Strategies for the labeling of halogen-substituted peroxisome proliferator-activated receptor γ ligands: Potential positron emission tomography and single photon emission computed tomography imaging agents

Well-known as an important regulator of lipid metabolism and adipocyte differentiation, the peroxisome proliferator-activated receptor γ(PPARγ) also has potential use as a target for antitumor therapy in certain cancers. To develop agents for radionuclide imaging PPARγ in vivo, we synthesized fluorine, bromine, and iodine-substituted analogs (1-3) of a high-affinity benzophenone-tyrosine PPARγ ligand; all three analogs retain very high affinity for the PPARγ receptor. In preparation for the synthesis of these PPARγ ligands in radiolabeled form, we have synthesized two types of precursors: (a) an aryltributylstannane (9), from which the bromine and iodine-substituted analogs (2 and 3) can readily be prepared by electrophilic destannylation, and (b) three diaryliodonium tosylate derivatives (12a-c), precursors for nucleophilic aromatic fluorination using fluoride ion. Conditions were developed whereby the thiophenyliodonium tosylate (12c) underwent nucleophilic aromatic substitution with fluoride ion, efficiently and in short reaction times, to produce the desired fluorine-substituted target compound 1. These reactions laid the groundwork for producing these three PPARγ ligands in radiolabeled form; in addition, our use of diaryliodonium ion precursors for aromatic fluorination in this series provides an example that should encourage application of this approach for radiofluorination of more complicated radiopharmaceuticals.