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3-{4-[2-[Benzoxazol-2-yl-methylamino]ethoxy]phenyl}-2-(2-[18F]fluoroethoxy)propionic acid

Compound [18F]22

Created: ; Last Update: May 15, 2007.

Chemical name:3-{4-[2-[-Benzoxazol-2-yl-methylamino]ethoxy]phenyl}-2-(2-[18F]fluoroethoxy)propionic acidimage 12964619 in the ncbi pubchem database
Abbreviated name:Compound [18F]22
Synonym:
Agent Category:SB 213 068
Target:Peroxisome proliferator–activated receptor γ
Target Category:Receptor binding
Method of detection:PET
Source of signal:18F
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Peroxisome proliferator–activated receptors (PPARs), once considered orphan receptors, are now believed to be the primary modulators of glucose and lipid metabolism in animals. PPARs are also believed to regulate the storage and catabolism of dietary fat (1). There are three subtypes of the receptors, designated as PPAR-α, PPAR-β/δ, and PPAR-γ (2). Among these, PPAR-γ is the most extensively investigated and has been cloned from a variety of species including fish, amphibians, rodents, and mammals (2). PPAR-γ has been shown to be an important transcription factor receptor that regulates adipocyte differentiation (3), represses the ob gene that regulates leptin expression (4), and modulates obesity and inflammation in mice (5). There is evidence that activation of PPAR-γ can have an anti-carcinogenic effect on colon cancer (6), and that PPAR-γ can alter the malignant phenotype of some human colon carcinoma cell lines (7, 8). PPAR-γ levels were shown to be elevated in breast cancer cell lines and during metastases in animal tumor models for breast cancer (9). Although PPAR-γ ligands induced tumor differentiation in animal models, not all cell lines that were positive for PPAR-γ respond to the ligands. With these observations the investigators suggest receptor phosphorylation may be necessary for responsiveness because the phosphorylated receptor had a low ligand affinity (10), which led to a reduced responsiveness of S112 cells that probably had a previously phosphorylated receptor (11). Kim et al (12). suggest that the nonphosphorylated form of PPAR-γ may be a novel target for tumor therapy and that radiotracers could be used to identify tumors retaining the ability to bind the ligands. They suggest that functional imaging of the tumors may help identify, and allow direction of therapy for, patients who are most likely to benefit. This would reduce time lost in providing therapies to individuals who are unlikely to respond to treatment, as such patients could be provided alternative therapies.

In an effort to develop a radiotracer compound that could be used to study tissue distribution of PPAR-γ and provide a high contrast between target and non-target tissue, Kim et al. selected a very potent synthetic ligand belonging to the 3-phenylpropionic acid (SB 213 068) class of compounds, a [18F]fluorine-substituted analog, 3-{4-[2-[-(benzoxazol-2-yl-methylamino])ethoxy]phenyl}-2-(2-[18F]fluoroethoxy)propionic acid (12), also designated as compound [18F]22. The tissue distribution of compound [18F]22 was studied in two animal models (rats and SCID mice) by the investigators.

Synthesis

[PubMed]

The synthesis of compound [18F]22 was described by Kim et al. (12). For this, methyl 3-[-{4-[2-[-(benzoxazol-2-yl-methylamino])ethoxy]phenyl]-}-2-(2-[18F]fluoroethoxy)propanoate was used as the base compound. It was prepared by incubation of tetrabutylammonium [18F]fluoride (n-BuN4[18F]F) with 3-[-{4-[2-[benzoxazol-2-yl-methylamino])ethoxy]phenyl}-2-(2-fluoroethoxy)acrylic acid at 80oC in an oil bath for 30 min. The substituted 18F methyl ester was purified by semipreparative high-performance liquid chromatography (HPLC) on a silica column. The labeled ester was dissolved in methanol and 10% NaOH solution, and then heated at 80oC for 15 min. The solution was then acidified with 1N HCl and extracted with hexane, passed through MgSO4, and purified by semipreparative HPLC. Fractions containing compound [18F]22 were combined, counted, and concentrated under reduced pressure. The typical radiochemical yield was 20–30%, decay corrected from (n-BuN4[18F]F), and the entire synthesis process took 2.5–3.5 h.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The binding affinity of compound [18F]22 was determined by competitive binding as described earlier (13, 14) using receptor preparations that consisted of the ligand-binding domains expressed in Escherichia coli. The Ki and Kd of compound [18F]22 for PPAR-γ were determined to be 7 nM and ~5 nM, respectively.

Animal Studies

Rodents

[PubMed]

The distribution of compound [18F]22 was studied in two animal models, adult rats and SCID mice bearing human breast tumor MCF-7 xenografts (12). On the basis of mRNA expression, the highest PPAR-γ levels were expected in the brown and white adipose tissue, and significant levels were also expected in the spleen and mucosa of the duodenum (12). The MCF-7 cells are positive for the estrogen receptor, require estradiol for growth, and exhibit a high level of PPAR-γ. Therefore, a significant level of the receptors would be expected to be present in the xenografts (12).

