Evaluation of the PBR/TSPO Radioligand [¹⁸F]DPA-714 in a Rat Model of Focal Cerebral Ischemia

Abstract

Focal cerebral ischemia leads to an inflammatory reaction involving an overexpression of the peripheral benzodiazepine receptor (PBR)/18-kDa translocator protein (TSPO) in the cerebral monocytic lineage (microglia and monocyte) and in astrocytes. Imaging of PBR/TSPO by positron emission tomography (PET) using radiolabeled ligands can document inflammatory processes induced by cerebral ischemia. We performed in vivo PET imaging with [(18)F]DPA-714 to determine the time course of PBR/TSPO expression over several days after induction of cerebral ischemia in rats. In vivo PET imaging showed significant increase in DPA (N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) uptake on the injured side compared with that in the contralateral area on days 7, 11, 15, and 21 after ischemia; the maximal binding value was reached 11 days after ischemia. In vitro autoradiography confirmed these in vivo results. In vivo and in vitro [(18)F]DPA-714 binding was displaced from the lesion by PK11195 and DPA-714. Immunohistochemistry showed increased PBR/TSPO expression, peaking at day 11 in cells expressing microglia/macrophage antigens in the ischemic area. At later times, a centripetal migration of astrocytes toward the lesion was observed, promoting the formation of an astrocytic scar. These results show that [(18)F]DPA-714 provides accurate quantitative information of the time course of PBR/TSPO expression in experimental stroke.

Imaging the role of toll-like receptor 4 on cell proliferation and inflammation after cerebral ischemia by positron emission tomography

“…17 Likewise, it has been shown that 45% of the total number of BrdU positive cells in infarcted zone after stroke corresponds to reactive microglia 18 and that TSPO expression has also been attributed to the activation of microglia/infiltrated macrophages following cerebral ischemia. 2 Indeed, our results confirmed the TSPO expression in microglial cells in both TRL4…”

“…Besides, the present study showed a relatively earlier TSPO overexpression in comparison to previous studies. 2,11,19,20 These differences may be related to differential pattern of leukocyte infiltration depending on the mice model of cerebral ischemia used. 21 According to this study, mice subjected to permanent MCAO showed both an earlier and extensive neuroinflammatory reaction than mice subjected to transient models of MCAO.…”

Reactive Astrocytes Overexpress TSPO and Are Detected by TSPO Positron Emission Tomography Imaging

“…However, using a model of hippocampal neurotoxicity, a landmark study reported that reactive astrocytes also overexpress TSPO and could contribute to TSPO radioligand binding ex vivo (Kuhlmann and Guilarte, 2000). This was later confirmed in other models (Chen et al, 2004;Chen and Guilarte, 2006;Maeda et al, 2007;Martín et al, 2010), but to our knowledge, only two in vivo studies have reported that reactive astrocytes overexpress TSPO to levels detectable by PET imaging (Rojas et al, 2007;Ji et al, 2008). However, the models used (middle cerebral artery occlusion and cuprizone intoxication) induce complex pathological effects, such as blood-brain barrier alteration, neuronal death, demyelination, and some levels of microglia activation.…”

“…18 F]DPA-714 has been mainly evaluated and quantified in rat models of excitotoxicity (Chauveau et al, 2009) and cerebral ischemia (Martín et al, 2010), whereas [ 11 C]SSR180575 has only been evaluated once in a rat model of excitotoxicity (Chauveau et al, 2011). In addition, [ 18 F]DPA-714 was studied in the healthy primate and displayed marked uptake in TSPOrich organs and specific binding in the brain as demonstrated using PK11195 .…”

Visualizing Cell Death in Experimental Focal Cerebral Ischemia: Promises, Problems, and Perspectives

“…Compared with MRI, nuclear imaging techniques such as PET or SPECT are by far less prevalent in experimental stroke research (Hsia et al, 2010;Martin et al, 2010;Rueger et al, 2010;Seo et al, 2007;Tang et al, 2007;Yui et al, 2011). The literature on the use of noninvasive fluorescence imaging (NFI) is also rare, primarily because of the depth limit of the method.…”