2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinolin-4-ol | 1607448-76-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinolin-4-ol
• CAS: 1607448-76-9
• 化学式: C₂₅H₂₀N₄O₂
• 分子量: 408.459
• InChiKey: SKDRPPMSKGPPNM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.98
• 重原子数：
  31.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  73.06
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinolin-4-ol 、 [(18)F]-2-fluoroethyltosylate 以 二甲基亚砜 为溶剂， 生成 4-((2-fluoro-18F)ethoxy)-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinoline
  参考文献：
  名称：

  In Vivo Characterization of Two ¹⁸F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains

  摘要：

  Positron emission tomography (PET) with phosphodiesterase 10A (PDE10A) specific radioligands provides a noninvasive and quantitative imaging tool to access the expression of this enzyme in vivo under normal and diseased conditions. We recently reported two potent F-18-labeled PDE10A radioligands (F-18-TZ19106B and F-18-TZ8110); initial evaluation in rats and nonhuman primates indicated stable metabolic profiles and excellent target-to-nontarget ratio (striatum/cerebellum) for both tracers. Herein, we focused on in vivo characterization of F-18-TZ19106B and F-18-TZ8110 to identify a suitable radioligand for imaging PDE10A in vivo. We directly compared microPET studies of these two radiotracers in adult male Macaca fascicularis nonhuman primates (NHPs). F-18-TZ19106B had higher striatal uptake and tracer retention in NHP brains than F-18-TZ8110, quantified by either standardized uptake values (SUVs) or nondisplaceable binding potential (BP (ND) ) estimated using reference-based modeling analysis. Blocking and displacement studies using the PDE10A inhibitor MP-10 indicated the binding of F-18-TZ19106B to PDE10A was specific and reversible. We also demonstrated sensitivity of F-18-TZ19106B binding to varying number of specific binding sites using escalating doses of MP-10 blockade (0.3, 0.5, 1.0, 1.5, and 2.0 mg/kg). Pretreatment with a dopamine D2-like receptor antagonist enhanced the striatal uptake of F-18-TZ19106B. Our results indicate that F-18-TZ19106B is a promising radioligand candidate for imaging PDE10A in vivo and it may be used to determine target engagement of PDE10A inhibitors and serve as a tool to evaluate the effect of novel antipsychotic therapies.

  DOI：

  10.1021/acschemneuro.7b00458
• 作为产物：
  描述：

  (4-(methoxymethoxy)quinolin-2-yl)methanol 在 偶氮二甲酸二叔丁酯 、 三苯基膦 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 42.0h， 生成 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinolin-4-ol
  参考文献：
  名称：

  Synthesis of Fluorine-Containing Phosphodiesterase 10A (PDE10A) Inhibitors and the In Vivo Evaluation of F-18 Labeled PDE10A PET Tracers in Rodent and Nonhuman Primate

  摘要：

  A series of fluorine-containing PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [C-11]MP-10. Twenty of the 22 new analogues had high potency and selectivity for PDE10A: 18a-j, 19d-j, 20a-b, and 21b had IC50 values <5 nM for PDE10A. Seven F-18 labeled compounds [F-18](18)a-e, [F-18]18g, and [F-18]20a were radiosynthesized by F-18-introduction onto the quinoline rather than the pyrazole moiety of the MP-10 pharmacophore and performed in vivo evaluation. Biodistribution studies in rats showed similar to 2-fold higher activity in the PDE10A-enriched striatum than nontarget brain regions; this ratio increased from 5 to 30 min postinjection, particularly for [F-18]18a-d and [F-18]20a. Micro-PET studies of [F-18]18d and [F-18]20a in nonhuman primates provided clear visualization of striatum with suitable equilibrium kinetics and favorable metabolic stability. These results suggest this strategy may identify a F-18-labeled PET tracer for quantifying the levels of PDE10A in patients with CNS disorders including Huntington's disease and schizophrenia.

  DOI：

  10.1021/acs.jmedchem.5b01205

文献信息

• Radiosyntheses and in vivo evaluation of carbon-11 PET tracers for PDE10A in the brain of rodent and nonhuman primate
  作者：Jinda Fan、Xiang Zhang、Junfeng Li、Hongjun Jin、Prashanth K. Padakanti、Lynne A. Jones、Hubert P. Flores、Yi Su、Joel S. Perlmutter、Zhude Tu

  DOI：10.1016/j.bmc.2014.03.028

  日期：2014.5

  The radiosyntheses and in vivo evaluation of four carbon-11 labeled quinoline group-containing radioligands are reported here. Radiolabeling of [C-11]1-4 was achieved by alkylation of their corresponding desmethyl precursors with [C-11]CH3I. Preliminary biodistribution evaluation in Sprague-Dawley rats demonstrated that [11C] 1 and [C-11]2 had high striatal accumulation (at peak time) for [C-11]1 and [C-11]2 were 6.0-fold and 4.5-fold at 60 min, respectively. Following MP-10 pretreatment, striatal uptake in rats of [C-11]1 and [C-11]2 was reduced, suggesting that the tracers bind specifically to PDE10A. MicroPET studies of [C-11]1 and [C-11]2 in nonhuman primates (NHP) also showed good tracer retention in the striatum with rapid clearance from non-target brain regions. Striatal uptake (SUV) of [C-11]1 reached 1.8 at 30 min with a 3.5-fold striatum: cerebellum ratio. In addition, HPLC analysis of solvent extracts from NHP plasma samples suggested that [C-11]1 had a very favorable metabolic stability. Our preclinical investigations suggest that [C-11]1 is a promising candidate for quantification of PDE10A in vivo using PET. (C) 2014 Elsevier Ltd. All rights reserved.