title: Synthesis and evaluation of 18F-labeled PPARγ antagonists.
abstract: BACKGROUND
  Peroxisome proliferator-activated receptor gamma (PPARγ) transcriptionally modulates fat metabolism and also plays a role in pathological conditions such as cancer, neurodegenerative disease and inflammation. PPARγ imaging agents are potential tools for investigating these diseases.
  
  
  METHODS
  Four analogs of GW9662, a PPARγ antagonist, with different fluorine-containing substituents at the para-position of the aniline ring were synthesized and evaluated using two different receptor binding assays for measuring PPARγ affinity. Micro-positron emission tomography (PET) imaging studies were performed in a transgenic mouse model having a heart-specific overexpression of PPARγ.
  
  
  RESULTS
  All four analogs were found to have binding affinities that were comparable to or better than the reference antagonist, GW9662, using a scintillation proximity assay (SPA). However, only the chloro-based analogs (compounds 3 and 4) had activity in a whole-cell assay measuring activation of the PPARγ/retinoid X receptor complex. The microPET imaging studies in an MHC-PPARγ transgenic mouse model showed high uptake and PPARγ-specific binding for the irreversible antagonist [(18)F]3, whereas the corresponding reversible methoxy analog ([(18)F]5) displayed only nonspecific uptake in heart.
  
  
  CONCLUSIONS
  The results of this preliminary study show that the irreversible antagonist [(18)F]3 may represent a novel strategy for imaging PPARγ in vivo with PET.
authors: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Hsiaoju
authors: H
authors: Lee
authors: Delphine L
authors: DL
authors: Chen
authors: Justin M
authors: JM
authors: Rothfuss
authors: Michael J
authors: MJ
authors: Welch
authors: Robert J
authors: RJ
authors: Gropler
authors: Robert H
authors: RH
authors: Mach
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000818:Animals; D001681:Biological Assay / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D006321:Heart / Q000000981:diagnostic imaging; D006331:Heart Diseases / Q000000981:diagnostic imaging*; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D051381:Rats; D011924:Rats, Zucker; D047488:Retinoid X Receptors; D014018:Tissue Distribution
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D005462:Fluorine Radioisotopes; D008024:Ligands; D047495:PPAR gamma; D047488:Retinoid X Receptors