Synthesis and Pharmacological Evaluation of [C]Granisetron and [F]Fluoropalonosetron as PET Probes for 5-HT Receptor Imaging.

Serotonin-gated ionotropic 5-HT 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-HT 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 (K = 0.26 ± 0.05 nM) similar to the parent drug (K = 0.21 ± 0.03 nM). We radiolabeled 15 by nucleophilic F-fluorination of an unsymmetrical diaryliodonium palonosetron precursor and achieved the radiosynthesis of 1-(methyl-C)-N-granisetron ([C]2) through N-alkylation with [C]CHI, respectively. Both compounds [F]15 (chemical and radiochemical purity >95%, specific activity 41 GBq/μmol) and [C]2 (chemical and radiochemical purity ≥99%, specific activity 170 GBq/μmol) were evaluated for their utility as positron emission tomography (PET) probes. Using mouse and rat brain slices, in vitro autoradiography with both [F]15 and [C]2 revealed a heterogeneous and displaceable binding in cortical and hippocampal regions that are known to express 5-HT receptors at significant levels. Subsequent PET experiments suggested that [F]15 and [C]2 are of limited utility for the PET imaging of brain 5-HT receptors in vivo.