Synthesis and biodistribution of 11C-GW7845, a positron-emitting agonist for peroxisome proliferator-activated receptor-γ

William B Mathews, Catherine Foss, Doris Stoermer, Hayden T. Ravert, Robert F Dannals, Brad R. Henke, Martin Gilbert Pomper

Research output: Contribution to journalArticle

Abstract

The goal of this study was to synthesize and evaluate in vivo the peroxisome proliferator-activated receptor-γ (PPARγ) agonist 11C-GW7845 ((S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl) ethoxy]phenyl}ethylamino)benzoic acid methyl ester) (11C-compound 1). PPARγ is a member of a family of nuclear receptors that plays a central role in the control of lipid and glucose metabolism. Compound 1 is an analog of tyrosine (inhibitor constant, 3.7 nmol/L), which is an inhibitor of experimental mammary carcinogenesis. Methods: Protection of the carboxylic acid moiety of compound 1 was effected by treatment with N,N-dimethylformamide di-tert-butyl acetal to provide compound 2. Hydrolysis of the carbomethoxy group of compound 2 provided the benzoic acid (compound 3) that served as an immediate precursor to radiolabeling. Compound 3 underwent treatment with 11C-methyl iodide followed by high-performance liquid chromatography to produce a radioactive peak sample that coeluted with a standard sample of compound 1. Analysis of biodistribution was undertaken by injecting male CD-1 mice via the tail vein with 6.03 MBq (163 μCi, 2.55 μg/kg) of 11C-compound 1. To determine the tumor uptake of the radiotracer, 6 female SCID mice bearing MCF-7 xenografts were injected via the tail vein with 10.5 MBq (283 μCi, 0.235 μg/kg) of 11C-compound 1. Results: 11C-Compound 1 was synthesized at an 8% radiochemical yield in 29 min with an average specific radioactivity of 1,222 GBq/μmol (33,024 mCi/μmol; n = 6) at the end of synthesis. Spleen (target)-to-muscle uptake and tumor-to-muscle uptake ratios were 3.1 and 1.5, respectively, but this uptake could not be blocked with unlabeled compound 1 at 2 mg/kg. Conclusion: Further structural modification, perhaps to generate a less lipophilic tyrosine analog, will be necessary to enable receptor-mediated PPARγ imaging by this class of agents.

Original languageEnglish (US)
Pages (from-to)1719-1726
Number of pages8
JournalJournal of Nuclear Medicine
Volume46
Issue number10
StatePublished - Oct 1 2005

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Peroxisome Proliferator-Activated Receptors
Electrons
Tyrosine
Tail
Veins
Muscles
Acetals
Dimethylformamide
Benzoic Acid
SCID Mice
Cytoplasmic and Nuclear Receptors
Carboxylic Acids
Lipid Metabolism
Heterografts
Radioactivity
Neoplasms
Carcinogenesis
Breast
Hydrolysis
Spleen

Keywords

  • C-GW7845
  • Biodistribution
  • PET
  • PPARγ
  • Synthesis

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

Synthesis and biodistribution of 11C-GW7845, a positron-emitting agonist for peroxisome proliferator-activated receptor-γ. / Mathews, William B; Foss, Catherine; Stoermer, Doris; Ravert, Hayden T.; Dannals, Robert F; Henke, Brad R.; Pomper, Martin Gilbert.

In: Journal of Nuclear Medicine, Vol. 46, No. 10, 01.10.2005, p. 1719-1726.

Research output: Contribution to journalArticle

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abstract = "The goal of this study was to synthesize and evaluate in vivo the peroxisome proliferator-activated receptor-γ (PPARγ) agonist 11C-GW7845 ((S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl) ethoxy]phenyl}ethylamino)benzoic acid methyl ester) (11C-compound 1). PPARγ is a member of a family of nuclear receptors that plays a central role in the control of lipid and glucose metabolism. Compound 1 is an analog of tyrosine (inhibitor constant, 3.7 nmol/L), which is an inhibitor of experimental mammary carcinogenesis. Methods: Protection of the carboxylic acid moiety of compound 1 was effected by treatment with N,N-dimethylformamide di-tert-butyl acetal to provide compound 2. Hydrolysis of the carbomethoxy group of compound 2 provided the benzoic acid (compound 3) that served as an immediate precursor to radiolabeling. Compound 3 underwent treatment with 11C-methyl iodide followed by high-performance liquid chromatography to produce a radioactive peak sample that coeluted with a standard sample of compound 1. Analysis of biodistribution was undertaken by injecting male CD-1 mice via the tail vein with 6.03 MBq (163 μCi, 2.55 μg/kg) of 11C-compound 1. To determine the tumor uptake of the radiotracer, 6 female SCID mice bearing MCF-7 xenografts were injected via the tail vein with 10.5 MBq (283 μCi, 0.235 μg/kg) of 11C-compound 1. Results: 11C-Compound 1 was synthesized at an 8{\%} radiochemical yield in 29 min with an average specific radioactivity of 1,222 GBq/μmol (33,024 mCi/μmol; n = 6) at the end of synthesis. Spleen (target)-to-muscle uptake and tumor-to-muscle uptake ratios were 3.1 and 1.5, respectively, but this uptake could not be blocked with unlabeled compound 1 at 2 mg/kg. Conclusion: Further structural modification, perhaps to generate a less lipophilic tyrosine analog, will be necessary to enable receptor-mediated PPARγ imaging by this class of agents.",
keywords = "C-GW7845, Biodistribution, PET, PPARγ, Synthesis",
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T1 - Synthesis and biodistribution of 11C-GW7845, a positron-emitting agonist for peroxisome proliferator-activated receptor-γ

