Fluorine-18 labeling and biodistribution studies on peroxisome proliferator-activated receptor-γ ligands: potential positron emission tomography imaging agents

Lee, Byung Chul; Dence, Carmen S.; Zhou, Haibing; Parent, Ephraim E.; Welch, Michael J.; Katzenellenbogen, John A.

doi:10.1016/j.nucmedbio.2008.11.002

« Previous Next »Nuclear Medicine and Biology
Volume 36, Issue 2 , Pages 147-153, February 2009

Fluorine-18 labeling and biodistribution studies on peroxisome proliferator-activated receptor-γ ligands: potential positron emission tomography imaging agents

Byung Chul Lee
- Department of Chemistry, University of Illinois, Urbana, IL 61801, USA
- Current address: Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea.
Carmen S. Dence
- Division of Radiological Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
Haibing Zhou
- Department of Chemistry, University of Illinois, Urbana, IL 61801, USA
- Current address: College of Pharmacy, Wuhan University, Wuhan 430072, China.
Ephraim E. Parent
- Department of Chemistry, University of Illinois, Urbana, IL 61801, USA
Michael J. Welch
- Division of Radiological Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
John A. Katzenellenbogen
- Department of Chemistry, University of Illinois, Urbana, IL 61801, USA
- Corresponding author. Tel.: +1 217 333 6310; fax: +1 217 333 7325.

Received 23 September 2008; received in revised form 24 October 2008; accepted 4 November 2008.

Abstract

Introduction

Peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of lipid metabolism; it controls the differentiation of preadipocytes and is also found at high levels in small metastatic tumors. In this report, we describe the radiochemical synthesis and evaluation of two ¹⁸F-labeled analogs of the potent and selective PPARγ agonist farglitazar.

Materials and methods

The isomeric aromatic fluorine-substituted target compounds [(2S)-(2-benzoylphenylamino)-3-(4-(2-[2-(4-[¹⁸F]fluorophenyl)-5-methyloxazol-4-yl]ethoxy)-phenyl)propionic acid ([¹⁸F]-1) and (2S)-[2-(4-fluorobenzoyl)phenylamino]-3-(4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-phenyl)propionic acid ([¹⁸F]-2)] were prepared in fluorine-18-labeled form, respectively, by radiofluorination of an iodonium salt precursor or by Ullmann-type condensation with 2-iodo-4′-[¹⁸F]fluorobenzophenone after nucleophilic aromatic substitution with [¹⁸F]fluoride ion. Each compound was obtained in high specific activity and good radiochemical yield.

Results and Discussion

¹⁸F-1 and ¹⁸F-2 have high and selective PPARγ binding affinities comparable to that of the parent molecule farglitazar, and they were found to have good metabolic stability. Tissue biodistribution studies of ¹⁸F-1 and ¹⁸F-2 were conducted, but PPARγ-mediated uptake of both agents was minimal.

Conclusion

This study completes our first look at an important class of PPARγ ligands as potential positron emission tomography (PET) imaging agents for breast cancer and vascular disease. Although ¹⁸F-1 and ¹⁸F-2 have high affinities for PPARγ and good metabolic stability, their poor target-tissue distribution properties, which likely reflect their high lipophilicity combined with the low titer of PPARγ in target tissues, indicate that they have limited potential as PPARγ PET imaging agents.

Keywords: Peroxisome proliferator-activated receptor-γ, PPARγ, Fluorine-18, Iodonium salt, Nucleophilic aromatic substitution, Ullmann coupling