Synthesis of carbon-11-labeled isonicotinamides as new potential PET agents for imaging of GSK-3 enzyme in Alzheimer's disease

Mingzhang Gao, Min Wang, Qi-Huang Zheng

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The authentic standards 2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide (4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-methoxyphenyl)pyridin-3-yl)isonicotinamide (7a), and their corresponding precursors 2-(cyclopropanecarboxamido)-N-(4-hydroxypyridin-3-yl)isonicotinamide (4b) and 2-(cyclopropanecarboxamido)-N-(4-(4-hydroxyphenyl)pyridin-3-yl)isonicotinamide (7b) were synthesized from methyl 2-aminoisonicotinate and cyclopropanecarbonyl chloride with overall chemical yield 47% in three steps, 22% in four steps, 40% in three steps, and 17% in four steps, respectively. The target tracers 2-(cyclopropanecarboxamido)-N-(4-[11C]methoxypyridin-3-yl)isonicotinamide ([11C]4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-[11C]methoxyphenyl)pyridin-3-yl)isonicotinamide ([11C]7a) were prepared from the precursors (4b and 7b) with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40–50% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370–1110 GBq/μmol with a total synthesis time of ∼40-min from EOB.

Original languageEnglish (US)
Pages (from-to)740-743
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number4
DOIs
StatePublished - Feb 15 2017

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Glycogen Synthase Kinase 3
Alzheimer Disease
Carbon
Imaging techniques
Enzymes
Methylation
isonicotinamide
Chlorides
High Pressure Liquid Chromatography

Keywords

  • Alzheimer's disease (AD)
  • Carbon-11-labeled isonicotinamides
  • Glycogen synthase kinase-3 (GSK-3)
  • Positron emission tomography (PET)
  • Radiosynthesis

ASJC Scopus subject areas

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

Cite this

Synthesis of carbon-11-labeled isonicotinamides as new potential PET agents for imaging of GSK-3 enzyme in Alzheimer's disease. / Gao, Mingzhang; Wang, Min; Zheng, Qi-Huang.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 27, No. 4, 15.02.2017, p. 740-743.

Research output: Contribution to journalArticle

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abstract = "The authentic standards 2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide (4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-methoxyphenyl)pyridin-3-yl)isonicotinamide (7a), and their corresponding precursors 2-(cyclopropanecarboxamido)-N-(4-hydroxypyridin-3-yl)isonicotinamide (4b) and 2-(cyclopropanecarboxamido)-N-(4-(4-hydroxyphenyl)pyridin-3-yl)isonicotinamide (7b) were synthesized from methyl 2-aminoisonicotinate and cyclopropanecarbonyl chloride with overall chemical yield 47{\%} in three steps, 22{\%} in four steps, 40{\%} in three steps, and 17{\%} in four steps, respectively. The target tracers 2-(cyclopropanecarboxamido)-N-(4-[11C]methoxypyridin-3-yl)isonicotinamide ([11C]4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-[11C]methoxyphenyl)pyridin-3-yl)isonicotinamide ([11C]7a) were prepared from the precursors (4b and 7b) with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40–50{\%} radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99{\%}, and the specific activity (SA) at EOB was 370–1110 GBq/μmol with a total synthesis time of ∼40-min from EOB.",
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AU - Wang, Min

AU - Zheng, Qi-Huang

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N2 - The authentic standards 2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide (4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-methoxyphenyl)pyridin-3-yl)isonicotinamide (7a), and their corresponding precursors 2-(cyclopropanecarboxamido)-N-(4-hydroxypyridin-3-yl)isonicotinamide (4b) and 2-(cyclopropanecarboxamido)-N-(4-(4-hydroxyphenyl)pyridin-3-yl)isonicotinamide (7b) were synthesized from methyl 2-aminoisonicotinate and cyclopropanecarbonyl chloride with overall chemical yield 47% in three steps, 22% in four steps, 40% in three steps, and 17% in four steps, respectively. The target tracers 2-(cyclopropanecarboxamido)-N-(4-[11C]methoxypyridin-3-yl)isonicotinamide ([11C]4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-[11C]methoxyphenyl)pyridin-3-yl)isonicotinamide ([11C]7a) were prepared from the precursors (4b and 7b) with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40–50% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370–1110 GBq/μmol with a total synthesis time of ∼40-min from EOB.

AB - The authentic standards 2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide (4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-methoxyphenyl)pyridin-3-yl)isonicotinamide (7a), and their corresponding precursors 2-(cyclopropanecarboxamido)-N-(4-hydroxypyridin-3-yl)isonicotinamide (4b) and 2-(cyclopropanecarboxamido)-N-(4-(4-hydroxyphenyl)pyridin-3-yl)isonicotinamide (7b) were synthesized from methyl 2-aminoisonicotinate and cyclopropanecarbonyl chloride with overall chemical yield 47% in three steps, 22% in four steps, 40% in three steps, and 17% in four steps, respectively. The target tracers 2-(cyclopropanecarboxamido)-N-(4-[11C]methoxypyridin-3-yl)isonicotinamide ([11C]4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-[11C]methoxyphenyl)pyridin-3-yl)isonicotinamide ([11C]7a) were prepared from the precursors (4b and 7b) with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40–50% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370–1110 GBq/μmol with a total synthesis time of ∼40-min from EOB.

KW - Alzheimer's disease (AD)

KW - Carbon-11-labeled isonicotinamides

KW - Glycogen synthase kinase-3 (GSK-3)

KW - Positron emission tomography (PET)

KW - Radiosynthesis

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