Utility of small-animal positron emission tomographic imaging of rats for preclinical development of drugs acting on the serotonin transporter

Takeaki Saijo, Jun Maeda, Takashi Okauchi, Jun Ichi Maeda, Yasunori Morio, Yasuhiro Kuwahara, Masayuki Suzuki, Nobuharu Goto, Kazutoshi Suzuki, Makoto Higuchi, Tetsuya Suhara

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1021-1032
Number of pages12
JournalInternational Journal of Neuropsychopharmacology
Volume12
Issue number8
DOIs
Publication statusPublished - 09-2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Medicine

Fingerprint

Dive into the research topics of 'Utility of small-animal positron emission tomographic imaging of rats for preclinical development of drugs acting on the serotonin transporter'. Together they form a unique fingerprint.

Cite this