(S)-tert-butyl 2-((5-(hydroxymethyl)pyridine-3-yloxy)methyl)azetidine-1-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂环丁烷
• 英文名称: (S)-tert-butyl 2-((5-(hydroxymethyl)pyridine-3-yloxy)methyl)azetidine-1-carboxylate
• 英文别名: tert-butyl (2S)-2-[[5-(hydroxymethyl)pyridin-3-yl]oxymethyl]azetidine-1-carboxylate
• 化学式: C₁₅H₂₂N₂O₄
• 分子量: 294.351
• InChiKey: FNGCZLFEKQTIBF-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  21
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  71.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-tert-butyl 2-((5-(hydroxymethyl)pyridine-3-yloxy)methyl)azetidine-1-carboxylate 在 1-氯-N,N,2-三甲基丙烯胺 、 potassium carbonate 、 potassium iodide 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 101.0h， 生成 5-[bis(2-pyridylmethyl)aminomethyl]-3-[(S)-1-(tert-butoxycarbonyl)-2-azetidinylmethoxy]pyridine
  参考文献：
  名称：

  Development of 99mTc radiolabeled A85380 derivatives targeting cerebral nicotinic acetylcholine receptor: Novel radiopharmaceutical ligand 99mTc-A-YN-IDA-C4

  摘要：

  Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that have been implicated in higher brain functions. To elucidate the functional mechanisms underlying nAChRs and contribute significantly to development of drugs targeting neurological and neuropsychiatric diseases, non-invasive nuclear medical imaging can be used for evaluation. In addition, technetium-99m (Tc-99m) is a versatile radionuclide used clinically as a tracer in single-photon emission computed tomography. Because A85380 is known as a potent alpha 4 beta 2-nAChR agonist, we prepared A85380 derivatives labeled with Tc-99m using a bifunctional chelate system. A computational scientific approach was used to design the probe efficiently. We used non-radioactive rhenium (Re) for a Tc-99m analog and found that one of the derivatives, Re-A-YN-IDA-C4, exhibited high binding affinity at alpha 4 beta 2-nAChR in both the docking simulation (-19.3 kcal/mol) and binding assay (Ki = 0.4 +/- 0.04 nM). Further, Tc-99m-A-YN-IDA-C4 was synthesized using microwaves, and its properties were examined. Consequently, we found that Tc-99m-A-YN-IDA-C4, with a structure optimized by using computational chemistry techniques, maintained affinity and selectivity for nAChR in vitro and possessed efficient characteristics as a nuclear medicine molecular imaging probe, demonstrated usefulness of computational scientific approach for molecular improvement strategy.

  DOI：

  10.1016/j.bmc.2019.07.053
• 作为产物：
  描述：

  (S)-1-BOC-2-氮杂环丁烷甲醇 在 lithium aluminium tetrahydride 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 1.0h， 生成 (S)-tert-butyl 2-((5-(hydroxymethyl)pyridine-3-yloxy)methyl)azetidine-1-carboxylate
  参考文献：
  名称：

  Development of 99mTc radiolabeled A85380 derivatives targeting cerebral nicotinic acetylcholine receptor: Novel radiopharmaceutical ligand 99mTc-A-YN-IDA-C4

  摘要：

  Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that have been implicated in higher brain functions. To elucidate the functional mechanisms underlying nAChRs and contribute significantly to development of drugs targeting neurological and neuropsychiatric diseases, non-invasive nuclear medical imaging can be used for evaluation. In addition, technetium-99m (Tc-99m) is a versatile radionuclide used clinically as a tracer in single-photon emission computed tomography. Because A85380 is known as a potent alpha 4 beta 2-nAChR agonist, we prepared A85380 derivatives labeled with Tc-99m using a bifunctional chelate system. A computational scientific approach was used to design the probe efficiently. We used non-radioactive rhenium (Re) for a Tc-99m analog and found that one of the derivatives, Re-A-YN-IDA-C4, exhibited high binding affinity at alpha 4 beta 2-nAChR in both the docking simulation (-19.3 kcal/mol) and binding assay (Ki = 0.4 +/- 0.04 nM). Further, Tc-99m-A-YN-IDA-C4 was synthesized using microwaves, and its properties were examined. Consequently, we found that Tc-99m-A-YN-IDA-C4, with a structure optimized by using computational chemistry techniques, maintained affinity and selectivity for nAChR in vitro and possessed efficient characteristics as a nuclear medicine molecular imaging probe, demonstrated usefulness of computational scientific approach for molecular improvement strategy.

