The goal of this study was to synthesize and evaluate in vivo the peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist (11)C-GW7845 ((S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}ethylamino)benzoic acid methyl ester) ((11)C-compound 1). PPARgamma is a member of a family of nuclear receptors that plays a central role in the control of lipid and glucose metabolism. Compound 1 is an analog of tyrosine (inhibitor constant, 3.7 nmol/L), which is an inhibitor of experimental mammary carcinogenesis.
Methods: Protection of the carboxylic acid moiety of compound 1 was effected by treatment with N,N-dimethylformamide di-tert-butyl acetal to provide compound 2. Hydrolysis of the carbomethoxy group of compound 2 provided the benzoic acid (compound 3) that served as an immediate precursor to radiolabeling. Compound 3 underwent treatment with (11)C-methyl iodide followed by high-performance liquid chromatography to produce a radioactive peak sample that coeluted with a standard sample of compound 1. Analysis of biodistribution was undertaken by injecting male CD-1 mice via the tail vein with 6.03 MBq (163 microCi, 2.55 microg/kg) of (11)C-compound 1. To determine the tumor uptake of the radiotracer, 6 female SCID mice bearing MCF-7 xenografts were injected via the tail vein with 10.5 MBq (283 microCi, 0.235 microg/kg) of (11)C-compound 1.
Results: (11)C-Compound 1 was synthesized at an 8% radiochemical yield in 29 min with an average specific radioactivity of 1,222 GBq/micromol (33,024 mCi/micromol; n = 6) at the end of synthesis. Spleen (target)-to-muscle uptake and tumor-to-muscle uptake ratios were 3.1 and 1.5, respectively, but this uptake could not be blocked with unlabeled compound 1 at 2 mg/kg.
Conclusion: Further structural modification, perhaps to generate a less lipophilic tyrosine analog, will be necessary to enable receptor-mediated PPARgamma imaging by this class of agents.