title: Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant.
abstract: BACKGROUND
  Aprepitant is a highly selective substance P (neurokinin 1 [NK(1)] receptor) antagonist that significantly improves the pharmacotherapy of acute and delayed highly emetogenic chemotherapy-induced nausea and vomiting, probably through an action in the brain stem region of the central nervous system. Here, we report the use of positron emission tomography imaging with the NK(1) receptor binding-selective tracer [(18)F]SPA-RQC to determine the levels of central NK(1) receptor occupancy achieved by therapeutically relevant doses of aprepitant in healthy humans.
  
  
  METHODS
  Two single-blind, randomized, placebo-controlled studies in healthy subjects were performed. The first study evaluated the plasma concentration-occupancy relationships for aprepitant dosed orally at 10, 30, 100, or 300 mg, or placebo (n = 12). The second study similarly evaluated oral aprepitant 30 mg and placebo (n = 4). In each study, dosing was once daily for 14 consecutive days. Data from both studies were combined for analyses. The ratio of striatal/cerebellar [(18)F]SPA-RQ (high receptor density region/reference region lacking receptors) was used to calculate trough receptor occupancy 24 hours after the last dose of aprepitant.
  
  
  RESULTS
  Brain NK(1) receptor occupancy increased after oral aprepitant dosing in both a plasma concentration-related (r =.97; 95% confidence interval [CI] =.94-1.00, p <.001) and a dose-related (r =.94; 95% CI =.86-1.00, p <.001) fashion. High (> or =90%) receptor occupancy was achieved at doses of 100 mg/day or greater. The plasma concentrations of aprepitant that achieved 50% and 90% occupancy were estimated as approximately 10 ng/mL and approximately 100 ng/mL, respectively.
  
  
  CONCLUSIONS
  Positron emission tomography imaging with [(18)F]SPA-RQ allows brain NK(1) receptor occupancy by aprepitant to be predicted from plasma drug concentrations and can be used to guide dose selection for clinical trials of NK(1) receptor antagonists in central therapeutic indications.
authors.affiliation: Uppsala Positron Emission Tomography Centre, Uppsala, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Bergström
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hargreaves
authors.forename: H Donald
authors.initials: HD
authors.lastname: Burns
authors.forename: Michael R
authors.initials: MR
authors.lastname: Goldberg
authors.forename: David
authors.initials: D
authors.lastname: Sciberras
authors.forename: Scott A
authors.initials: SA
authors.lastname: Reines
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Petty
authors.forename: Mattias
authors.initials: M
authors.lastname: Ogren
authors.forename: Gunnar
authors.initials: G
authors.lastname: Antoni
authors.forename: Bengt
authors.initials: B
authors.lastname: Långström
authors.forename: Olli
authors.initials: O
authors.lastname: Eskola
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.forename: Olof
authors.initials: O
authors.lastname: Solin
authors.forename: Anup K
authors.initials: AK
authors.lastname: Majumdar
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Constanzer
authors.forename: Wendy P
authors.initials: WP
authors.lastname: Battisti
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Bradstreet
authors.forename: Cynthia
authors.initials: C
authors.lastname: Gargano
authors.forename: Jarmo
authors.initials: J
authors.lastname: Hietala
mesh_terms: D000328:Adult; D000077608:Aprepitant; D001665:Binding Sites; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D001931:Brain Mapping; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D009025:Morpholines / Q000097:blood / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000737:chemistry / Q000378:metabolism*; D016037:Single-Blind Method; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: D007457:Iodine Radioisotopes; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant