Metabolism and quantification of [(18)F]DPA-714, a new TSPO positron emission tomography radioligand.
[(18)F]DPA-714 [N,N-diethyl-2-(2-(4-(2[(18)F]-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 [(18)F]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 [(18)F]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 [(18)F]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 [(18)F]DPA-714 by solid-phase extraction was developed. In vivo, an extensive metabolism of [(18)F]DPA-714 was observed in rats and baboons, identified as [(18)F]deethyl, [(18)F]hydroxyl, and [(18)F]carboxylic acid derivatives of [(18)F]DPA-714. The main route of excretion of the unchanged radioligand in baboons was hepatobiliary while that of radiometabolites was the urinary system.
CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, 4 Place du Général Leclerc, 91406 Orsay, France. marie-anne.schollhorn@cea.fr
Marie-Anne
MA
Peyronneau
Wadad
W
Saba
Sébastien
S
Goutal
Annelaure
A
Damont
Frédéric
F
Dollé
Michael
M
Kassiou
Michel
M
Bottlaender
Héric
H
Valette
D000818:Animals; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods*; D011720:Pyrazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000378:metabolism / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D052616:Solid Phase Extraction; D013056:Spectrophotometry, Ultraviolet
D005462:Fluorine Radioisotopes; C530129:N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; D011720:Pyrazoles; D011743:Pyrimidines; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human