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

Bioorg Med Chem Lett. 2018 May 15;28(9):1603-1609. doi: 10.1016/j.bmcl.2018.03.044. Epub 2018 Mar 17.

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.

Keywords: Competitive binding assay; Positron emission tomography (PET); Purinergic P2X7 receptor (P2X7R); Radiosynthesis; [(18)F]IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-[(18)F]fluoroethyl)-5-oxopyrrolidine-2-carboxamide).

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Dose-Response Relationship, Drug
  • Fluorine Radioisotopes
  • Humans
  • Molecular Structure
  • Radioligand Assay
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / chemistry*
  • Receptors, Purinergic P2X7 / chemistry*
  • Structure-Activity Relationship

Substances

  • Fluorine Radioisotopes
  • P2RX7 protein, human
  • Radiopharmaceuticals
  • Receptors, Purinergic P2X7
  • Fluorine-18