Original articleHuman positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant
Section snippets
Subjects
Healthy male subjects, aged between 18 and 45 years, were enrolled at two study sites (Uppsala University, Uppsala, Sweden and University of Turku, Turku, Finland). History, physical examination, and laboratory assessments were conducted within 3 weeks before study initiation to assess health status. All volunteers were medication free for at least 2 weeks before the initiation of the study and were nonsmokers for at least 6 months before the study.
The studies were reviewed and approved by the
Demographics
In the first dose-ranging study, 12 healthy, white, male subjects (mean age = 26 years [range: 23–41], mean height = 180 cm [range: 167–191], mean weight = 75 kg [range: 66–92]) were randomized to receive either aprepitant 10 mg/day (n = 2), 30 mg/day (n = 3), 100 mg/day (n = 3), 300 mg/day (n = 2), or placebo (n = 2). In the second study, four healthy, white, male subjects (mean age = 24 years [range: 23–25], mean height = 180 cm [range: 173–186], mean weight = 77 kg [range: 72–83]) were
Discussion
These are the first studies to demonstrate a clinically useful method of assessing NK1 receptors and their occupancy by an NK1 receptor antagonist in the human brain in vivo. We used the high affinity and specificity of a novel PET ligand, [18F]SPA-RQ (Hargreaves, 2002, Solin et al.), to assess the strength of the relationship between both dose and plasma concentration of aprepitant (a high-affinity, reversibly binding NK1 receptor antagonist) with receptor occupancy, and then to estimate the
Acknowledgements
These studies were funded by Merck Research Laboratories, West Point, Pennsylvania.
We thank the staff of the Positron Emission Tomography Laboratories at Uppsala and Turku for their help; Dr. Kevin Gingrich for oversight of some of these studies; and Dr. Christopher Lines for assistance with preparing the manuscript.
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