Comparative evaluation of the translocator protein radioligands 11C-DPA-713, 18F-DPA-714, and 11C-PK11195 in a rat model of acute neuroinflammation.
Overexpression of the translocator protein, TSPO (18 kDa), formerly known as the peripheral benzodiazepine receptor, is a hallmark of activation of cells of monocytic lineage (microglia and macrophages) during neuroinflammation. Radiolabeling of TSPO ligands enables the detection of neuroinflammatory lesions by PET. Two new radioligands, (11)C-labeled N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-alpha]pyrimidin-3-yl]acetamide (DPA-713) and (18)F-labeled N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-alpha]pyrimidin-3-yl)acetamide (DPA-714), both belonging to the pyrazolopyrimidine class, were compared in vivo and in vitro using a rodent model of neuroinflammation.


METHODS
(11)C-DPA-713 and (18)F-DPA-714, as well as the classic radioligand (11)C-labeled (R)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide (PK11195), were used in the same rat model, in which intrastriatal injection of (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolopropionique gave rise to a strong neuroinflammatory response. Comparative endpoints included in vitro autoradiography and in vivo imaging on a dedicated small-animal PET scanner under identical conditions.


RESULTS
(11)C-DPA-713 and (18)F-DPA-714 could specifically localize the neuroinflammatory site with a similar signal-to-noise ratio in vitro. In vivo, (18)F-DPA-714 performed better than (11)C-DPA-713 and (11)C-PK11195, with the highest ratio of ipsilateral to contralateral uptake and the highest binding potential.


CONCLUSIONS
(18)F-DPA-714 appears to be an attractive alternative to (11)C-PK11195 because of its increased bioavailability in brain tissue and its reduced nonspecific binding. Moreover, its labeling with (18)F, the preferred PET isotope for radiopharmaceutical chemistry, favors its dissemination and wide clinical use. (18)F-DPA-714 will be further evaluated in longitudinal studies of neuroinflammatory conditions such as are encountered in stroke or neurodegenerative diseases.
Chauveau
Fabien
F
CEA, DSV, I2BM, LIME, Orsay, France.
Van Camp
Nadja
N
Dollé
Frédéric
F
Kuhnast
Bertrand
B
Hinnen
Françoise
F
Damont
Annelaure
A
Boutin
Hervé
H
James
Michelle
M
Kassiou
Michael
M
Tavitian
Bertrand
B
D000081:Acetamides / Q000378:metabolism*; D000208:Acute Disease; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging* / Q000276:immunology / Q000378:metabolism; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D007249:Inflammation / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism; D007546:Isoquinolines / Q000378:metabolism*; D008024:Ligands; D008297:Male; D049268:Positron-Emission Tomography; D011720:Pyrazoles / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000378:metabolism*
D000081:Acetamides; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D007546:Isoquinolines; D008024:Ligands; C530129:N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; C507091:N,N-diethyl-2-(2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo(1,5-a)pyrimidin-3-yl)-acetamide; D011720:Pyrazoles; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D018079:Receptors, GABA; C499229:TSPO protein, human; C037850:PK 11195