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

Mu, Linjing; Müller Herde, Adrienne; Rüefli, Pascal; Sladojevich, Filippo; Sephton, Selena Milicevic; Krämer, Stefanie D.; Thompson, Andrew James; Schibli, Roger; Ametamey, Simon M.; Lochner, Martin (2016). Synthesis and Pharmacological Evaluation of [11C]granisetron and [18F]fluoropalonosetron as PET Probes for 5-HT3 Receptor Imaging. ACS chemical neuroscience, 7(11), pp. 1552-1564. American Chemical Society 10.1021/acschemneuro.6b00192

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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.

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