  DOI：

  10.1016/j.bmc.2019.07.053

文献信息

• Synthesis and biological evaluation of Tc-99m-cyclopentadienyltricarbonyl-technetium-labeled A-85380: An imaging probe for single-photon emission computed tomography investigation of nicotinic acetylcholine receptors in the brain
  作者：Hiroyuki Kimura、Masashi Ueda、Hidekazu Kawashima、Kenji Arimitsu、Yusuke Yagi、Hideo Saji

  DOI：10.1016/j.bmc.2019.04.030

  日期：2019.6

  We have designed (S)-(5-(azetidin-2-ylmethoxy)pyridine-3-yl)methyl cyclopentadienyltricarbonyl technetium carboxylate ([99mTc]CPTT-A-E) with high affinity for nicotinic acetylcholine receptors (nAChRs) using (2(S)-azetidinylmethoxy)-pyridine (A-85380) as the lead compound to develop a Tc-99m-cyclopentadienyltricarbonyl-technetium (99mTc)-labeled nAChR imaging probe. Because technetium does not contain

  我们设计了（S）-（5-（氮杂环丁烷-2-基甲氧基）吡啶-3-基）甲基环戊二烯基三羰基羧酸tech（[99mTc] CPTT-AE），其对烟碱乙酰胆碱受体（nAChRs）具有高亲和力，使用（2（S ）-氮杂环丁烷基甲氧基）-吡啶（A-85380）作为先导化合物，以开发Tc-99m-环戊二烯基三羰基-（（99mTc）标记的nAChR成像探针。由于tech不包含稳定的同位素，因此通过配位rh来合成环戊二烯基三羰基rh（CPTR），rh是与tech具有相同配位结构的同源元素。此外，评估了对nAChR的结合亲和力。CPTR-AE对nAChR表现出高结合亲和力（Ki = 0.55 nM）。通过[99mTc] CPTT-AE的放射合成，得到的目标化合物的放射化学产率为33％，放射化学纯度大于97％。大脑的体外放射自显影研究表明，局部nAChR密度与在每个目标区域中积累的[99mTc] CPTT-AE的
• NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS AND THE USES THEREOF
  申请人：Chandrasekhar Jayaraman

  公开号：US20100152450A1

  公开（公告）日：2010-06-17

  The invention relates to pyridinyl nicotinic acetylcholine receptor ligands, compositions comprising an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand and methods to treat or prevent a condition, such as depression and nicotine dependence, comprising administering to an animal in need thereof an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand.

  本发明涉及吡啶基烟碱乙酰胆碱受体配体，包含有效量的吡啶基烟碱乙酰胆碱受体配体的组合物，以及治疗或预防状况（如抑郁和尼古丁依赖症）的方法，包括向需要的动物中投与有效量的吡啶基烟碱乙酰胆碱受体配体。
• [EN] NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS AND THE USES THEREOF<br/>[FR] LIGANDS DES RÉCEPTEURS CHOLINERGIQUES NICOTINIQUES ET LEURS UTILISATIONS
  申请人：PSYCHOGENICS INCSTATUTS

  公开号：WO2010045212A2

  公开（公告）日：2010-04-22

  The invention relates to pyridinyl nicotinic acetylcholine receptor ligands, compositions comprising an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand and methods to treat or prevent a condition, such as depression and nicotine dependence, comprising administering to an animal in need thereof an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand.