title: Radiofluorinated histamine H₃ receptor antagonist as a potential probe for in vivo PET imaging: radiosynthesis and pharmacological evaluation.
abstract: The histamine H(3) receptor (H(3)R) plays a role in cognition and memory processes and is implicated in different neurological disorders, including Alzheimer's disease, schizophrenia, and narcolepsy. In vivo studies of the H(3)R occupancy using a radiolabeled PET tracer would be very useful for CNS drug discovery and development. We report here the radiosynthesis, in vitro and in vivo evaluation of a novel (18)F-labeled high-affinity H(3)R antagonist (18)F-ST889. The radiosynthesis was accomplished via nucleophilic substitution of the mesylate leaving group with a radiochemical yield of 8-20%, radiochemical purity >99%, and specific radioactivity > 65 GBq/μmol. (18)F-ST889 exhibited high in vivo stability and rather low lipophilicity (logD(7.4)=0.35 ± 0.09). In vitro autoradiography showed specific binding in H(3)R-rich brain regions such as striatum and cortex. However, in vivo PET imaging of the rat brain with (18)F-ST889 was not successful. Possible reasons are discussed.
authors.affiliation: Center for Radiopharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich (Swiss Federal Institute of Technology), Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland. svetlana.selivanova@pharma.ethz.ch
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Selivanova
authors.forename: Michael
authors.initials: M
authors.lastname: Honer
authors.forename: Francine
authors.initials: F
authors.lastname: Combe
authors.forename: Kathleen
authors.initials: K
authors.lastname: Isensee
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.forename: P August
authors.initials: PA
authors.lastname: Schubiger
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D002460:Cell Line; D004285:Dogs; D004355:Drug Stability; D005462:Fluorine Radioisotopes / Q000737:chemistry; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism
chemical_list: C574177:18F-ST889; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005462:Fluorine Radioisotopes; D054828:Histamine H3 Antagonists; D010880:Piperidines; D019275:Radiopharmaceuticals; D018100:Receptors, Histamine H3