Female Sprague-Dawley rats (200–225 g) were administered a low (5 µCi) or high (30 µCi) dose of compound [18F]22 through the tail vein. A group of animals also received a blocking dose as a combination of unlabeled and labeled compound [18F]22. Animals were sacrificed 1 h after administration of the low or high dose, with or without the block, whereas animals sacrificed after 3 h that received only the low dose, with or without the block, were sacrificed after 3 h. Blood and tissue from these animals were collected, weighed, and counted for radioactivity.

Tissue distribution of compound [18F]22 was expected to be similar to the distribution of PPAR-γ given above and it was expected to be displaced by the unlabelled compound. However, the investigators observed that compound [18F]22 did not have a tissue selective uptake, and high levels were observed only in the liver and kidney. Uptake in the white and brown adipose tissue was not significantly different from that of other tissue such as the heart and muscle. The investigators were unable to evaluate the uptake in duodenal mucosa because a high level of the radiotracer was present in the intestinal contents, probably as a result of compound [18F]22 metabolite excretion through the hepatobiliary system.

Female SCID mice were implanted with MCF-7 cells by subcutaneous injections in the left and right flanks, and the tumors were allowed to grow for 4 weeks in presence of estradiol; each animal had a timed-release estradiol pellet (1.7 mg/60 days) inserted at the side of the neck. The tumor-bearing animals were treated with cold or labeled compound [18F]22 as detailed above for the rats. Tissues from these animals were collected as described for the rats, and the gall bladder and tumors were also harvested. With the SCID mice, uptake was observed mainly in the liver, kidney, and the lungs. A high uptake in the gall bladder was also observed, which indicated that the tracer was excreted through the hepatobiliary system, as observed with the rats. Uptake in the other tissues of the SCID mice was also similar to that observed in the rats. In addition, the investigators observed that uptake in the tumors was not different, selective, or blocked, similar to observations in the other tissues.

With data obtained from this study (12), Kim et al. concluded that uptake of compound [18F]22 in the normal tissue or tumors was not selective as expected. The investigators recommend the development of compounds with better tissue selectivity that can be used to perform uptake and imaging studies. For this purpose, Kim et al. discuss the possible use of a tyrosine-benzophenone class of compounds that have a higher affinity and invivo potency against PPAR-γ. However, in their opinion, it would be a challenge to develop imaging agents for PPAR-γ (12).

Other Non-Primate Mammals

[PubMed]

No publications are currently available.

Non-Human Primates

[PubMed]

No publications are currently available.

Human Studies

[PubMed]

No publications are currently available.

References

1.
Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature. 1998;395(6698):137–43. [PubMed: 9744270]
2.
Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000;43(4):527–50. [PubMed: 10691680]
3.
Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994;79(7):1147–56. [PubMed: 8001151]
4.
De Vos P, Lefebvre AM, Miller SG, Guerre-Millo M, Wong K, Saladin R, Hamann LG, Staels B, Briggs MR, Auwerx J. Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma. J Clin Invest. 1996;98(4):1004–9. [PMC free article: PMC507516] [PubMed: 8770873]
5.
Stienstra R, Mandard S, Patsouris D, Maass C, Kersten S, Muller M. and , PPAR{alpha} protects against obesity-induced hepatic inflammation. Endocrinology. 2007 [PubMed: 17347305]
6.
Bull AW. The role of peroxisome proliferator-activated receptor gamma in colon cancer and inflammatory bowel disease. Arch Pathol Lab Med. 2003;127(9):1121–3. [PubMed: 12946234]
7.
Kato M, Kusumi T, Tsuchida S, Tanaka M, Sasaki M, Kudo H. Induction of differentiation and peroxisome proliferator-activated receptor gamma expression in colon cancer cell lines by troglitazone. J Cancer Res Clin Oncol. 2004;130(2):73–9. [PubMed: 14634802]
8.
Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher C, Spiegelman BM. Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med. 1998;4(9):1046–52. [PubMed: 9734398]
9.
Mueller E, Sarraf P, Tontonoz P, Evans RM, Martin KJ, Zhang M, Fletcher C, Singer S, Spiegelman BM. Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell. 1998;1(3):465–70. [PubMed: 9660931]
10.
Shao D, Rangwala SM, Bailey ST, Krakow SL, Reginato MJ, Lazar MA. Interdomain communication regulating ligand binding by PPAR-gamma. Nature. 1998;396(6709):377–80. [PubMed: 9845075]
11.
Hu E, Kim JB, Sarraf P, Spiegelman BM. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science. 1996;274(5295):2100–3. [PubMed: 8953045]
12.
Kim SH, Jonson SD, Welch MJ, Katzenellenbogen JA. Fluorine-substituted ligands for the peroxisome proliferator-activated receptor gamma (PPARgamma): potential imaging agents for metastatic tumors. Bioconjug Chem. 2001;12(3):439–50. [PubMed: 11353543]
13.
Nichols JS, Parks DJ, Consler TG, Blanchard SG. Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain. Anal Biochem. 1998;257(2):112–9. [PubMed: 9514791]
14.
Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, Willson TM, Kliewer SA, Milburn MV. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell. 1999;3(3):397–403. [PubMed: 10198642]
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