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

[F-18] DPA-714 [N,N-diethyl-2-(2-(4-(2[F-18]-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 [F-18] 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 [F-18] 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 [F-18] DPA-714 by solid-phase extraction was developed. In vivo, an extensive metabolism of [F-18] DPA-714 was observed in rats and baboons, identified as [F-18] deethyl, [F-18] hydroxyl, and [F-18] carboxylic acid derivatives of [F-18] DPA-714. The main route of excretion of the unchanged radioligand in baboons was hepatobiliary while that of radiometabolites was the urinary system.