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

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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 [18F]MNI-698 and [18F]MNI-699 were consistent with the known densities of 5-HT4 in brain. [18F]MNI-698 and [18F]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.

References and notes (29)

  • M. Filip et al.

    Pharmacol. Rep.

    (2009)
  • L.B. Jakeman et al.

    Neuropharmacology

    (1994)
  • S.W. Tsang et al.

    J. Neurol. Sci.

    (2010)
  • A. Bauman et al.

    Tetrahedron Lett.

    (2003)
  • M. Laruelle et al.

    Mol. Imaging Biol.

    (2003)
  • P. Bonaventure et al.

    Synapse

    (2000)
  • A.M. Brown et al.

    Br. J. Pharmacol.

    (1993)
  • J. Bockaert et al.

    CNS Neurol. Disord.-Dr.

    (2004)
  • G.P. Reynolds et al.

    Br. J. Pharmacol.

    (1995)
  • E.H.F. Wong et al.

    Behav. Brain Res.

    (1996)
  • R.M. Eglen et al.

    Expert Opin. Invest. Drug

    (1996)
  • J.L. Warner-Schmidt et al.

    J. Neurosci.

    (2009)
  • L.M. Gaster et al.

    J. Med. Chem.

    (1993)
  • P.G. McLean et al.

    Naunyn-Schmiedeberg’s Arch. Parmacol.

    (1995)
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