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 Territo, Mark Green, Gary Hutchins, Hamideh Zarrinmayeh, Qi-Huang Zheng

Research output: Contribution to journalArticle

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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 1 2019

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evaluation
synthesis
propane
carboxylates
tracers
animals
affinity
bombardment
purity
decay

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

Cite this

Synthesis and initial in vitro characterization of a new P2X7R radioligand [18F]IUR-1602. / Gao, Mingzhang; Wang, Min; Glick-Wilson, Barbara E.; Meyer, Jill A.; Peters, Jonathan S.; Territo, Paul; Green, Mark; Hutchins, Gary; Zarrinmayeh, Hamideh; Zheng, Qi-Huang.

In: Applied Radiation and Isotopes, Vol. 144, 01.02.2019, p. 10-18.

Research output: Contribution to journalArticle

Gao, Mingzhang ; Wang, Min ; Glick-Wilson, Barbara E. ; Meyer, Jill A. ; Peters, Jonathan S. ; Territo, Paul ; Green, Mark ; Hutchins, Gary ; Zarrinmayeh, Hamideh ; Zheng, Qi-Huang. / Synthesis and initial in vitro characterization of a new P2X7R radioligand [18F]IUR-1602. In: Applied Radiation and Isotopes. 2019 ; Vol. 144. pp. 10-18.
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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.",
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AU - Meyer, Jill A.

AU - Peters, Jonathan S.

AU - Territo, Paul

AU - Green, Mark

AU - Hutchins, Gary

AU - Zarrinmayeh, Hamideh

AU - Zheng, Qi-Huang

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AB - 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.

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