11C-DPA-713:: A novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation

The induction of neuroinflammatory processes, characterized by upregulation of the peripheral benzodiazepine receptor (PBR) expressed by microglial cells, is well correlated with neurodegenerative diseases and with acute neuronal loss. The continually increasing incidence of neurodegenerative diseases in developed countries has become a major health problem, for which the development of diagnostic and follow-up tools is required. Here we investigated a new PBR ligand suitable for PET to monitor neuroinflammatory processes as an indirect hallmark of neurodegeneration. Methods: We compared PK1 1195, the reference compound for PBR binding sites, with the new ligand DPA-713 (N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-ajpyrimidin-3-yl]acetamide), using a small-animal dedicated PET camera in a model of neuroinflammation in rats. Seven days after intrastriatal injection of ci-amino-3-hydroxy-5methyl-4-isoxazolepropionate (AMPA), a PETscan was performed using C-11-PK11195 or C-11-DPA-713. Immunohistochemistry for neuronal (NeuN), astrocyte (glial fibrillary acidic protein), and microglial (CD1 1) specific markers as well as H-3-PK11195 autoradiographic studies were then correlated with the imaging data. Results: Seven days after a unilateral injection of AMPA in the striatum, C-11-DPA-713 exhibits a bettercontrast between healthy and damaged brain parenchyma than C-11-PK11195 (2.5-fold-4-0.14 increase vs. 1.6-fold +/- 0.05 increase, respectively). (11)CDPA-713 and C-11-PK11195 exhibit similar brain uptake in the ipsilateral side, whereas, in the contralateral side, "C-DPA-713 uptake was significantly lower than C-11-PK11195. Modeling of the data using the simplified reference tissue model shows that the binding potential was significantly higher for "C-DPA-713 than for C-11-PK11195. Conclusion: "C-DPA-713 displays a higher signal-to-noise ratio than C-11-PK11195 because of a lower level of unspecific binding that is likely related to the lower lipophilicity of "C-DPA-713. Although further studies in humans are required, C-11-DPA-713 represents a suitable alternative to C-11-PK11195 for PET of PBR as a tracer of neuroinflammatory processes induced by neuronal stress.