title: The Cannabinoid Receptor-1 Is an Imaging Biomarker of Brown Adipose Tissue.
abstract: Recently, the existence of significant deposits of brown adipose tissue (BAT) in human adults was confirmed. Its role in the human metabolism is unknown but could be substantial. Inhibition of the cannabinoid receptor-1 (CB1) by the antagonist rimonabant (SR141716) has been associated with activation of BAT thermogenesis and weight loss in mice and rats. The role of peripheral and central CB1 in the activation of BAT merits further investigation. Here we developed a technique for quantifying CB1 in BAT by PET.
  
  
  METHODS
  Sections of rat BAT and subcutaneous white adipose tissue (WAT) were stained for CB1 and uncoupling protein-1 by immunofluorescent staining. Binding of the radiolabeled CB1 antagonist (3R,5R)-5-(3-(18F-fluoromethoxy)phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)-phenyl)pyrrolidin-2-one ((18)F-FMPEP-d2) to BAT in vivo and in vitro was assessed in rats by PET.
  
  
  RESULTS
  We found that CB1 was colocalized with uncoupling protein-1 in BAT, but neither protein was found in WAT. Binding of the radiotracer to BAT sections (but not WAT) in vitro was high and displaceable by pretreatment with rimonabant. Deposits of BAT in rats had significant binding of (18)F-FMPEP-d2 in vivo, indicating high CB1 density. WAT deposits were negative for (18)F-FMPEP-d2, consistent with the immunofluorescent staining and in vitro results.
  
  
  CONCLUSIONS
  (18)F-FMPEP-d2 PET can quantify CB1 density noninvasively in vivo in rats. CB1 is therefore a promising surrogate imaging biomarker for assessing the presence of BAT deposits as well as for elucidating the mechanism of CB1 antagonist-mediated weight loss.
authors.affiliation: Turku PET Centre, University of Turku, Turku, Finland Department of Biosciences, Åbo Akademi University, Turku, Finland olof.eriksson@pet.medchem.uu.se.
authors.forename: Olof
authors.initials: O
authors.lastname: Eriksson
authors.affiliation: Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Mikkola
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Espes
authors.affiliation: Turku PET Centre, University of Turku, Turku, Finland Department of Psychiatry, University of Turku, Turku, Finland.
authors.forename: Lauri
authors.initials: L
authors.lastname: Tuominen
authors.affiliation: Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Virtanen
authors.affiliation: Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Sarita
authors.initials: S
authors.lastname: Forsbäck
authors.affiliation: Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Haaparanta-Solin
authors.affiliation: Turku PET Centre, University of Turku, Turku, Finland Department of Psychiatry, University of Turku, Turku, Finland.
authors.forename: Jarmo
authors.initials: J
authors.lastname: Hietala
authors.affiliation: Turku PET Centre, University of Turku, Turku, Finland Accelerator Laboratory, Åbo Akademi University, Turku, Finland; and.
authors.forename: Olof
authors.initials: O
authors.lastname: Solin
authors.affiliation: Turku PET Centre, University of Turku, Turku, Finland Department of Endocrinology, Turku University Hospital, Turku, Finland.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Nuutila
mesh_terms: D002001:Adipose Tissue, Brown / Q000000981:diagnostic imaging* / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D015415:Biomarkers; D005455:Fluorescent Antibody Technique; D007091:Image Processing, Computer-Assisted; D008297:Male; D049268:Positron-Emission Tomography; D011760:Pyrrolidinones; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D050151:Subcutaneous Fat / Q000000981:diagnostic imaging
chemical_list: C554672:5-((3-fluoromethoxy)phenyl)-3-(1-phenylethylamino)-1-(4-trifluoromethylphenyl)pyrrolidin-2-one; D015415:Biomarkers; D011760:Pyrrolidinones; D019275:Radiopharmaceuticals; D043884:Receptor, Cannabinoid, CB1
keywords: 18F-FMPEP-d2; brown adipose tissue; cannabinoid 1 receptor; positron emission tomography