PT  - JOURNAL ARTICLE
AU  - Peyronneau, Marie-Anne
AU  - Saba, Wadad
AU  - Goutal, Sébastien
AU  - Damont, Annelaure
AU  - Dollé, Frédéric
AU  - Kassiou, Michael
AU  - Bottlaender, Michel
AU  - Valette, Héric
TI  - Metabolism and Quantification of [<sup>18</sup>F]DPA-714, a New TSPO Positron Emission Tomography Radioligand
AID  - 10.1124/dmd.112.046342
DP  - 2013 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 122--131
VI  - 41
IP  - 1
4099  - http://dmd.aspetjournals.org/content/41/1/122.short
4100  - http://dmd.aspetjournals.org/content/41/1/122.full
SO  - Drug Metab Dispos2013 Jan 01; 41
AB  - [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.