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Journal of Nuclear Medicine Vol. 46 No. 10 1719-1726
© 2005 by Society of Nuclear Medicine

Basic Science Investigations

Synthesis and Biodistribution of 11C-GW7845, a Positron-Emitting Agonist for Peroxisome Proliferator–Activated Receptor-{gamma}

William B. Mathews, PhD1, Catherine A. Foss, PhD1, Doris Stoermer, PhD2, Hayden T. Ravert, PhD1, Robert F. Dannals, PhD1, Brad R. Henke, PhD3 and Martin G. Pomper, MD, PhD1

1 Department of Radiology, Johns Hopkins University, Baltimore, Maryland
2 Guilford Pharmaceuticals, Baltimore, Maryland
3 Research and Development, GlaxoSmithKline, Research Triangle Park, North Carolina

The goal of this study was to synthesize and evaluate in vivo the peroxisome proliferator–activated receptor-{gamma} (PPAR{gamma}) agonist 11C-GW7845 ((S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}ethylamino)benzoic acid methyl ester) (11C-compound 1). PPAR{gamma} 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 11C-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 µCi, 2.55 µg/kg) of 11C-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 µCi, 0.235 µg/kg) of 11C-compound 1. Results: 11C-Compound 1 was synthesized at an 8% radiochemical yield in 29 min with an average specific radioactivity of 1,222 GBq/µmol (33,024 mCi/µmol; 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 PPAR{gamma} imaging by this class of agents.

Key Words: 11C-GW7845 • PET • PPAR{gamma} • synthesis • biodistribution


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