RT Journal Article
SR Electronic
T1 Metabolism and Quantification of [18F]DPA-714, a New TSPO Positron Emission Tomography Radioligand
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.112.046342
DO 10.1124/dmd.112.046342
A1 Marie-Anne Peyronneau
A1 Wadad Saba
A1 Sebastien Goutal
A1 Annelaure Damont
A1 Frederic Dolle
A1 Michael Kassiou
A1 Michel Bottlaender
A1 Heric Valette
YR 2012
UL http://dmd.aspetjournals.org/content/early/2012/10/12/dmd.112.046342.abstract
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 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, HPLC metabolic profiles showed three major radiometabolites accounting for 85% and 89% of total radioactivity at 120 min p.i., respectively. Rat microsomal incubations and analyses by LC/MS identified seven metabolites, characterized as O-deethyl, hydroxyl and N-deethyl derivatives of 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 non radioactive 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.