[18F]-LBT-999 | 940949-46-2

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 托烷生物碱
• 英文名称: [18F]-LBT-999
• 英文别名: 8-((E)-4-[18F]fluoro-but-2-enyl)-3β-p-tolyl-8-aza-bicyclo[3.2.1]octane-2β-carboxylic acid methyl ester；Unii-13B48I9dyt；methyl (1R,2S,3S,5S)-8-[(E)-4-(18F)fluoranylbut-2-enyl]-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate
• CAS: 940949-46-2
• 化学式: C₂₀H₂₆FNO₂
• 分子量: 330.432
• InChiKey: XZWRXMFAFBSAJC-INCYSKAQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (E)-4-(2-(methoxycarbonyl)-3-p-tolyl-8-azabicyclo[3.2.1]octan-8-yl)but-2-enyl methanesulfonate 在 kryptofix 222 、 potassium carbonate 作用下， 以 乙腈 为溶剂， 175.0 ℃ 、1.8 MPa 条件下， 反应 0.01h， 以27%的产率得到[18F]-LBT-999
  参考文献：
  名称：

  高效的微波辅助直接放射性合成[ 18 F] PR04.MZ和[ 18 F] LBT999：选择性多巴胺转运蛋白配体，可通过PET进行定量分子成像

  摘要：

  PR04.MZ 8-（4-氟-丁-2-炔基）-3-对甲苯基-8-氮杂-双环[3.2.1]辛烷-2-羧酸甲酯（1）和LBT999 8-（（E）-4-氟丁-2-烯基）-3b-对甲苯基-8-氮杂-双环[3.2.1]辛烷-2β-羧酸甲酯（2）是可卡因衍生的选择性多巴胺再摄取抑制剂。使用微波增强的直接亲核氟化作用，化合物1和2在其末端氟化的N-取代基上用氟18标记。K [ 18 F]˚F -的Kryptofix ® 222穴状化合物，四丁基铵[ 18 F]氟化物和铯[ 18在常规条件和微波增强条件下，将F]氟化物作为氟化物源进行了比较。在微波照射下，所有三种氟化物盐的氟化产率均显着增加。放射化学纯（> 98％）[ 18 F] PR04.MZ（0.95–1.09 GBq，42–135 GBq /μmol）在3.0–40qq [ 18 F]氟离子中以32–36％的非离子浓度开始获得（34.135 GBq

  DOI：

  10.1016/j.bmc.2009.09.054

文献信息

• One-step radiosynthesis of [18F]LBT-999: a selective radioligand for the visualization of the dopamine transporter with PET
  作者：Frédéric Dollé、Julie Helfenbein、Françoise Hinnen、Sylvie Mavel、Zoïa Mincheva、Wadad Saba、Marie-Anne Schöllhorn-Peyronneau、Heric Valette、Lucette Garreau、Sylvie Chalon、Christer Halldin、Jean-Claude Madelmont、Jean-Bernard Deloye、Michel Bottlaender、Joël Le Gailliard、Denis Guilloteau、Patrick Emond

  DOI：10.1002/jlcr.1412

  日期：2007.7

  LBT-999 (8-((E)-4-fluoro-but-2-enyl)-3-beta-p-tolyl-8-aza-bicyclo[3.2.1]octane-2-beta-carboxylicacid methyl ester) is a recently developed cocaine derivative belonging to a new generation of highly selective dopamine transporter (DAT) ligands (KD: 9 nM for the DAT and IC50 > 1000 nM for the serotonin and norepinephrine transporter). Initial fluorine-18-labelling of LBT-999 was based on the robust and reliable two-step radiochemical pathway often reported for such tropane derivatives, involving first the preparation of (E)-1-[18F]fluoro-4-tosyloxybut-2-ene followed by a N-alkylation reaction with the appropriate nor-tropane moiety. In the present work, a simple one-step fluorine-18-labelling of LBT-999 is reported, based on a chlorine-for-fluorine nucleophilic aliphatic substitution, facilitating as expected both automation and final high-performance liquid chromatography (HPLC) purification. The process involves: (A) reaction of K[18F]F–Kryptofix®222 with the chlorinated precursor (3.5–4.5 mg) at 165°C for 10 min in DMSO (0.6 mL) followed by (B) C-18 PrepSep cartridge pre-purification and finally (C) semi-preparative HPLC purification on a Waters Symmetry® C-18. Typically, 3.70–5.92 GBq of [18F]LBT-999 (> 95% chemically and radiochemically pure) could be obtained with specific radioactivities ranging from 37 to 111 GBq/µmol within 85–90 min (HPLC purification and Sep-Pak-based formulation included), starting from a 37.0 GBq [18F]fluoride batch (overall radiochemical yields: 10–16%, non-decay-corrected). Copyright © 2007 John Wiley & Sons, Ltd.

