title: Synthesis and evaluation of (S)-[(18)F]fesetron in the rat brain as a potential PET imaging agent for serotonin 5-HT3 receptors.
abstract: Serotonin 5-HT3 receptors are involved in various brain functions including as an emesis target during cancer chemotherapy. We report here the development of (S)-2,3-dimethoxy-5-(3'-[(18)F]fluoropropyl)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide ([(18)F]fesetron) as a potential PET imaging agent for serotonin 5-HT3 receptors. By radiolabeling((S)-2,3-dimethoxy-5-(3'-tosyloxypropyl)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide) with fluorine-18, (S)-[(18)F]fesetron was obtained in 5 to 10% decay-corrected yields and with specific activities >74GBq/μmol at the end of radiosynthesis. PET imaging in rats showed low uptake of [(18)F]fesetron in the brain with retention of binding in the striatal and cerebellar regions. Using colliculi as a reference region, ratios were 3.4 for striata and 2.5 for cerebellum. Ex vivo brain PET analysis displayed binding of [(18)F]fesetron in the hippocampus, striatum and cerebellar regions. Cerebellar regions corresponded to area postrema and nucleus tract solitaris known to contain 5-HT3 receptors. Dorsal hippocampus showed the highest uptake with ratio of >17 with respect to colliculi, while area postrema and striata had ratios of >10. Thus, [(18)F]fesetron exhibited a unique binding profile to rat brain regions known to contain significant amounts of serotonin 5-HT3 receptors. However, the very low brain uptake limits its usefulness as a PET radiotracer in this animal model.
authors.affiliation: Preclinical Imaging, B140 Medical Sciences, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697-5000, United States.
authors.forename: Neema K
authors.initials: NK
authors.lastname: Pithia
authors.affiliation: Preclinical Imaging, B140 Medical Sciences, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697-5000, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Liang
authors.affiliation: Preclinical Imaging, B140 Medical Sciences, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697-5000, United States.
authors.forename: Xiang-Zuo
authors.initials: XZ
authors.lastname: Pan
authors.affiliation: Preclinical Imaging, B140 Medical Sciences, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697-5000, United States.
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Pan
authors.affiliation: Preclinical Imaging, B140 Medical Sciences, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697-5000, United States. Electronic address: mukherjj@uci.edu.
authors.forename: Jogeshwar
authors.initials: J
authors.lastname: Mukherjee
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D001549:Benzamides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism*; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D051381:Rats; D017207:Rats, Sprague-Dawley; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*
chemical_list: C000612186:2,3-dimethoxy-5-(30-(18F)fluoropropyl)- N-(1-azabicyclo(2.2.2)oct-3-yl)benzamide; D053961:Azabicyclo Compounds; D001549:Benzamides; D011849:Radioactive Tracers; D044406:Receptors, Serotonin, 5-HT3
keywords: Autoradiography; Cancer chemotherapy; Fesetron; PET; Palonosetron; Serotonin 5-HT(3) receptors; Zacopride