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

Abstract

Well-known as an important regulator of lipid metabolism and adipocyte differentiation, the peroxisome proliferator-activated receptor gamma (PPARgamma) also has potential use as a target for antitumor therapy in certain cancers. To develop agents for radionuclide imaging PPARgamma in vivo, we synthesized fluorine, bromine, and iodine-substituted analogs (1-3) of a high-affinity benzophenone-tyrosine PPARgamma ligand; all three analogs retain very high affinity for the PPARgamma receptor. In preparation for the synthesis of these PPARgamma 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 PPARgamma 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.

4-[18F]Fluoro-m-hydroxyphenethylguanidine: A Radiopharmaceutical for Quantifying Regional Cardiac Sympathetic Nerve Density with Positron Emission Tomography

“…17–21 This approach provides specific activities that are sufficiently high for successful PET imaging studies of receptors in various organs. 22–25 Although this method has been shown to be suitable for preparing small 18 F-labeled molecules with relatively simple structures, difficulties are sometimes encountered when trying to label more complex molecular structures, as evidenced by a lack of consistency in radiochemical yields with more complex diaryliodonium salts precursors. 16 …”

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

“…Unlabeled compounds and precursors were synthesized in our laboratory following published reports [22, 23]. H 2 18 O was purchased from Rotem Industries.…”

“…We recently described the synthesis and PPARγ binding affinity of two Farglitazar analogs that are fluorine-substituted on either the distal benzene ring (the oxazole phenyl substituent) or the proximal benzene ring (part of the benzophenone group) (Figure 1) [22, 23]. The binding affinities of these two analogs of Farglitazar were 3-fold better (for 1 ) or 6-fold poorer (for 2 ) than that of the parent ligand, respectively [22, 23]. …”

“…To label the distal phenyl ( 18 F- 1 ), we synthesized various iodonium salt precursors using Koser’s reagents [22, 24-27], which allowed fluorine incorporation simply by warming these salts with fluoride ion. To label the proximal ring ( 18 F- 2 ), we prepared a trimethylammonium benzophenone precursor that could be readily labeled at the para position with fluoride ion, and subsequently coupled to the tyrosine core of the ligand by a rapid Ullmann-type amine arylation reaction [23, 28-30].…”

Applications of iodonium salts and iodonium ylides as precursors for nucleophilic fluorination in Positron Emission Tomography

“…71,72 In particular, the radioligand 42 was prepared by nucleophilic fluorination of phenyliodonium salt 41 in good radiochemical yield (Scheme 20). 71 Interestingly, the reactions of iodonium salts 41 bearing the 3-methoxyphenyl or 2-thienyl substituents instead of the phenyl did not afford any fluorinated product 42.…”