorocarazolol is of interest for use as a radiopharmaceutical for estimation of beta-adrenergic receptors with positron tomography.

  DOI：

  10.1021/jm00046a005

文献信息

• [EN] LIGANDS FOR CARDIAC BETA1 ADRENOCEPTOR FOR IMAGING CONGESTIVE HEART FAILURE<br/>[FR] LIGANDS POUR L'ADRÉNORÉCEPTEUR BÊTA1 CARDIAQUE, DESTINÉS À DES APPLICATIONS D'IMAGERIE DE L'INSUFFISANCE CARDIAQUE CONGESTIVE
  申请人：BRISTOL MYERS SQUIBB PHARMA CO

  公开号：WO2008083054A2

  公开（公告）日：2008-07-10

  [EN] Novel ß₁ adrenoreceptor ligands that find use as imaging agents within nuclear medicine applications (e.g., PET imaging and SPECT imaging) are provided. Methods of imaging, including methods of imaging congestive heart failure, are also provided. The novel compounds may exhibit high affinity and selectivity, minimal metabolism, minimal non-specific binding and have a favorable log P value (< 0). In some instances, ß₁-AR selective ligands are conjugated to an imaging moiety in such a way that it does not impact the antagonist affinity and their use. In other instances, the conjugation may be directly to the antagonist at several sites that will not impact affinity. In further instances, the conjugation may be by means of a linking group, which can be used to alter the pharmacokinetics and clearance of the complex.
  [FR] L'invention concerne de nouveaux ligands d'adrénorécepteurs ß₁ utilisés comme agents d'imagerie dans des applications de médecine nucléaire (en imagerie TEP et en imagerie TEM, par exemple). L'invention concerne également des procédés d'imagerie, y compris des procédés d'imagerie de l'insuffisance cardiaque congestive. Les nouveaux composés peuvent présenter une affinité et une sélectivité élevées, un métabolisme minimal, une fixation non spécifique minimale et posséder une valeur log P favorable (<0). Dans certains cas, des ligands sélectifs des récepteurs adrénergiques bêta 1 sont conjugués avec un groupe fonctionnel d'imagerie de façon à ne pas avoir d'effet sur l'affinité de l'antagoniste et leur utilisation. Dans d'autres cas, les ligands sont conjugués directement avec l'antagoniste au niveau de différents sites qui n'ont aucun effet sur l'affinité. Dans d'autres cas, les ligands peuvent être conjugués à l'aide d'un groupe de liaison, pour modifier la pharmacocinétique et la clairance du complexe.
• Synthesis, Binding Properties, and 18F Labeling of Fluorocarazolol, a High-Affinity .beta.-Adrenergic Receptor Antagonist
  作者：Lei Zheng、Marc S. Berridge、Paul Ernsberger

  DOI：10.1021/jm00046a005

  日期：1994.9

  New beta-adrenergic receptor antagonists, 2-(R)-(+)- and 2-(S)-(-)-1-(9H-earbazol-4-yl-oxy)-3-[[1-(fluoromethyl)ethyl]amino]-2-propanol ((S)- and (R)-fluorocarazolols), were labeled with fluorine-18 at the no-carrier-added level by reductive alkylation of desisopropylcarazolol (4-(2-hydroxy-3-amino-1-propoxy)carbazole) with [F-18]fluoroacetone. The latter was prepared by nucleophilic substitution of fluoride on acetol tosylate and may serve as a useful synthetic precursor for other radiotracers. The radiochemical yield of [F-18]fluorocarazolol (500-1200 Ci/mmol) from [F-18]fluoride was 40 +/- 10% at the end of the 45 min synthesis. Chiral HPLC showed >99% enantiomeric purity of 2-(S)- and 2-(R)- [F-18] fluorocarazolols. The log P of fluorocarazolol was 2.2 at pH 7.4. The in vitro K-D values of(S)- and (R)-fluorocarazolol for the beta-adrenergic receptor were measured in a rat heart preparation to be K-D= 68 and 1128 pM, respectively. Biodistribution experiments in mice demonstrated specific beta-adrenergic receptor binding of (S)-[F-18]fluorocarazolol. (R)-[F-18]fluorocarazolol showed no observable specific binding to beta-receptors in vivo. The uptake of (R)-[F-18]fluorocarazolol may therefore be used as an estimation of nonspecific binding. Positron emission tomography images of pigs showed receptor-specific uptake of(S)-[F-18]fluorocarazolol in the heart and lung. Washout of dissociated ligand from the tissue was observed only after 70 min postinjection. The maximum ratio of specific to nonspecific uptake in pig heart and lung was ca. 10 at 150 min postinjection. Observed levels of fluorocarazolol metabolites in mouse and pig blood were relatively low and remained fairly constant during the period from 10 to 180 min postinjection. These results indicate that (S)-(-)-[F-18]fluorocarazolol is of interest for use as a radiopharmaceutical for estimation of beta-adrenergic receptors with positron tomography.