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Synthesis and Pharmacological Evaluation of [11C]Granisetron and [18F]Fluoropalonosetron as PET Probes for 5-HT3 Receptor Imaging

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2016
Author Mu Linjing, Müller Herde Adrienne, Rüefli Pascal M., Sladojevich Filippo, Milicevic Sephton Selena, Krämer Stefanie D., Thompson Andrew J., Schibli Roger, Ametamey Simon M., Lochner Martin,
Project Synthetic Neurochemistry - Introduction of Biophysical Tools into Ion Channels Using Chemical Approaches
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Original article (peer-reviewed)

Journal ACS Chemical Neuroscience
Volume (Issue) 7(11)
Page(s) 1552 - 1564
Title of proceedings ACS Chemical Neuroscience
DOI 10.1021/acschemneuro.6b00192


Serotonin-gated ionotropic 5-HT3 receptors are the major pharmacological targets for antiemetic compounds. Furthermore, they have become a focus for the treatment of irritable bowel syndrome (IBS) and there is some evidence that pharmacological modulation of 5-HT3 receptors might alleviate symptoms of other neurological disorders. Highly selective, high-affinity antagonists, such as granisetron (Kytril®) and palonosetron (Aloxi®), belong to a family of drugs (the ‘setrons’) that are well established for clinical use. To enable us to better understand the actions of these drugs in vivo, we report the synthesis of 8-fluoropalonosetron (15) that has a binding affinity (Ki = 0.26 ± 0.05 nM) similar to the parent drug (Ki = 0.21 ± 0.03 nM). We radiolabeled 15 by nucleophilic 18F-fluorination of an unsymmetrical diaryliodonium palonosetron precursor and achieved the radiosynthesis of 1-(methyl-11C)-N-granisetron ([11C]2) through N-alkylation with [11C]CH3I, respectively. Both compounds [18F]15 (chemical and radiochemical purity >95%, specific activity 41 GBq/μmol) and [11C]2 (chemical and radiochemical purity ≥99%, specific activity 170 GBq/μmol) were evaluated for their utility as PET probes. Using mouse and rat brain slices, in vitro autoradiography with both [18F]15 and [11C]2 revealed a heterogeneous and displaceable binding in cortical and hippocampal regions that are known to express 5 HT3 receptors at significant levels. Subsequent PET experiments suggested that [18F]15 and [11C]2 are of limited utility for the PET imaging of brain 5-HT3 receptors in vivo.