In vivo Imaging of Cannabinoid Type 2 Receptors: Functional and Structural Alterations in Mouse Model of Cerebral Ischemia by PET and MRI

Abstract

Purpose Stroke is one of the most prevalent vascular diseases. 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 receptor (CB2R) levels in transient middle cerebral artery occlusion (tMCAO) mouse models at subacute stage using positron emission tomography (PET) with our novel tracer [18F]RoSMA-18-d6 and structural imaging by magnetic resonance imaging (MRI). Procedures Our recently developed CB2R PET tracer [18F]RoSMA-18-d6 was used for imaging neuroinflammation at 24 h after reperfusion in tMCAO mice. The RNA expression levels of CB2R 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. [18F]fluorodeoxyglucose (FDG) was included for evaluation of the cerebral metabolic rate of glucose (CMRglc). In addition, diffusion-weighted imaging and T2-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 to 1.3–2.5 fold 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 to ca. 50 %. Reduced [18F]FDG uptake was observed in the ischemic striatum of tMCAO mouse brain at 24 h after reperfusion. Although higher activity of [18F]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 [18F]RoSMA-18-d6 was confirmed only in the CB2R-rich spleen. Conclusions This study revealed an increased [18F]RoSMA-18-d6 measure of CB2R and a reduced [18F]FDG measure of CMRglc in the ischemic striatum of tMCAO mice at subacute stage. [18F]RoSMA-18-d6 might be a promising PET tracer for detecting CB2R alterations in animal models of neuroinflammation without neuronal loss.

Positron Emission Tomography in Animal Models of Tauopathies

“…Imaging microglia activation and astrocytosis: There is a lack of imaging tracers for detecting the dynamic phenotypes of microglia, especially the disease-associated microglia with more specific cellular location and activation status (proinflammatory/anti-inflammatory). Several promising targets are currently under investigation such as purinergic P2X7 receptors, P2Y12 receptors ( Beaino et al, 2017 , 2020 ; Van Weehaeghe et al, 2020 ), cyclooxygenase-1 and cyclooxygenase-2 ( Ohnishi et al, 2014 , 2016 ; Shukuri et al, 2016 ), macrophage colony-stimulating factor 1 receptor ( Horti et al, 2019 ; Zhou X. et al, 2021 ), cannabinoid receptor type 2 ( Savonenko et al, 2015 ; Ni et al, 2019 , 2021a ), imidazoline-2 binding sites, and receptor for advanced glycation end products ( Cary et al, 2016 ; Luzi et al, 2020 ). Recent studies highlighted the role of astrocyte in tau pathology and the associated neurodegeneration ( Bussian et al, 2018 ; Ferrer et al, 2018 ; Richetin et al, 2020 ; Maté de Gérando et al, 2021 ; Wang C. et al, 2021 ; Wang and Ye, 2021 ).…”

“…Several promising targets are currently under investigation such as purinergic P2X7 receptors, P2Y12 receptors (Beaino et al, 2017(Beaino et al, , 2020Van Weehaeghe et al, 2020), cyclooxygenase-1 and cyclooxygenase-2 (Ohnishi et al, 2014(Ohnishi et al, , 2016Shukuri et al, 2016), macrophage colonystimulating factor 1 receptor (Horti et al, 2019;, cannabinoid receptor type 2 (Savonenko et al, 2015;Ni et al, 2019Ni et al, , 2021a, imidazoline-2 binding sites, and receptor for advanced glycation end products (Cary et al, 2016;Luzi et al, 2020). Recent studies highlighted the role of astrocyte in tau pathology and the associated neurodegeneration (Bussian et al, 2018;Ferrer et al, 2018;Richetin et al, 2020;Maté de Gérando et al, 2021;Wang C. et al, 2021;Wang and Ye, 2021).…”

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

“…PET using various 18 kDa translocator protein (TSPO) tracers have demonstrated an early microgliosis preceding the Aβ deposition in several animal models of amyloidosis including APP23, hAPP-J20, APPSL70, App NL-G-F and PS2APP mice [184,[192][193][194][195][196][197]. Due to the diverse cellular location of TSPO expression on astrocytes and endothelial cells in addition to that on microglia, tracers specific for microglial expression and of disease-associated profile are of high interest [198][199][200].…”

Evaluation of CB2R expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

“…The aim of the current study was to assess the alterations in CB 2 R and distribution in the brain of the arcAβ mouse model of AD amyloidosis and to evaluate the recently developed pyridine-derived CB 2 R tracers [ 11 C]RS-028, [ 18 F]RoSMA-18-d6 and [ 11 C]RSR-056, which exhibit subnanomolar affinity and high selectivity towards CB 2 R [40].…”

“…]RoSMA-18-d6 (affinity Ki = 0.8 nM, CB 2 R/CB 1 R > 12000), [ 11 C]RSR-056 and [ 11 C]RS-028 were synthesized and purified as described previously[40] and formulated with 5% ethanol in water. The molar activities were 156-194 GBq/μmol, 52.3 GBq/μmol, and 86.7-178 GBq/μmol for [18 F]RoSMA-18-d6, [ 11 C]RSR-056, and [ 11 C]RS-028, respectively.…”