Synthesis and preliminary biological evaluation of a novel P2X7R radioligand [18F]IUR-1601

Mingzhang Gao, Min Wang, Barbara E. Glick-Wilson, Jill A. Meyer, Jonathan S. Peters, Paul R. Territo, Mark A. Green, Gary D. Hutchins, Hamideh Zarrinmayeh, Qi Huang Zheng

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The reference standard IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from tert-butyl (S)-5-oxopyrrolidine-2-carboxylate, fluoroethylbromide, and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 12% in three steps. The target tracer [18F]IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-[18F]fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from desmethyl-GSK1482160 with 2-[18F]fluoroethyl tosylate, prepared from 1,2-ethylene glycol-bis-tosylate and K[18F]F/Kryptofix2.2.2, in two steps and isolated by HPLC combined with SPE in 1–3% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity at end of bombardment (EOB) was 74–370 GBq/μmol. The potency of IUR-1601 in comparison with GSK1482160 was determined by a radioligand competitive binding assay using [11C]GSK1482160, and the binding affinity Ki values for IUR-1601 and GSK1482160 are 4.31 and 5.14 nM, respectively.

Original languageEnglish (US)
Pages (from-to)1603-1609
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number9
DOIs
StatePublished - May 15 2018

Keywords

  • Competitive binding assay
  • Positron emission tomography (PET)
  • Purinergic P2X7 receptor (P2X7R)
  • Radiosynthesis
  • [F]IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-[F]fluoroethyl)-5-oxopyrrolidine-2-carboxamide)

ASJC Scopus subject areas

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

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