Fluorine-Substituted Ligands for the Peroxisome Proliferator-Activated Receptor Gamma (PPARγ):  Potential Imaging Agents for Metastatic Tumors

Kim, Sung Hoon; Jonson, Stephanie D.; Welch, Michael J.; Katzenellenbogen, John A.

doi:10.1021/bc000153b

Cited by 8 publications

(8 citation statements)

References 30 publications

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“…Kim et al suggested a new approach for PET oncology in chosing the peroxisome proliferator-activated receptor Á (PPARÁ) as target for tracer devlopment (44). This receptor was found in many in vitro and in vivo tumour models.…”

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confidence: 99%

Applications of positron-emitting halogens in PET oncology (Review)

Glaser

Luthra²,

Brady³

2003

Int J Oncol

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The positron-emitting radiohalogens 18 F, 75 Br, 76 Br, and 124 I are reviewed regarding their relevance for positron emission tomography (PET) in oncology. Relevant production routes of these cyclotron-generated isotopes are given, followed by publications that deal with applications of these radiohalogens. This article tries to cover the whole literature for the non-conventional isotopes 75 Br, 76 Br, and 124 I. From the literature on 18 F, only articles since 2000 are considered. Here, the emphasis is also given to alternative biomarkers beyond [ 18 ]2-fluoro-2-deoxyglucose ([ 18 F]FDG). Contents 1. Introduction 2. Fluorine-18 3. Bromine-75 4. Bromine-76 5. Iodine-124 6. Conclusions

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confidence: 99%

Applications of positron-emitting halogens in PET oncology (Review)

Glaser

Luthra²,

Brady³

2003

Int J Oncol

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“…To develop agents for imaging PPARγ by positron emission tomography (PET), our group initially evaluated two fluorine-18 labeled PPARγ receptor ligands based on the known 2-alkoxy-3-phenylpropanoic acid PPARγ ligand, SB 213 068 [13]. Tissue distribution studies of these compounds, however, did not show evidence of receptor-mediated uptake in brown fat, the most receptor-rich tissue [14, 15].…”

Section: Introductionmentioning

confidence: 99%

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

Lee¹,

Dence²,

Zhou³

et al. 2009

Nuclear Medicine and Biology

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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.

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“…With this goal in mind, some time ago our group evaluated as PET imaging agents a set of fluorine-18 labeled PPARγ receptor ligands, based on the known compound SB 213068 (Scheme 1) (17). The binding of these fluorine-substituted compounds was selective for PPARγ compared to the PPARR and PPARδ subtypes; however, their affinity for PPARγ, though good, was not in the low nanomolar region as would be desirable for in vivo imaging.…”

Section: Introductionmentioning

confidence: 99%

“…The binding of these fluorine-substituted compounds was selective for PPARγ compared to the PPARR and PPARδ subtypes; however, their affinity for PPARγ, though good, was not in the low nanomolar region as would be desirable for in vivo imaging. Also, one SB 213068 analogue (5), prepared in the fluorine-18 labeled form (17), did not show evidence of receptor-mediated uptake in tissue distribution studies in brown fat, the most receptor-rich tissue (18).…”

Section: Introductionmentioning

confidence: 99%

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

Lee

et al. 2007

Bioconjugate Chem.

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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.

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Fluorine-Substituted Ligands for the Peroxisome Proliferator-Activated Receptor Gamma (PPARγ): Potential Imaging Agents for Metastatic Tumors

Cited by 8 publications

References 30 publications

Applications of positron-emitting halogens in PET oncology (Review)

Applications of positron-emitting halogens in PET oncology (Review)

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

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

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