title: Synthesis, radiofluorination and first evaluation of [18F]fluorophenylsulfonyl- and [18F]fluorophenylsulfinyl-piperidines as serotonin 5-HT2A receptor antagonists for PET.
abstract: In psychiatric disorders, 5-HT(2A) receptors play an important role. In order to study these receptors in vivo by positron emission tomography (PET), there is an increasing interest for subtype selective and high affinity radioligands. Up to now, no optimal radiotracer is available. Thus, 1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfonyl)piperidine (9), possessing high affinity and sufficient subtype selectivity for 5-HT(2A) receptors, and 1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfinyl)piperidine (15) have been (18)F-labelled by a nucleophilic one-step reaction. Both radiotracers could be prepared and isolated within 45 min, [(18)F]9 in a radiochemical yield (RCY) of 34.5+/-8% and [(18)F]15 of 9.5+/-2.5%. The K(i) values of 9 and 15 at 5-HT(2A) receptors towards [(3)H]ketanserin were determined to be 1.9+/-0.6 and 198+/-8 nM, respectively. Autoradiography with [(18)F]9 and [(18)F]15 on rat brain sections showed a very high nonspecific binding of >80% for [(18)F]9 and 30% to 40% nonspecific binding for [(18)F]15; however, it is still too high in order to compensate for its lower affinity. Even though the affinity of 9 is more promising compared with 15, the high nonspecific binding of both radiofluorinated tracers in rat brain does not recommend those as an in vivo PET imaging agent for serotonin 5-HT(2A) receptors in humans.
authors.affiliation: Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Mühlhausen
authors.forename: Wiebke
authors.initials: W
authors.lastname: Sihver
authors.forename: Johannes
authors.initials: J
authors.lastname: Ermert
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Coenen
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D054879:Halogenation; D057927:Hydrophobic and Hydrophilic Interactions; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists; D013450:Sulfones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D013454:Sulfoxides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C552744:1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfinyl)piperidine; C552743:1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfonyl)piperidine; D010880:Piperidines; D044348:Receptors, Serotonin, 5-HT2; D058830:Serotonin 5-HT2 Receptor Antagonists; D013450:Sulfones; D013454:Sulfoxides