  LBT-999（8-((E)-4-氟-丁-2-烯基)-3-β-对甲苯基-8-氮杂双环[3.2.1]辛烷-2-β-羧酸甲酯）是最近开发的一种可卡因衍生物，属于新一代高选择性多巴胺转运体（DAT）配体（DAT 的 KD：9 nM，5-羟色胺和去甲肾上腺素转运体的 IC50 > 1000 nM）。LBT-999 最初的氟-18 标记是基于此类托烷衍生物经常报道的稳健可靠的两步放射化学途径，首先制备 (E)-1-[18F]氟-4-tosyloxybut-2-ene，然后与适当的正托烷分子进行 N- 烷基化反应。本研究报告了一种简单的一步法氟-18 标记 LBT-999，该方法基于氯对氟的亲核脂肪族取代，有助于实现自动化和最终的高效液相色谱（HPLC）纯化。该过程包括：(A) K[18F]F-Kryptofix®222 与氯化前体（3.5-4.5 毫克）在 165°C 下于 DMSO（0.6 毫升）中反应 10 分钟，然后 (B) C-18 PrepSep 滤芯预纯化，最后 (C) 在 Waters Symmetry® C-18 上进行半制备型 HPLC 纯化。通常情况下，从 37.0 GBq [18F]氟化物批次开始，在 85-90 分钟内可获得 3.70-5.92 GBq [18F]LBT-999（化学纯度和放射化学纯度大于 95%），特定放射性活度范围为 37-111 GBq/µmol（包括 HPLC 纯化和基于 Sep-Pak 的配方）（总体放射化学收率：10-16%，非衰变校正）。Copyright © 2007 John Wiley & Sons, Ltd. All Rights Reserved.
• Synthesis, Fluorine-18 Radiolabeling, and Biological Evaluation of <i>N</i>-((<i>E</i>)-4-Fluorobut-2-en-1-yl)-2β-carbomethoxy-3β-(4′-halophenyl)nortropanes: Candidate Radioligands for In Vivo Imaging of the Brain Dopamine Transporter with Positron Emission Tomography
  作者：Jeffrey S. Stehouwer、Lauryn M. Daniel、Ping Chen、Ronald J. Voll、Larry Williams、Susan J. Plott、John R. Votaw、Michael J. Owens、Leonard Howell、Mark M. Goodman

  DOI：10.1021/jm100269c

  日期：2010.8.12

  The N-(E)-fluorobutenyl-3 beta-(para-halo-phenyl)nortropanes 9-12 were synthesized as ligands of the dopamine transporter (DAT) for use as F-18-labeled positron emission tomography (PET) imaging agents. In vitro competition binding assays demonstrated that compounds 9-12 have a high affinity for the DAT and are selective for the DAT compared to the serotonin and norepinephrine transporters. MicroPET imaging with [F-18]9 [F-18]11 in anesthetized cynomolgus monkeys showed high uptake in the putamen with lesser uptake in the caudate, but significant washout of the radiotracer was only observed for [F-18]9. PET imaging with [E-18]9 in an awake rhesus monkey showed high and nearly equal uptake in both the putamen and caudate with peak uptake achieved after 20 min followed by a leveling-off for about 10 min and then a steady washout and attainment of a quasi-equilibrium. During the time period 40-80 min postinjection of [F-18]9, the ratio of uptake in the putamen and caudate vs cerebellum uptake was a >= 4.
• WO2008/59349
  申请人：——

  公开号：——

  公开（公告）日：——
• Efficient microwave-assisted direct radiosynthesis of [18F]PR04.MZ and [18F]LBT999: Selective dopamine transporter ligands for quantitative molecular imaging by means of PET
  作者：Patrick J. Riss、Frank Roesch

  DOI：10.1016/j.bmc.2009.09.054

  日期：2009.11

  1]octane-2β-carboxylic acid methyl ester (2) are selective dopamine reuptake inhibitors, derived from cocaine. Compounds 1 and 2 were labelled with fluorine-18 at their terminally fluorinated N-substituents employing microwave enhanced direct nucleophilic fluorination. K[18F]F− Kryptofix®222 cryptate, tetrabutyl ammonium [18F]fluoride and caesium [18F]fluoride were compared as fluoride sources under

  PR04.MZ 8-（4-氟-丁-2-炔基）-3-对甲苯基-8-氮杂-双环[3.2.1]辛烷-2-羧酸甲酯（1）和LBT999 8-（（E）-4-氟丁-2-烯基）-3b-对甲苯基-8-氮杂-双环[3.2.1]辛烷-2β-羧酸甲酯（2）是可卡因衍生的选择性多巴胺再摄取抑制剂。使用微波增强的直接亲核氟化作用，化合物1和2在其末端氟化的N-取代基上用氟18标记。K [ 18 F]˚F -的Kryptofix ® 222穴状化合物，四丁基铵[ 18 F]氟化物和铯[ 18在常规条件和微波增强条件下，将F]氟化物作为氟化物源进行了比较。在微波照射下，所有三种氟化物盐的氟化产率均显着增加。放射化学纯（> 98％）[ 18 F] PR04.MZ（0.95–1.09 GBq，42–135 GBq /μmol）在3.0–40qq [ 18 F]氟离子中以32–36％的非离子浓度开始获得（34.135 GBq