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¹¹C-DPA-713: A Novel Peripheral Benzodiazepine Receptor PET Ligand for In Vivo Imaging of Neuroinflammation

¹ CEA, Institut d'Imagerie Biomédicale, Service hospitalier Frédéric Joliot, Laboratoire d'Imagerie Moléculaire Expérimentale, Orsay, France; ² INSERM, U803, Orsay, France; ³ Faculty of Life Sciences, Neurobiology Group, University of Manchester, Manchester, United Kingdom; ⁴ CNRS URA 2210, CEA, DSV, 12BM, SHFJ, Orsay, France; ⁵ RRI, ANSTO, Menai, Australia; ⁶ Department of Pharmacology, University of Sydney, Sydney, New South Wales, Australia; ⁷ School of Medical Radiation Sciences, University of Sydney, Sydney, New South Wales, Australia; ⁸ School of Chemistry, University of Sydney, Sydney, New South Wales, Australia; and ⁹ Ramaciotti Centre for Brain Imaging, Brain and Mind Research Institute, University of Sydney, Sydney, New South Wales, Australia

View larger version (25K): [in this window] [in a new window]   FIGURE 1.  After 2 d, quantification of lesion volumes (left) highlights a reproducible lesion volume in ipsilateral striatum. In cortical areas, lesion size was more variable and essentially due to the needle track, except in 1 rat, and in thalamic nuclei, in which lesion had extended for 3 of 6 rats. Lesion was clearly delineated on coronal section (20 µm) with cresyl violet staining in ipsilateral striatum after AMPA injection (right) (x4).

View larger version (20K): [in this window] [in a new window]   FIGURE 2.  Immunohistochemistry was performed 7 d after intrastriatal injection on 2 adjacent sets of rat brain sections (postfixed with paraformaldehyde): 1 for GFAP (green staining) and CD11b antigen (Ox42, red staining) (A and B); the other for GFAP (green) and neuron-specific nuclear protein (NeuN, red staining) (C and D). In contralateral side (A and C), clear NeuN staining was observed, whereas no activated microglial cells or astrocytes could be seen. In ipsilateral side, intense microglial activation (red) was observed within lesion core surrounded by a clear astroglial activation (green) (delineated by dashed arrows in B), whereas neuronal loss was clearly seen in lesion core when compared with surrounding healthy tissue (delineated by solid arrows in D).

View larger version (60K): [in this window] [in a new window]   FIGURE 3.  High magnification of immunostaining of the lesion area. (A and B) Intense microglial activation (Ox42, red staining) was observed within lesion core surrounded by clear astroglial activation (GFAP, green staining). (C and D) NeuN immunostaining (red) was clearly decreased in lesion core when compared with surrounding healthy tissue.

View larger version (28K): [in this window] [in a new window]   FIGURE 4.  Cresyl violet–stained coronal section of a rat brain with lesion delineated by dashed area (A), 3H-PK11195 autoradiographic image (B), and 11C-PK11195 PET image (C).

View larger version (44K): [in this window] [in a new window]   FIGURE 5.  Time–activity curves for 11C-PK11195 (n = 5) (A) and 11C-DPA-713 (n = 4) (B) and corresponding quantitative PET images (right) and comparison between these 2 radioligands (C). Data are expressed as percentage of injected dose per cubic centimeter (%ID/cm3; mean ± SD) as a function of postinjection time (min). Significant statistical differences are shown between ipsilateral and contralateral curves (P < 0.05 from 2.5 min after injection for 11C-PK11195 (A) and from 1.5 min after injection for 11C-DPA-713 (B)) and between 11C-PK11195 and 11C-DPA-713 in the contralateral side (C) (P < 0.05, from 1.5 min after injection to end of measurement) (Mann–Whitney tests). Images shown at right are summed images between 2 and 70 min after injection. ipsi = ipsilateral; NS = not significant.

View larger version (25K): [in this window] [in a new window]   FIGURE 6.  Time–activity curves for 11C-DPA-713 displaced by excess of 1 mg/kg of either PK11195 (A) or DPA-713 (B) (n = 4 in each group) 20 min after injection of 11C-DPA-713. Data are expressed as percentage of injected dose per cubic centimeter (%ID/cm3; mean ± SD) as a function of postinjection time (min). #Significantly different from contralateral striatum (P < 0.05; Mann–Whitney test).