量研学術機関リポジトリ「QST-Repository」は、国立研究開発法人 量子科学技術研究開発機構に所属する職員等が生み出した学術成果（学会誌発表論文、学会発表、研究開発報告書、特許等）を集積しインターネット上で広く公開するサービスです。 Welcome to QST-Repository where we accumulates and discloses the academic research results(Journal Publications, Conference presentation, Research and Development Report, Patent, etc.) of the members of National Institutes for Quantum and Radiological Science and Technology.
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Central substance P receptors, termed NK-1 receptors, have been considered as therapeutic targets in the development of drugs against diverse conditions including emesis, overactive bladder and depression. Here, we applied small animal positron emission tomography (PET) and a radioligand for NK-1 receptors, [18F]FE-SPA-RQ, for measuring occupancies of these receptors by a selective antagonist, aprepitant, in order to examined the validity of this in vivo imaging system for preclinical characterization of candidate agents acting on NK-1 receptors, and as a tool for predicting optimal doses in humans. PET in gerbils depicted high uptake in the striatum and dose-dependent displacement with increasing dose of aprepitant. Occupancies increased as a function of aprepitant plasma concentrations according to a one-site competition model, in good agreement with reported occupancy-concentration relationships in clinical studies after correction for species differences in plasma protein-unbound aprepitant fractions. These occupancy data were further supported by ex vivo autoradiography of brain samples from aprepitant-treated gerbils. In a pilot study of a marmoset, we obtained more accurate determinations of NK-1 receptor occupancy, less affected by spillover of signals from extracranial tissues than in gerbil experiments. These findings support the utility of small animals and quantitative PET in the development of drugs targeting NK-1 receptors.
雑誌名
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)
Quantification of central substance P receptor occupancy by aprepitant using small animal positron emission tomography.
