Hetero-aryl bromide precursor fluorine-18 radiosynthesis and preclinical evaluation of a novel positron emission tomography (PET) tracer [18F]GSK1482160

Bioorg Med Chem. 2022 Nov 1:73:116996. doi: 10.1016/j.bmc.2022.116996. Epub 2022 Sep 15.

Abstract

The purinergic P2X7 receptor (P2X7R), an ATP gated ion channel, is an important therapeutic target for various inflammatory immune and neurodegenerative diseases. A novel P2X7R targeting radiotracer GSK1482160 was radiosynthesized by hetero-aryl bromides precursor 10 with [18F]Et4NF, 20-30 % radiochemical yield, > 68 GBq/μmol specific activity, >98 % radiochemical purity. Evaluation in healthy male Sprague-Dawley rats revealed that [18F]GSK1482160 ([18F]11) was stably retained 87.81 %, 72.45 %, and 56.32 % in brain, blood and liver respectively 60-min post-injection. Ex-vivo biodistribution of [18F]11 proved that it was able to target the P2X7R in vivo and there was no defluorination in the major organs. PET/MRI imaging and autoradiography revealed that [18F]11 was able to penetrate the blood-brain barrier (BBB) and to be a promising P2X7R PET radioligand for clinical translation.

Keywords: ATP; Neurodegenerative diseases; Neuroinflammation; P2X7 receptor (P2X7R); Positron emission tomography (PET).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate
  • Animals
  • Brain / diagnostic imaging
  • Bromides*
  • Fluorine Radioisotopes
  • Male
  • Positron-Emission Tomography / methods
  • Pyrrolidonecarboxylic Acid
  • Radiopharmaceuticals
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Purinergic P2X7*
  • Tissue Distribution

Substances

  • Bromides
  • Fluorine Radioisotopes
  • N-(2-chloro-3-(trifluoromethyl)benzyl)-N-methyl-5-oxopyrrolidine-2-carboxamide
  • Radiopharmaceuticals
  • Receptors, Purinergic P2X7
  • Adenosine Triphosphate
  • Fluorine-18
  • Pyrrolidonecarboxylic Acid