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Research ArticleArticle

Metabolism and Quantification of [18F]DPA-714, a New TSPO Positron Emission Tomography Radioligand

Marie-Anne Peyronneau, Wadad Saba, Sébastien Goutal, Annelaure Damont, Frédéric Dollé, Michael Kassiou, Michel Bottlaender and Héric Valette
Drug Metabolism and Disposition January 2013, 41 (1) 122-131; DOI: https://doi.org/10.1124/dmd.112.046342
Marie-Anne Peyronneau
Service Hospitalier Frédéric Joliot, CEA, Orsay, France (MA.P., W.S., S.G., A.D., F.D., M.B., H.V); and Brain and Mind Research Institute, School of Chemistry, and Discipline of Medical Radiation Sciences, University of Sydney, Sydney, New South Wales, Australia (M.K.)
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Wadad Saba
Service Hospitalier Frédéric Joliot, CEA, Orsay, France (MA.P., W.S., S.G., A.D., F.D., M.B., H.V); and Brain and Mind Research Institute, School of Chemistry, and Discipline of Medical Radiation Sciences, University of Sydney, Sydney, New South Wales, Australia (M.K.)
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Sébastien Goutal
Service Hospitalier Frédéric Joliot, CEA, Orsay, France (MA.P., W.S., S.G., A.D., F.D., M.B., H.V); and Brain and Mind Research Institute, School of Chemistry, and Discipline of Medical Radiation Sciences, University of Sydney, Sydney, New South Wales, Australia (M.K.)
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Annelaure Damont
Service Hospitalier Frédéric Joliot, CEA, Orsay, France (MA.P., W.S., S.G., A.D., F.D., M.B., H.V); and Brain and Mind Research Institute, School of Chemistry, and Discipline of Medical Radiation Sciences, University of Sydney, Sydney, New South Wales, Australia (M.K.)
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Frédéric Dollé
Service Hospitalier Frédéric Joliot, CEA, Orsay, France (MA.P., W.S., S.G., A.D., F.D., M.B., H.V); and Brain and Mind Research Institute, School of Chemistry, and Discipline of Medical Radiation Sciences, University of Sydney, Sydney, New South Wales, Australia (M.K.)
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Michael Kassiou
Service Hospitalier Frédéric Joliot, CEA, Orsay, France (MA.P., W.S., S.G., A.D., F.D., M.B., H.V); and Brain and Mind Research Institute, School of Chemistry, and Discipline of Medical Radiation Sciences, University of Sydney, Sydney, New South Wales, Australia (M.K.)
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Michel Bottlaender
Service Hospitalier Frédéric Joliot, CEA, Orsay, France (MA.P., W.S., S.G., A.D., F.D., M.B., H.V); and Brain and Mind Research Institute, School of Chemistry, and Discipline of Medical Radiation Sciences, University of Sydney, Sydney, New South Wales, Australia (M.K.)
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Héric Valette
Service Hospitalier Frédéric Joliot, CEA, Orsay, France (MA.P., W.S., S.G., A.D., F.D., M.B., H.V); and Brain and Mind Research Institute, School of Chemistry, and Discipline of Medical Radiation Sciences, University of Sydney, Sydney, New South Wales, Australia (M.K.)
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Abstract

[18F]DPA-714 [N,N-diethyl-2-(2-(4-(2[18F]-fluoroethoxy)phenyl)5,7dimethylpyrazolo[1,5a]pyrimidin-3-yl)acetamide] is a new radioligand currently used for imaging the 18-kDa translocator protein in animal models of neuroinflammation and recently in humans. The biodistribution by positron emission tomography (PET) in baboons and the in vitro and in vivo metabolism of [18F]DPA-714 were investigated in rats, baboons, and humans. Whole-body PET experiments showed a high uptake of radioactivity in the kidneys, heart, liver, and gallbladder. The liver was a major route of elimination of [18F]DPA-714, and urine was a route of excretion for radiometabolites. In rat and baboon plasma, high-performance liquid chromatography (HPLC) metabolic profiles showed three major radiometabolites accounting for 85% and 89% of total radioactivity at 120 minutes after injection, respectively. Rat microsomal incubations and analyses by liquid chromatography–mass spectrometry (LC-MS) identified seven metabolites, characterized as O-deethyl, hydroxyl, and N-deethyl derivatives of nonradioactive DPA-714, two of them having the same retention times than those detected in rat and baboon plasma. The third plasma radiometabolite was suggested to be a carboxylic acid compound that accounted for 15% of the rat brain radioactivity. O-deethylation led to a nonradioactive compound and [18F]fluoroacetic acid. Human CYP3A4 and CYP2D6 were shown to be involved in the oxidation of the radioligand. Finally an easy, rapid, and accurate method—indispensable for PET quantitative clinical studies—for quantifying [18F]DPA-714 by solid-phase extraction was developed. In vivo, an extensive metabolism of [18F]DPA-714 was observed in rats and baboons, identified as [18F]deethyl, [18F]hydroxyl, and [18F]carboxylic acid derivatives of [18F]DPA-714. The main route of excretion of the unchanged radioligand in baboons was hepatobiliary while that of radiometabolites was the urinary system.

Footnotes

  • dx.doi.org/10.1124/dmd.112.046342.

  • Received July 9, 2012.
  • Accepted October 11, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (1)
Drug Metabolism and Disposition
Vol. 41, Issue 1
1 Jan 2013
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Research ArticleArticle

Metabolism of [18F]DPA-714 in Rodents and Nonhuman Primates

Marie-Anne Peyronneau, Wadad Saba, Sébastien Goutal, Annelaure Damont, Frédéric Dollé, Michael Kassiou, Michel Bottlaender and Héric Valette
Drug Metabolism and Disposition January 1, 2013, 41 (1) 122-131; DOI: https://doi.org/10.1124/dmd.112.046342

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Research ArticleArticle

Metabolism of [18F]DPA-714 in Rodents and Nonhuman Primates

Marie-Anne Peyronneau, Wadad Saba, Sébastien Goutal, Annelaure Damont, Frédéric Dollé, Michael Kassiou, Michel Bottlaender and Héric Valette
Drug Metabolism and Disposition January 1, 2013, 41 (1) 122-131; DOI: https://doi.org/10.1124/dmd.112.046342
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