Synthesis and in vitro biological evaluation of new P2X7R radioligands [ 11 C]halo-GSK1482160 analogs

Mingzhang Gao, Min Wang, Jill A. Meyer, Paul Territo, Gary Hutchins, Hamideh Zarrinmayeh, Qi-Huang Zheng

Research output: Contribution to journalArticle

Abstract

The reference standards halo-GSK1482160 (F-, Br-, and I-) and their corresponding precursors desmethyl-halo-GSK1482160 (F-, Br-, and I-) were synthesized from (S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid or (S)-5-oxopyrrolidine-2-carboxylic acid and 2-halo-3-(trifluoromethyl)benzylamine (F-, Br-, and I-) in one step with 45–93% yields. The target tracers [ 11 C]halo-GSK1482160 (F-, Br-, and I-) were prepared from desmethyl-halo-GSK1482160 (F-, Br-, and I-) with [ 11 C]CH 3 OTf under basic conditions (NaOH-Na 2 CO 3 , solid, w/w 1:2) through N-[ 11 C]methylation and isolated by HPLC combined with SPE in 40–50% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity (A M ) at end of bombardment (EOB) was 370–740 GBq/μmol. The potency of halo-GSK1482160 (F-, Br-, and I-) in comparison with GSK1482160 (Cl-) was determined by a radioligand competitive binding assay using [ 11 C]GSK1482160, and the binding affinity K i values for halo-GSK1482160 (F-, Br-, and I-) and GSK1482160 (Cl-) are 54.2, 2.5, 1.9 and 3.1 nM, respectively.

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

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Pyrrolidonecarboxylic Acid
N-(2-chloro-3-(trifluoromethyl)benzyl)-N-methyl-5-oxopyrrolidine-2-carboxamide
In Vitro Techniques
Methylation
Competitive Binding
Carbon Monoxide
Assays
High Pressure Liquid Chromatography
benzylamine
4-dimethylamino-3',4'-dimethoxychalcone

Keywords

  • Competitive binding assay
  • Positron emission tomography (PET)
  • Purinergic P2X7 receptor (P2X7R)
  • Radiosynthesis
  • [ C]Halo-GSK1482160 (F-, Br-, and I-)

ASJC Scopus subject areas

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

Cite this

Synthesis and in vitro biological evaluation of new P2X7R radioligands [ 11 C]halo-GSK1482160 analogs . / Gao, Mingzhang; Wang, Min; Meyer, Jill A.; Territo, Paul; Hutchins, Gary; Zarrinmayeh, Hamideh; Zheng, Qi-Huang.

In: Bioorganic and Medicinal Chemistry Letters, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "The reference standards halo-GSK1482160 (F-, Br-, and I-) and their corresponding precursors desmethyl-halo-GSK1482160 (F-, Br-, and I-) were synthesized from (S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid or (S)-5-oxopyrrolidine-2-carboxylic acid and 2-halo-3-(trifluoromethyl)benzylamine (F-, Br-, and I-) in one step with 45–93{\%} yields. The target tracers [ 11 C]halo-GSK1482160 (F-, Br-, and I-) were prepared from desmethyl-halo-GSK1482160 (F-, Br-, and I-) with [ 11 C]CH 3 OTf under basic conditions (NaOH-Na 2 CO 3 , solid, w/w 1:2) through N-[ 11 C]methylation and isolated by HPLC combined with SPE in 40–50{\%} decay corrected radiochemical yield. The radiochemical purity was >99{\%}, and the molar activity (A M ) at end of bombardment (EOB) was 370–740 GBq/μmol. The potency of halo-GSK1482160 (F-, Br-, and I-) in comparison with GSK1482160 (Cl-) was determined by a radioligand competitive binding assay using [ 11 C]GSK1482160, and the binding affinity K i values for halo-GSK1482160 (F-, Br-, and I-) and GSK1482160 (Cl-) are 54.2, 2.5, 1.9 and 3.1 nM, respectively.",
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T1 - Synthesis and in vitro biological evaluation of new P2X7R radioligands [ 11 C]halo-GSK1482160 analogs

AU - Gao, Mingzhang

AU - Wang, Min

AU - Meyer, Jill A.

AU - Territo, Paul

AU - Hutchins, Gary

AU - Zarrinmayeh, Hamideh

AU - Zheng, Qi-Huang

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The reference standards halo-GSK1482160 (F-, Br-, and I-) and their corresponding precursors desmethyl-halo-GSK1482160 (F-, Br-, and I-) were synthesized from (S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid or (S)-5-oxopyrrolidine-2-carboxylic acid and 2-halo-3-(trifluoromethyl)benzylamine (F-, Br-, and I-) in one step with 45–93% yields. The target tracers [ 11 C]halo-GSK1482160 (F-, Br-, and I-) were prepared from desmethyl-halo-GSK1482160 (F-, Br-, and I-) with [ 11 C]CH 3 OTf under basic conditions (NaOH-Na 2 CO 3 , solid, w/w 1:2) through N-[ 11 C]methylation and isolated by HPLC combined with SPE in 40–50% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity (A M ) at end of bombardment (EOB) was 370–740 GBq/μmol. The potency of halo-GSK1482160 (F-, Br-, and I-) in comparison with GSK1482160 (Cl-) was determined by a radioligand competitive binding assay using [ 11 C]GSK1482160, and the binding affinity K i values for halo-GSK1482160 (F-, Br-, and I-) and GSK1482160 (Cl-) are 54.2, 2.5, 1.9 and 3.1 nM, respectively.

AB - The reference standards halo-GSK1482160 (F-, Br-, and I-) and their corresponding precursors desmethyl-halo-GSK1482160 (F-, Br-, and I-) were synthesized from (S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid or (S)-5-oxopyrrolidine-2-carboxylic acid and 2-halo-3-(trifluoromethyl)benzylamine (F-, Br-, and I-) in one step with 45–93% yields. The target tracers [ 11 C]halo-GSK1482160 (F-, Br-, and I-) were prepared from desmethyl-halo-GSK1482160 (F-, Br-, and I-) with [ 11 C]CH 3 OTf under basic conditions (NaOH-Na 2 CO 3 , solid, w/w 1:2) through N-[ 11 C]methylation and isolated by HPLC combined with SPE in 40–50% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity (A M ) at end of bombardment (EOB) was 370–740 GBq/μmol. The potency of halo-GSK1482160 (F-, Br-, and I-) in comparison with GSK1482160 (Cl-) was determined by a radioligand competitive binding assay using [ 11 C]GSK1482160, and the binding affinity K i values for halo-GSK1482160 (F-, Br-, and I-) and GSK1482160 (Cl-) are 54.2, 2.5, 1.9 and 3.1 nM, respectively.

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KW - Positron emission tomography (PET)

KW - Purinergic P2X7 receptor (P2X7R)

KW - Radiosynthesis

KW - [ C]Halo-GSK1482160 (F-, Br-, and I-)

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JF - Bioorganic and Medicinal Chemistry Letters

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