title: Synthesis and evaluation of a bromine-76-labeled PPARgamma antagonist 2-bromo-5-nitro-N-phenylbenzamide.
abstract: Peroxisome proliferator activated-receptor gamma (PPARgamma) binds to peroxisome receptor response elements with its heterodimeric partner, retinoid X receptor, and regulates downstream gene expression. PPARgamma transcriptionally modulates fat metabolism, and receptor agonists have been developed to treat type II diabetes. PPARgamma is also overexpressed in some tumor cell lines and primary tumors, including breast and prostate tumors. Two PPARgamma antagonists, 2-chloro-5-nitro-N-phenylbenzamide (GW9662) and 2-chloro-5-nitro-N-pyridin-4-yl-benzamide (T0070907), represent good lead compounds for radiotracer development. In the current study, four additional halogen substituted analogs were synthesized and evaluated in a whole cell screening assay for PPARgamma binding activity. Two bromine-containing analogs having EC50 values <5 nM were chosen for bromine-76 radiolabeling. Bromine-76-labeled 2-bromo-5-nitro-N-phenyl-benzamide was selected for subsequent in vitro and in vivo studies due to its superior radiolabeling yield (approximately 70%) and the well-characterized pharmacological properties of its analog GW9662. An in vitro stability study showed that 40% of the compound remained intact in plasma and about 25% in whole blood after 30 min. Biodistribution studies in MDA-MB-435 human breast tumor-bearing nude mice were carried out at 5 min, 30 min, 2 h and 24 h post injection of the radiotracer. Although in vivo metabolite studies demonstrated rapid compound degradation, at least 10% of the parent compound was delivered to the tumor. We are currently exploring second generation analogs of these lead compounds for the development of radiolabeled antagonists of the PPARgamma receptor.
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Hsiaoju
authors.initials: H
authors.lastname: Lee
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Jones
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welch
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000813:Anilides / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D001967:Bromine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D007553:Isotope Labeling; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009928:Organ Specificity; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C515942:2-bromo-5-nitro-N-phenylbenzamide; D000813:Anilides; D001549:Benzamides; D001967:Bromine Radioisotopes; D047495:PPAR gamma; D019275:Radiopharmaceuticals