Comparative Evaluation of the Translocator Protein Radioligands ¹¹C-DPA-713, ¹⁸F-DPA-714, and ¹¹C-PK11195 in a Rat Model of Acute Neuroinflammation

Abstract

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, ¹¹C-labeled N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-α]pyrimidin-3-yl]acetamide (DPA-713) and ¹⁸F-labeled N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-α]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: ¹¹C-DPA-713 and ¹⁸F-DPA-714, as well as the classic radioligand ¹¹C-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)-α-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: ¹¹C-DPA-713 and ¹⁸F-DPA-714 could specifically localize the neuroinflammatory site with a similar signal-to-noise ratio in vitro. In vivo, ¹⁸F-DPA-714 performed better than ¹¹C-DPA-713 and ¹¹C-PK11195, with the highest ratio of ipsilateral to contralateral uptake and the highest binding potential. Conclusion: ¹⁸F-DPA-714 appears to be an attractive alternative to ¹¹C-PK11195 because of its increased bioavailability in brain tissue and its reduced nonspecific binding. Moreover, its labeling with ¹⁸F, the preferred PET isotope for radiopharmaceutical chemistry, favors its dissemination and wide clinical use. ¹⁸F-DPA-714 will be further evaluated in longitudinal studies of neuroinflammatory conditions such as are encountered in stroke or neurodegenerative diseases.