title: Synthesis and Pharmacological Evaluation of [11C]Granisetron and [18F]Fluoropalonosetron as PET Probes for 5-HT3Receptor Imaging.
abstract: Serotonin-gated ionotropic 5-HT3receptors 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-HT3receptors 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 nucleophilic18F-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 positron emission tomography (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-HT3receptors at significant levels. Subsequent PET experiments suggested that [18F]15 and [11C]2 are of limited utility for the PET imaging of brain 5-HT3receptors in vivo.
authors: Department of Nuclear Medicine, University Hospital Zürich , Rämistrasse 100, 8091 Zürich, Switzerland.
authors: Linjing
authors: L
authors: Mu
authors: Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
authors: Adrienne
authors: A
authors: Müller Herde
authors: Department of Chemistry and Biochemistry, University of Bern , Freiestrasse 3, 3012 Bern, Switzerland.
authors: Pascal M
authors: PM
authors: Rüefli
authors: Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
authors: Filippo
authors: F
authors: Sladojevich
authors: Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
authors: Selena
authors: S
authors: Milicevic Sephton
authors: Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
authors: Stefanie D
authors: SD
authors: Krämer
authors: Department of Pharmacology, University of Cambridge , Tennis Court Road, Cambridge CB2 1PD, United Kingdom.
authors: Andrew J
authors: AJ
authors: Thompson
authors: Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
authors: Roger
authors: R
authors: Schibli
authors: Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
authors: Simon M
authors: SM
authors: Ametamey
authors: Department of Chemistry and Biochemistry, University of Bern , Freiestrasse 3, 3012 Bern, Switzerland.
authors: Martin
authors: M
authors: Lochner
mesh_terms: D000818:Animals; D001345:Autoradiography; D001931:Brain Mapping; D002250:Carbon Radioisotopes; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D017829:Granisetron / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D000077924:Palonosetron; D049268:Positron-Emission Tomography; D011812:Quinuclidines / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D017208:Rats, Wistar; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D002250:Carbon Radioisotopes; D017829:Granisetron; D007546:Isoquinolines; D000077924:Palonosetron; D011812:Quinuclidines; D019275:Radiopharmaceuticals; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; C000620653:fluoropalonosetron
keywords: 5-HT3 receptor; antagonist; granisetron; imaging; palonosetron; positron emission tomography