Synthesis and initial in vitro characterization of a new P2X7R radioligand [18F]IUR-1602

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

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Abstract

The overexpression of P2X7R is associated with neuroinflammation and plays an important role in various neurodegenerative diseases. The [18F]fluoropropyl derivative of GSK1482160, [18F]IUR-1602, has been first prepared and examined as a new potential P2X7R radioligand. The reference standard IUR-1602 was synthesized from tert-butyl (S)-5-oxopyrrolidine-2-carboxylate, fluoropropylbromide, and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 13% in three steps. The target tracer [18F]IUR-1602 was synthesized from desmethyl-GSK1482160 with 3-[18F]fluoropropyl tosylate, prepared from propane-1,3-diyl bis(4-methylbenzenesulfonate) and K[18F]F/Kryptofix2.2.2, in two steps and isolated by HPLC combined with SPE in 2–7% 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-1602 in comparison with GSK1482160 was determined by a radioligand competitive binding assay using [11C]GSK1482160, and the binding affinity Ki values for IUR-1602 and GSK1482160 are 23.6 and 3.07 nM, respectively. The initial in vitro evaluation results, 8-fold less potency of [18F]IUR-1602 compared to [11C]GSK1482160, prevent further in vivo evaluation of [18F]IUR-1602 in animals and human.

Original languageEnglish (US)
Pages (from-to)10-18
Number of pages9
JournalApplied Radiation and Isotopes
Volume144
DOIs
StatePublished - Feb 2019

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Keywords

  • Competitive binding assay
  • Positron emission tomography (PET)
  • Purinergic P2X7 receptor (P2X7R)
  • Radiosynthesis
  • [F]IUR-1602 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-[F]fluoropropyl)-5-oxopyrrolidine-2-carboxamide)

ASJC Scopus subject areas

  • Radiation

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