¹¹C-DPA-713 versus ¹⁸F-GE-180: A preclinical comparison of TSPO-PET tracers to visualize acute and chronic neuroinflammation in a mouse model of ischemic stroke

Abstract

Neuroinflammation plays a key role in neuronal injury following ischemic stroke. Positron emission tomography (PET) imaging of translocator protein 18 kDa (TSPO) permits longitudinal, non-invasive visualization of neuroinflammation in both pre-clinical and clinical settings. Many TSPO tracers have been developed, however it is unclear which tracer is the most sensitive and accurate for monitoring the in vivo spatiotemporal dynamics of neuroinflammation across applications. Hence, there is a need for head-to-head comparisons of promising TSPO-PET tracers across different disease states. Accordingly, the aim of this study was to directly compare two promising second-generation TSPO tracers; ¹¹C-DPA-713 and ¹⁸F-GE-180, for the first time at acute and chronic time-points following ischemic stroke. Methods: Following distal middle cerebral artery occlusion (dMCAO) or sham surgery, mice underwent consecutive PET/CT imaging with ¹¹C-DPA-713 and ¹⁸F-GE-180 at 2, 6, and 28 days after stroke. T2-weighted magnetic resonance (MR) images were acquired to enable delineation of ipsilateral (infarct) and contralateral brain regions of interest (ROIs). PET images were analyzed by calculating % injected dose per gram (%ID/g) in MR-guided ROIs. Standardized uptake value ratios were determined using the contralateral thalamus as a pseudo-reference region (SUVTh). Ex vivo autoradiography and immunohistochemistry were performed to verify in vivo findings. Results: Significantly increased tracer uptake was observed in the ipsilateral compared to contralateral ROI (SUVTh, 50-60 min summed data) at acute and chronic time-points using ¹¹C-DPA-713 and ¹⁸F-GE-180. Ex vivo autoradiography confirmed in vivo findings demonstrating increased TSPO-tracer uptake in infarcted versus contralateral brain tissue. Importantly, a significant correlation was identified between microglial/macrophage activation (CD68 immunostaining) and ¹¹C-DPA-713-PET signal, that was not evident with ¹⁸F-GE-180. No significant correlations were observed between TSPO-PET and activated astrocytes (GFAP immunostaining). Conclusion: Both ¹¹C-DPA-713 and ¹⁸F-GE-180-PET enable detection of neuroinflammation at early and chronic time-points following cerebral ischemia in mice. ¹¹C-DPA-713-PET reflects the extent of microglial activation in infarcted dMCAO mouse brain tissue more accurately compared to ¹⁸F-GE-180, and appears to be slightly more sensitive. These results highlight the potential of ¹¹C-DPA-713 for tracking microglial activation in vivo after stroke, and warrants further investigation in both pre-clinical and clinical settings.