title: Quantification of central substance P receptor occupancy by aprepitant using small animal positron emission tomography.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Here, we applied small animal positron emission tomography (PET) and a radioligand for NK-1 receptors ([(18)F]FE-SPA-RQ) for measuring occupancies of these receptors by a selective antagonist (aprepitant) in order to examine 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.
  
  
  RESULTS
  PET in gerbils depicted high uptake in the striatum and dose-dependent displacement with increasing doses of aprepitant. Occupancies increased as a function of aprepitant plasma concentrations according to a one-site competition model, which agrees 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.
  
  
  CONCLUSIONS
  These findings support the utility of small animals and quantitative PET in the development of drugs targeting NK-1 receptors.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Drs Endo, Saijo, Haneda, Maeda, Tokunaga, Zhang, Suhara, Higuchi); Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai, Japan (Drs Endo, Saijo, Suhara, and Higuchi); DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan (Drs Endo, Saijo, and Kannami); Clinical & Research Quality Assurance Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Asai); Clinical Pharmacology Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Suzuki).
authors.forename: Tadashi
authors.initials: T
authors.lastname: Endo
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Drs Endo, Saijo, Haneda, Maeda, Tokunaga, Zhang, Suhara, Higuchi); Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai, Japan (Drs Endo, Saijo, Suhara, and Higuchi); DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan (Drs Endo, Saijo, and Kannami); Clinical & Research Quality Assurance Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Asai); Clinical Pharmacology Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Suzuki).
authors.forename: Takeaki
authors.initials: T
authors.lastname: Saijo
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Drs Endo, Saijo, Haneda, Maeda, Tokunaga, Zhang, Suhara, Higuchi); Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai, Japan (Drs Endo, Saijo, Suhara, and Higuchi); DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan (Drs Endo, Saijo, and Kannami); Clinical & Research Quality Assurance Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Asai); Clinical Pharmacology Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Suzuki).
authors.forename: Eisuke
authors.initials: E
authors.lastname: Haneda
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Drs Endo, Saijo, Haneda, Maeda, Tokunaga, Zhang, Suhara, Higuchi); Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai, Japan (Drs Endo, Saijo, Suhara, and Higuchi); DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan (Drs Endo, Saijo, and Kannami); Clinical & Research Quality Assurance Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Asai); Clinical Pharmacology Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Suzuki).
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Drs Endo, Saijo, Haneda, Maeda, Tokunaga, Zhang, Suhara, Higuchi); Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai, Japan (Drs Endo, Saijo, Suhara, and Higuchi); DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan (Drs Endo, Saijo, and Kannami); Clinical & Research Quality Assurance Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Asai); Clinical Pharmacology Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Suzuki).
authors.forename: Masaki
authors.initials: M
authors.lastname: Tokunaga
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Drs Endo, Saijo, Haneda, Maeda, Tokunaga, Zhang, Suhara, Higuchi); Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai, Japan (Drs Endo, Saijo, Suhara, and Higuchi); DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan (Drs Endo, Saijo, and Kannami); Clinical & Research Quality Assurance Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Asai); Clinical Pharmacology Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Suzuki).
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Drs Endo, Saijo, Haneda, Maeda, Tokunaga, Zhang, Suhara, Higuchi); Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai, Japan (Drs Endo, Saijo, Suhara, and Higuchi); DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan (Drs Endo, Saijo, and Kannami); Clinical & Research Quality Assurance Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Asai); Clinical Pharmacology Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Suzuki).
authors.forename: Ayako
authors.initials: A
authors.lastname: Kannami
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Drs Endo, Saijo, Haneda, Maeda, Tokunaga, Zhang, Suhara, Higuchi); Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai, Japan (Drs Endo, Saijo, Suhara, and Higuchi); DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan (Drs Endo, Saijo, and Kannami); Clinical & Research Quality Assurance Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Asai); Clinical Pharmacology Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Suzuki).
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Asai
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Drs Endo, Saijo, Haneda, Maeda, Tokunaga, Zhang, Suhara, Higuchi); Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai, Japan (Drs Endo, Saijo, Suhara, and Higuchi); DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan (Drs Endo, Saijo, and Kannami); Clinical & Research Quality Assurance Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Asai); Clinical Pharmacology Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Suzuki).
authors.forename: Masayuki
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Drs Endo, Saijo, Haneda, Maeda, Tokunaga, Zhang, Suhara, Higuchi); Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai, Japan (Drs Endo, Saijo, Suhara, and Higuchi); DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan (Drs Endo, Saijo, and Kannami); Clinical & Research Quality Assurance Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Asai); Clinical Pharmacology Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Suzuki).
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Drs Endo, Saijo, Haneda, Maeda, Tokunaga, Zhang, Suhara, Higuchi); Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai, Japan (Drs Endo, Saijo, Suhara, and Higuchi); DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan (Drs Endo, Saijo, and Kannami); Clinical & Research Quality Assurance Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Asai); Clinical Pharmacology Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan (Dr Suzuki). mhiguchi@nirs.go.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
mesh_terms: D000818:Animals; D000077608:Aprepitant; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D002144:Callithrix; D004305:Dose-Response Relationship, Drug; D005849:Gerbillinae; D006801:Humans; D008297:Male; D009025:Morpholines / Q000493:pharmacokinetics*; D064729:Neurokinin-1 Receptor Antagonists / Q000493:pharmacokinetics*; D010865:Pilot Projects; D049268:Positron-Emission Tomography / Q000379:methods; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*
chemical_list: D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant
keywords: NK-1 receptor; receptor occupancy; small-animal PET; substance P