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

Hanne D Hansen; Valdemar L Andersen; Szabolcs Lehel; Janus H Magnussen; Agnete Dyssegaard; Nikolas Stroth; Jesper L Kristensen; Gitte M Knudsen; Matthias M Herth

doi:10.1016/j.bmcl.2015.03.039

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. Epub 2015 Mar 21.

Authors

Hanne D Hansen¹, Valdemar L Andersen², Szabolcs Lehel³, Janus H Magnussen¹, Agnete Dyssegaard¹, Nikolas Stroth⁴, Jesper L Kristensen⁵, Gitte M Knudsen¹, Matthias M Herth⁶

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / metabolism
Carbon Radioisotopes
Dose-Response Relationship, Drug
Molecular Structure
Positron-Emission Tomography
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Receptors, Serotonin / metabolism*
Serotonin Receptor Agonists / chemical synthesis
Serotonin Receptor Agonists / chemistry
Serotonin Receptor Agonists / pharmacology*
Staining and Labeling
Structure-Activity Relationship
Swine

Substances

Carbon Radioisotopes
Pyrazoles
Receptors, Serotonin
Serotonin Receptor Agonists
dimethyl-(2-(3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethyl)amine dihydrochloride
serotonin 7 receptor