Facile synthesis of carbon-11-labeled sEH/PDE4 dual inhibitors as new potential PET agents for imaging of sEH/PDE4 enzymes in neuroinflammation

Limeng Jia, Caihong Miao, Fugui Dong, Wei Li, Min Wang, Qi-Huang Zheng, Zhidong Xu

Research output: Contribution to journalArticle

Abstract

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-[ 11 C]methoxy-2-(trifluoromethyl)benzyl)benzamide ([ 11 C]1) and N-(4-[ 11 C]methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide ([ 11 C]MPPA, [ 11 C]4) were prepared from their corresponding precursors 2 and 5 with [ 11 C]CH 3 OTf through O-[ 11 C]methylation and isolated by HPLC combined with SPE in 25–35% radiochemical yield, based on [ 11 C]CO 2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (A M ) at EOB was 370–740 GBq/μmol with a total synthesis time of 35–40-minutes from EOB.

Original languageEnglish (US)
JournalBioorganic and Medicinal Chemistry Letters
DOIs
StatePublished - Jan 1 2019

Fingerprint

Phosphodiesterase 4 Inhibitors
Carbon
Imaging techniques
Enzymes
Benzoic Acid
Methylation
Carbon Monoxide
High Pressure Liquid Chromatography
benzamide
15-phenyl-beta-methylpentadecanoic acid
methylamine

Keywords

  • Carbon-11-labeled sEH/PDE4 dual inhibitors
  • Neuroinflammation
  • Phosphodiesterase 4 (PDE4)
  • Positron emission tomography (PET)
  • Radiosynthesis
  • Soluble epoxide hydrolase (sEH)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Facile synthesis of carbon-11-labeled sEH/PDE4 dual inhibitors as new potential PET agents for imaging of sEH/PDE4 enzymes in neuroinflammation. / Jia, Limeng; Miao, Caihong; Dong, Fugui; Li, Wei; Wang, Min; Zheng, Qi-Huang; Xu, Zhidong.

In: Bioorganic and Medicinal Chemistry Letters, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "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-[ 11 C]methoxy-2-(trifluoromethyl)benzyl)benzamide ([ 11 C]1) and N-(4-[ 11 C]methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide ([ 11 C]MPPA, [ 11 C]4) were prepared from their corresponding precursors 2 and 5 with [ 11 C]CH 3 OTf through O-[ 11 C]methylation and isolated by HPLC combined with SPE in 25–35{\%} radiochemical yield, based on [ 11 C]CO 2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99{\%}, and the molar activity (A M ) at EOB was 370–740 GBq/μmol with a total synthesis time of 35–40-minutes from EOB.",
keywords = "Carbon-11-labeled sEH/PDE4 dual inhibitors, Neuroinflammation, Phosphodiesterase 4 (PDE4), Positron emission tomography (PET), Radiosynthesis, Soluble epoxide hydrolase (sEH)",
author = "Limeng Jia and Caihong Miao and Fugui Dong and Wei Li and Min Wang and Qi-Huang Zheng and Zhidong Xu",
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T1 - Facile synthesis of carbon-11-labeled sEH/PDE4 dual inhibitors as new potential PET agents for imaging of sEH/PDE4 enzymes in neuroinflammation

AU - Jia, Limeng

AU - Miao, Caihong

AU - Dong, Fugui

AU - Li, Wei

AU - Wang, Min

AU - Zheng, Qi-Huang

AU - Xu, Zhidong

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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-[ 11 C]methoxy-2-(trifluoromethyl)benzyl)benzamide ([ 11 C]1) and N-(4-[ 11 C]methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide ([ 11 C]MPPA, [ 11 C]4) were prepared from their corresponding precursors 2 and 5 with [ 11 C]CH 3 OTf through O-[ 11 C]methylation and isolated by HPLC combined with SPE in 25–35% radiochemical yield, based on [ 11 C]CO 2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (A M ) at EOB was 370–740 GBq/μmol with a total synthesis time of 35–40-minutes from EOB.

AB - 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-[ 11 C]methoxy-2-(trifluoromethyl)benzyl)benzamide ([ 11 C]1) and N-(4-[ 11 C]methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide ([ 11 C]MPPA, [ 11 C]4) were prepared from their corresponding precursors 2 and 5 with [ 11 C]CH 3 OTf through O-[ 11 C]methylation and isolated by HPLC combined with SPE in 25–35% radiochemical yield, based on [ 11 C]CO 2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (A M ) at EOB was 370–740 GBq/μmol with a total synthesis time of 35–40-minutes from EOB.

KW - Carbon-11-labeled sEH/PDE4 dual inhibitors

KW - Neuroinflammation

KW - Phosphodiesterase 4 (PDE4)

KW - Positron emission tomography (PET)

KW - Radiosynthesis

KW - Soluble epoxide hydrolase (sEH)

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