Jia Limeng, Miao Caihong, Dong Fugui, Li Wei, Wang Min, Zheng Qi-Huang, Xu Zhidong
Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, College of Chemistry and Environmental Science, Hebei University, Baoding, Hebei 071002, China.
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 1345 West 16(th) Street, Room 202, Indianapolis, IN 46202, USA.
Bioorg Med Chem Lett. 2019 Jul 1;29(13):1654-1659. doi: 10.1016/j.bmcl.2019.04.036. Epub 2019 Apr 25.
To develop PET tracers for imaging of neuroinflammation, new carbon-11-labeled sEH/PDE4 dual inhibitors have been synthesized. The reference standard N-(4-methoxy-2-(trifluoromethyl)benzyl)benzamide (1) and its corresponding desmethylated precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)benzamide (2) were synthesized from (4-methoxy-2-(trifluoromethyl)phenyl)methanamine and benzoic acid in one and two steps with 84% and 49% overall chemical yield, respectively. The standard N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA, 4) and its precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (5) were synthesized from methyl 4-piperidinecarboxylate, propionyl chloride and (4-methoxy-2-(trifluoromethyl)phenyl)methanamine in two and three steps with 62% and 34% overall chemical yield, respectively. The target tracers N-(4-[C]methoxy-2-(trifluoromethyl)benzyl)benzamide ([C]1) and N-(4-[C]methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide ([C]MPPA, [C]4) were prepared from their corresponding precursors 2 and 5 with [C]CHOTf through O-[C]methylation and isolated by HPLC combined with SPE in 25-35% radiochemical yield, based on [C]CO and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (A) at EOB was 370-740 GBq/μmol with a total synthesis time of 35-40-minutes from EOB.
为了开发用于神经炎症成像的正电子发射断层显像（PET）示踪剂，已合成了新型碳-11标记的可溶性环氧化物水解酶（sEH）/磷酸二酯酶4（PDE4）双重抑制剂。参考标准品N-(4-甲氧基-2-(三氟甲基)苄基)苯甲酰胺（1）及其相应的去甲基化前体N-(4-羟基-2-(三氟甲基)苄基)苯甲酰胺（2）分别由(4-甲氧基-2-(三氟甲基)苯基)甲胺和苯甲酸经一步和两步合成，总化学产率分别为84%和49%。标准品N-(4-甲氧基-2-(三氟甲基)苄基)-1-丙酰基哌啶-4-甲酰胺（MPPA，4）及其前体N-(4-羟基-2-(三氟甲基)苄基)-1-丙酰基哌啶-4-甲酰胺（5）分别由4-哌啶甲酸甲酯、丙酰氯和(4-甲氧基-2-(三氟甲基)苯基)甲胺经两步和三步合成，总化学产率分别为62%和34%。目标示踪剂N-(4-[C]甲氧基-2-(三氟甲基)苄基)苯甲酰胺（[C]1）和N-(4-[C]甲氧基-2-(三氟甲基)苄基)-1-丙酰基哌啶-4-甲酰胺（[C]MPPA，[C]4）由其相应的前体2和5通过O-[C]甲基化反应，用[C]CHOTf制备，并通过高效液相色谱（HPLC）结合固相萃取（SPE）分离，基于[C]CO并校正到轰击结束（EOB）时的放射性化学产率为25%-35%。放射性化学纯度>99%，EOB时的摩尔活度（A）为370-740 GBq/μmol，从EOB开始的总合成时间为35-40分钟。
