Synthesis and biological evaluation of positron emission tomography radiotracers targeting serotonin 4 receptors in brain: [18F]MNI-698 and [18F]MNI-699

Bioorg Med Chem Lett. 2013 Dec 1;23(23):6243-7. doi: 10.1016/j.bmcl.2013.09.097. Epub 2013 Oct 9.

Abstract

Two new benzodioxane derivatives were synthesized as candidates to image the serotonin 4 receptors by positron emission tomography (PET) and radiolabeled with fluorine-18 via a two-step procedure. Competition binding assays demonstrated that MNI-698 and MNI-699 had sub-nanomolar binding affinities against rat striatal 5-HT4 receptors (Ki of 0.20 and 0.07 nM, respectively). PET imaging in rhesus monkey showed that the regional brain distribution of [(18)F]MNI-698 and [(18)F]MNI-699 were consistent with the known densities of 5-HT4 in brain. [(18)F]MNI-698 and [(18)F]MNI-699 are among the first fluorine-18 radiotracers developed for imaging the 5-HT4 receptors in vivo and are currently under preclinical investigation in primates for future human use.

Keywords: 5-HT(4); Alzheimer’s disease; Fluorine-18; PET imaging; Serotonin receptors.

MeSH terms

  • Animals
  • Binding, Competitive
  • Brain / diagnostic imaging*
  • Brain / metabolism
  • Dioxanes / chemical synthesis*
  • Dioxanes / chemistry
  • Fluorine Radioisotopes / chemistry*
  • Macaca mulatta
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Positron-Emission Tomography / methods
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / metabolism
  • Rats
  • Receptors, Serotonin, 5-HT4 / analysis*
  • Receptors, Serotonin, 5-HT4 / metabolism

Substances

  • (1-(2-fluoroethyl)piperidin-4-yl)methyl 8-amino-7-chloro-2,3-dihydrobenzo(b)(1,4)dioxine-5-carboxylate
  • Dioxanes
  • Fluorine Radioisotopes
  • Piperidines
  • Radiopharmaceuticals
  • Receptors, Serotonin, 5-HT4