[11C]Carfentanil PET Study of GSK1521498
Condition: Obesity
MeSH terms: Obesity
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to determine whether GSK1521498 attaches to sites in the brain
      called mu-opioid receptors that are involved in the liking reactions to palatable high fat
      and high sugar foods. We hope that blocking these receptors may modify certain behaviours
      that may lead to obesity.
    

Detailed description: 
      This imaging study will be an open-label, non-randomised PET receptor occupancy study in
      healthy male volunteers. The degree and time course of μ-opioid receptor occupancy (RO)
      following single oral doses of GSK1521498 will be estimated by [11C]carfentanil displacement.
      Previous pre-clinical and human PET studies indicate that [11C]carfentanil is selective for
      the μ-opioid receptor and can be used to estimate μ-opioid receptor occupancy in vivo.

      The PK/PD relationship between plasma concentrations of GSK1521498 and μ-opioid RO will be
      described. Potential relationships between μ-opioid RO and functional magnetic resonance
      imaging (fMRI) endpoints, measured in a food reward paradigm, will be assessed as an
      exploratory aim. Additionally, the PK/PD relationships between plasma concentrations of
      naltrexone (a generic μ-opioid receptor antagonist), μ-opioid receptor occupancy, and fMRI
      measures of reward processing will also be investigated.
    

Intervention name(s): Part A Assessing GSK1521498; Part B Assessing GSK1521498; Part C Assessing Naltrexone
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Each participant will receive up to three [11C]carfentanil PET scans and up to two doses of GSK1521498 in total. The doses used will span the expected receptor occupancy range providing these were well tolerated in the first-time in human study.
Each subject will receive baseline [11C]carfentanil PET and fMRI scans (PET Scan 1 and fMRI Scan 1, respectively), followed by two treatment sessions (Treatment Sessions 1 and 2). Treatment session 1 and 2 are followed by PET scans and an fMRI scan (session 1 only). Sessions will be separated by at least 12 days. PET scans will be timed to coincide with peak brain occupancy. fMRI will begin approximately 30-60 minutes after completion of the PET scan.; The purpose of Part B is to establish the timecourse of receptor occupancy of GSK1521498. Each participant in Part B will receive up to three [11C]carfentanil PET scans and one single oral dose of GSK1521498 expected to provide 50-75% receptor occupancy (selected with reference to data from Part A).
Each Part B subject will receive baseline [11C]carfentanil PET and fMRI scans (PET Scan 1 and fMRI Scan 1, respectively) followed by a single treatment session. The treatment session will consist of a single oral dose of GSK1521498 followed by two subsequent PET scans (PET Scans 2 and 3) and one fMRI scan (fMRI Scan 2).; A range of doses of naltrexone will be tested in up to 12 participants in an adaptive design. Each Part C participant will receive up to three [11C]carfentanil PET scans and a single oral dose of naltrexone. No dose of naltrexone will exceed 50 mg, the dose usually used therapeutically in the treatment of opiate and alcohol dependence. Each Part C subject will receive baseline [11C]carfentanil PET and fMRI scans (PET Scan 1 and fMRI Scan 1, respectively) followed by a single treatment session. The treatment session will consist of a single oral dose of naltrexone followed by two subsequent PET scans (PET Scans 2 and 3) and one fMRI scan (fMRI Scan 2).
Intervention MeSH terms: Naltrexone
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Obesity; Naltrexone; Carfentanil; Receptor Occupancy; mu-opioid Receptor; PET (Positron Emission Tomography); BOLD-fMRI