AU - Mathews, William B

AU - Foss, Catherine

AU - Stoermer, Doris

AU - Ravert, Hayden T.

AU - Dannals, Robert F

AU - Henke, Brad R.

AU - Pomper, Martin Gilbert

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N2 - The goal of this study was to synthesize and evaluate in vivo the peroxisome proliferator-activated receptor-γ (PPARγ) agonist 11C-GW7845 ((S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl) ethoxy]phenyl}ethylamino)benzoic acid methyl ester) (11C-compound 1). PPARγ is a member of a family of nuclear receptors that plays a central role in the control of lipid and glucose metabolism. Compound 1 is an analog of tyrosine (inhibitor constant, 3.7 nmol/L), which is an inhibitor of experimental mammary carcinogenesis. Methods: Protection of the carboxylic acid moiety of compound 1 was effected by treatment with N,N-dimethylformamide di-tert-butyl acetal to provide compound 2. Hydrolysis of the carbomethoxy group of compound 2 provided the benzoic acid (compound 3) that served as an immediate precursor to radiolabeling. Compound 3 underwent treatment with 11C-methyl iodide followed by high-performance liquid chromatography to produce a radioactive peak sample that coeluted with a standard sample of compound 1. Analysis of biodistribution was undertaken by injecting male CD-1 mice via the tail vein with 6.03 MBq (163 μCi, 2.55 μg/kg) of 11C-compound 1. To determine the tumor uptake of the radiotracer, 6 female SCID mice bearing MCF-7 xenografts were injected via the tail vein with 10.5 MBq (283 μCi, 0.235 μg/kg) of 11C-compound 1. Results: 11C-Compound 1 was synthesized at an 8% radiochemical yield in 29 min with an average specific radioactivity of 1,222 GBq/μmol (33,024 mCi/μmol; n = 6) at the end of synthesis. Spleen (target)-to-muscle uptake and tumor-to-muscle uptake ratios were 3.1 and 1.5, respectively, but this uptake could not be blocked with unlabeled compound 1 at 2 mg/kg. Conclusion: Further structural modification, perhaps to generate a less lipophilic tyrosine analog, will be necessary to enable receptor-mediated PPARγ imaging by this class of agents.

AB - The goal of this study was to synthesize and evaluate in vivo the peroxisome proliferator-activated receptor-γ (PPARγ) agonist 11C-GW7845 ((S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl) ethoxy]phenyl}ethylamino)benzoic acid methyl ester) (11C-compound 1). PPARγ is a member of a family of nuclear receptors that plays a central role in the control of lipid and glucose metabolism. Compound 1 is an analog of tyrosine (inhibitor constant, 3.7 nmol/L), which is an inhibitor of experimental mammary carcinogenesis. Methods: Protection of the carboxylic acid moiety of compound 1 was effected by treatment with N,N-dimethylformamide di-tert-butyl acetal to provide compound 2. Hydrolysis of the carbomethoxy group of compound 2 provided the benzoic acid (compound 3) that served as an immediate precursor to radiolabeling. Compound 3 underwent treatment with 11C-methyl iodide followed by high-performance liquid chromatography to produce a radioactive peak sample that coeluted with a standard sample of compound 1. Analysis of biodistribution was undertaken by injecting male CD-1 mice via the tail vein with 6.03 MBq (163 μCi, 2.55 μg/kg) of 11C-compound 1. To determine the tumor uptake of the radiotracer, 6 female SCID mice bearing MCF-7 xenografts were injected via the tail vein with 10.5 MBq (283 μCi, 0.235 μg/kg) of 11C-compound 1. Results: 11C-Compound 1 was synthesized at an 8% radiochemical yield in 29 min with an average specific radioactivity of 1,222 GBq/μmol (33,024 mCi/μmol; n = 6) at the end of synthesis. Spleen (target)-to-muscle uptake and tumor-to-muscle uptake ratios were 3.1 and 1.5, respectively, but this uptake could not be blocked with unlabeled compound 1 at 2 mg/kg. Conclusion: Further structural modification, perhaps to generate a less lipophilic tyrosine analog, will be necessary to enable receptor-mediated PPARγ imaging by this class of agents.

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