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

Abstract

Introduction The peroxisome proliferator-activated receptor gamma (PPARγ) is an important regulator of lipid metabolism; it controls the differentiation of pre-adipocytes 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 ([18F]1 and [18F]2) were prepared in fluorine-18 labeled form, respectively, by radiofluorination of an iodonium salt precursor or by an 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 PPARγ ligands as potential PET imaging agents for breast cancer and vascular disease. Although 18F-1 and 18F-2 have high affinity for PPARγ and good metabolic stability, their poor target-tissue distribution properties, which likely reflects their high lipophilicity combined with the low titer of PPARγ in target tissues, indicate that they have limited potential as PPARγ-PET imaging agents.

Radiofluorination of diaryliodonium tosylates under aqueous–organic and cryptand-free conditions

“…The preparation of [ 18 F]fluoroarenes from the reactions of [ 18 F]fluoride ion with diaryliodonium salts (Scheme 1) [9,10] is finding increasing application for preparing labeling synthons [11–13] and PET radiotracers [14–17]. This radiofluorination method, unlike aromatic nucleophilic substitution ( S N Ar) in non-hypervalent substrates, allows NCA [ 18 F]fluoride ion to be introduced readily into electron-deficient or electron-rich rings, irrespective of ring substituent positions [9,10,18,19].…”

Synthesis and evaluation of 18F-labeled PPARγ antagonists

“…However, recent tissue distribution studies of two fluorine-18 analogs of GI262570 in normal female rats did not demonstrate increased tracer uptake in target tissues, and blocking studies showed little in vivo selectivity. Metabolic stability studies and the low fluoride incorporation into the bone suggested that the compounds were stable [14], and rapid metabolism was not responsible for the low uptake of radiotracers in the target tissue.…”

“…These fluorine-18 labeled radiotracers had good potential for PPARγ imaging because of their high subtype specificity (PPARγ/PPARα > 100). However, despite high affinity and good metabolic stability, in vivo studies demonstrated poor uptake in target tissues, which was attributed to their high lipophilicity [14]. …”

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.…”