title: Utility of small-animal positron emission tomographic imaging of rats for preclinical development of drugs acting on the serotonin transporter.
abstract: Visualization of neurotransmission components in living small animals using positron emission tomography (PET) has the potential of contributing to the preclinical development of neuroactive drugs, although it is yet to be examined whether quantitative animal PET data on candidate compounds can be extrapolated to humans. Here, we investigated the comparability of the occupancies of serotonin transporter (5-HTT) by therapeutic agents in rat PET studies with our predetermined data from ex- vivo animal experiments and clinical PET scans. Rats were treated with varying doses of fluvoxamine and a newly developed compound, (2S)-1-[4-(3,4-dichlorophenyl) piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride (Wf-516), and underwent PET scans with [11C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([11C]DASB), a selective radioligand for in-vivo quantification of 5-HTT. PET images indicated a reduction of [11C]DASB binding to 5-HTT as a function of the doses and/or plasma concentrations of fluvoxamine and Wf-516. The doses of these drugs at half-maximal effect (15.2 mg/kg and 3.1 mg/kg, respectively), determined that using binding potentials for [11C]DASB, were comparable to those estimated by our previous ex-vivo measurements in rats (4.5 mg/kg and 1.1 mg/kg, respectively), as there was only a 3-fold difference between these results. Moreover, the plasma concentration of fluvoxamine needed for 50% occupancy of central 5-HTT (6.1 ng/ml) was almost equivalent to the value determined in human PET studies (4.6 ng/ml). These findings support the view that the conjunctive use of small-animal PET and [11C]DASB facilitates a quantitative comparison of in-development drugs targeting 5-HTT with established inhibitors and a predictive estimation of their plasma concentrations exerting therapeutic effects in humans.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Saijo
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Maeda
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Morio
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kuwahara
authors.forename: Masayuki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Nobuharu
authors.initials: N
authors.lastname: Goto
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000097:blood / Q000494:pharmacology*; D001596:Benzylamines / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D001931:Brain Mapping; D002247:Carbon Isotopes / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016666:Fluvoxamine / Q000097:blood / Q000494:pharmacology*; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D010069:Oxadiazoles / Q000097:blood / Q000494:pharmacology*; D010880:Piperidines / Q000097:blood / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013997:Time Factors; D014851:Wakefulness / Q000187:drug effects
chemical_list: D018685:Anesthetics, Inhalation; D000928:Antidepressive Agents; D001596:Benzylamines; D002247:Carbon Isotopes; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; D010069:Oxadiazoles; D010880:Piperidines; D050486:Serotonin Plasma Membrane Transport Proteins; C527744:Wf-516; D007530:Isoflurane; D016666:Fluvoxamine