Labeling and preliminary in vivo evaluation of the 5-HT(7) receptor selective agonist [(11)C]E-55888

  • Bioorg Med Chem Lett. 2015 May 1;25(9):1901-4. doi: 10.1016/j.bmcl.2015.03.039.
Hanne D Hansen  1 ,  Valdemar L Andersen  2 ,  Szabolcs Lehel  3 ,  Janus H Magnussen  1 ,  Agnete Dyssegaard  1 ,  Nikolas Stroth  4 ,  Jesper L Kristensen  5 ,  Gitte M Knudsen  1 ,  Matthias M Herth  6
Affiliations
  • 1. Center for Integrated Molecular Brain Imaging, Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
  • 2. Center for Integrated Molecular Brain Imaging, Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
  • 3. PET and Cyclotron Unit, Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
  • 4. Center for Molecular Medicine, Department of Neurology and Clinical Neuroscience, Karolinska Institute and Karolinska University Hospital, 17176 Stockholm, Sweden.
  • 5. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
  • 6. Center for Integrated Molecular Brain Imaging, Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: [email protected].
PMID: 25857944 DOI: 10.1016/j.bmcl.2015.03.039
Abstract

E-55888 has been identified as a selective serotonin 7 (5-HT7) receptor agonist. In this study, we describe the synthesis, radiolabeling and in vivo evaluation of [(11)C]E-55888 as a radioligand for positron emission tomography (PET) imaging. [(11)C]E-55888 was obtained by N-methylation of an appropriate precursor using [(11)C]MeOTf in acetone at 60 °C giving isolated quantities in the range of 1.7-2.4 GBq. Studies in Danish Landrace pigs demonstrated that [(11)C]E-55888 has good brain uptake, however, the distribution in the brain tissue was dominated by non-specific binding, as binding could neither be displaced by the structurally different 5-HT7 receptor ligand SB-269970 nor by self-block with unlabeled E-55888. Based on these data, [(11)C]E-55888 does not show promise as a PET radioligand for imaging the 5-HT7 receptor in vivo.

Keywords
5-HT(7) receptor; Agonist; Carbon-11; E-55888; PET.
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