In vivo imaging of cannabinoid type 2 receptors, functional and structural alterations in mouse model of cerebral ischemia by PET and MRI

Abstract

Abstract Background and purpose Brain ischemia is one of the most important pathologies of the central nervous system. Non-invasive molecular imaging methods have the potential to provide critical insights into the temporal dynamics and follow alterations of receptor expression and metabolism in ischemic stroke. The aim of this study was to assess the cannabinoid type 2 receptors (CB 2 R) levels in transient middle cerebral artery occlusion (tMCAO) mouse models at subacute stage using positron emission tomography (PET) with our novel tracer [ 18 F]RoSMA-18-d6, and structural imaging by magnetic resonance imaging (MRI). Methods Our recently developed CB 2 R PET tracer [ 18 F]RoSMA-18-d6 was used for imaging the neuroinflammation at 24 h after reperfusion in tMCAO mice. The RNA expression levels of CB 2 R and other inflammatory markers were analyzed by quantitative real-time polymerase chain reaction using brain tissues from tMCAO (1 h occlusion) and sham-operated mice. [ 18 F]fluorodeoxyglucose (FDG) was included for evaluation of the cerebral metabolic rate of glucose (CMRglc). In addition, diffusion-weighted imaging and T 2 -weighted imaging were performed for anatomical reference and delineating the lesion in tMCAO mice. Results mRNA expressions of inflammatory markers TNF-α , Iba1, MMP9 and GFAP, CNR2 were increased at 24 h after reperfusion in the ipsilateral compared to contralateral hemisphere of tMCAO mice, while mRNA expression of the neuronal marker MAP-2 was markedly reduced. Reduced [ 18 F]FDG uptake was observed in the ischemic striatum of tMCAO mouse brain at 24 h after reperfusion. Although higher activity of [ 18 F]RoSMA-18-d6 in ex-vivo biodistribution studies and higher standard uptake value ratio (SUVR) were detected in the ischemic ipsilateral compared to contralateral striatum in tMCAO mice, the in-vivo specificity of [ 18 F]RoSMA-18-d6 was confirmed only in the CB 2 R-rich spleen. Conclusions This study revealed an increased [ 18 F]RoSMA-18-d6 measure of CB 2 R and a reduced [ 18 F]FDG measure of CMRglc in ischemic striatum of tMCAO mice at subacute stage. [ 18 F]RoSMA-18-d6 might be a promising PET tracer for detecting CB 2 R alterations in animal models of neuroinflammation without neuronal loss.