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J Nucl Med. 2008; 49 (Supplement 1):299P
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Radiopharmaceutical Chemistry: New Chemistry-Other

New Chemistry-Other Posters

Fluorine-18 labeled PPAR{gamma} antagonists for PET imaging studies

Hsiaoju Lee1, Delphine Chen1, Michael Welch1 and Robert Mach1

1 Radiological Science, Washington University in St. Louis, Saint Louis, Missouri

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Objectives: Peroxisome proliferator activated-receptor gamma (PPAR{gamma}) has been shown to play an important role in various pathological conditions, making it a good candidate for PET imaging. Previous studies have focused on the development of radiolabeled PPAR{gamma} agonists, which have not yielded promising results. The goal of current strategy was to prepare 18F-labeled analogs of the irreversible PPAR{gamma} antagonist, GW9662, by substituting the para-position of the aniline ring with either a 2-fluoroethyl or 2-fluoroethoxy group to facilitate labeling with fluorine-18.

Methods: The synthesis of the target compounds was achieved by coupling the benzoate and respective amines. Affinity screening was performed with a cell-free system using histidine-tagged PPAR{gamma}, copper and scintillant coated beads, and 3H-rosiglitazone, a PPAR{gamma} agonist. The IC50 values of the two new compounds were in the nanomolar range. Compounds were then labeled with fluorine-18 by displacement of the corresponding mesylate precursors with [18F]fluoride.

Results: Blood stability studies suggested that both ligands were more stable than our previous 76Br-labeled compound (Nucl Med Biol 2006. 33: 847-54). Thiol challenge experiments indicate that both compounds are irreversible antagonists of PPAR{gamma}. MicroPET studies with cardiomyocyte-specific PPAR{gamma} transgenic mice indicate that both 18F-labeled analogs of GW9662 exhibit high transgenic/control ratios over time (~5). The accumulation of each radiotracer in heart was blocked with pretreatment of GW9662 (10 mg/kg), confirming the specificity of these radiotracers for PPAR{gamma}.

Conclusions: 18F-labeled analogs of GW9662, an irreversible PPAR{gamma} antagonist, represent a novel strategy for the development of radiotracers imaging PPAR{gamma} in vivo with PET.

Research Support: The work is supported by grants from both NIH (HL13851, CA86307) and DOE (ER60218).





This Article
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Right arrow Articles by Mach, R.