Dataset Information

¹¹C-DPA-713 Versus ¹⁸F-GE-180: A Preclinical Comparison of Translocator Protein 18 kDa PET Tracers to Visualize Acute and Chronic Neuroinflammation in a Mouse Model of Ischemic Stroke.

ABSTRACT: Neuroinflammation plays a key role in neuronal injury after ischemic stroke. PET imaging of translocator protein 18 kDa (TSPO) permits longitudinal, noninvasive visualization of neuroinflammation in both preclinical 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 2 promising second-generation TSPO tracers, ¹¹C-DPA-713 and ¹⁸F-GE-180, for the first time at acute and chronic time points after ischemic stroke. Methods: After distal middle cerebral artery occlusion or sham surgery, mice underwent consecutive PET/CT imaging with ¹¹C-DPA-713 and ¹⁸F-GE-180 at 2, 6, and 28 d after stroke. T2-weighted MR images were acquired to enable delineation of ipsilateral (infarct) and contralateral brain regions of interest (ROIs). PET/CT images were analyzed by calculating percentage injected dose per gram in MR-guided ROIs. SUV ratios were determined using the contralateral thalamus (SUV_Th) as a pseudoreference region. Ex vivo autoradiography and immunohistochemistry were performed to verify in vivo findings. Results: Significantly increased tracer uptake was observed in the ipsilateral compared with contralateral ROI (SUV_Th, 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 (cluster of differentiation 68 immunostaining) and ¹¹C-DPA-713- PET signal, which was not evident with ¹⁸F-GE-180. No significant correlations were observed between TSPO PET and activated astrocytes (glial fibrillary acidic protein immunostaining). Conclusion: ¹¹C-DPA-713 and ¹⁸F-GE-180 PET enable detection of neuroinflammation at acute and chronic time points after cerebral ischemia in mice. ¹¹C-DPA-713 PET reflects the extent of microglial activation in infarcted distal middle cerebral artery occlusion mouse brain tissue more accurately than 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 warrant further investigation in both preclinical and clinical settings.

SUBMITTER: Chaney A

PROVIDER: S-EPMC6354224 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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<sup>11</sup>C-DPA-713 Versus <sup>18</sup>F-GE-180: A Preclinical Comparison of Translocator Protein 18 kDa PET Tracers to Visualize Acute and Chronic Neuroinflammation in a Mouse Model of Ischemic Stroke.

Chaney Aisling A Cropper Haley C HC Johnson Emily M EM Lechtenberg Kendra J KJ Peterson Todd C TC Stevens Marc Y MY Buckwalter Marion S MS James Michelle L ML

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20180705 1

Neuroinflammation plays a key role in neuronal injury after ischemic stroke. PET imaging of translocator protein 18 kDa (TSPO) permits longitudinal, noninvasive visualization of neuroinflammation in both preclinical 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 pro ...[more]

PMID: 29976695

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Project description:PurposePET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO radioligand [11C]PK-11195 limits accurate quantification. [18F]GE-180, a novel TSPO ligand, displays superior binding to [11C]PK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of [18F]GE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures.MethodsTen volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of [18F]GE-180. Kinetic modelling of time-activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution (V T) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region.ResultsThe two-tissue compartment model was the best model. The average regional delivery rate constant (K 1) was 0.01 mL cm-3 min-1 indicating low extraction across the blood-brain barrier (1 %). The estimated median V T across all ROIs was also low, ranging from 0.16 mL cm-3 in the striatum to 0.38 mL cm-3 in the thalamus. There were no significant differences in V T between HABs and MABs across all ROIs.ConclusionA reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low V T estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of [18F]GE-180 in populations with neuroinflammatory disease is needed to determine its suitability for quantitative assessment of TSPO expression.

Project description:Purpose[18F]SF51 was previously found to have high binding affinity and selectivity for 18 kDa translocator protein (TSPO) in mouse brain. This study sought to assess the ability of [18F]SF51 to quantify TSPO in rhesus monkey brain.MethodsPositron emission tomography (PET) imaging was performed in monkey brain (n = 3) at baseline and after pre-blockade with the TSPO ligands PK11195 and PBR28. TSPO binding was calculated as total distribution volume corrected for free parent fraction in plasma (VT/fP) using a two-tissue compartment model. Receptor occupancy and nondisplaceable uptake were determined via Lassen plot. Binding potential (BPND) was calculated as the ratio of specific binding to nondisplaceable uptake. Time stability of VT was used as an indirect probe to detect radiometabolite accumulation in the brain. In vivo and ex vivo experiments were performed in mice to determine the distribution of the radioligand.ResultsAfter [18F]SF51 injection, the concentration of brain radioactivity peaked at 2.0 standardized uptake value (SUV) at ~ 10 min and declined to 30% of the peak at 180 min. VT/fP at baseline was generally high (203 ± 15 mL· cm-3) and decreased by ~ 90% after blockade with PK11195. BPND of the whole brain was 7.6 ± 4.3. VT values reached levels similar to terminal 180-min values by 100 min and remained relatively stable thereafter with excellent identifiability (standard errors < 5%), suggesting that no significant radiometabolites accumulated in the brain. Ex vivo experiments in mouse brain showed that 96% of radioactivity was parent. No significant uptake was observed in the skull, suggesting a lack of defluorination in vivo.ConclusionThe results demonstrate that [18F]SF51 is an excellent radioligand that can quantify TSPO with a good ratio of specific to nondisplaceable uptake and has minimal radiometabolite accumulation in brain. Collectively, the results suggest that [18F]SF51 warrants further evaluation in humans.

Dataset Information

¹¹C-DPA-713 Versus ¹⁸F-GE-180: A Preclinical Comparison of Translocator Protein 18 kDa PET Tracers to Visualize Acute and Chronic Neuroinflammation in a Mouse Model of Ischemic Stroke.

Publications

<sup>11</sup>C-DPA-713 Versus <sup>18</sup>F-GE-180: A Preclinical Comparison of Translocator Protein 18 kDa PET Tracers to Visualize Acute and Chronic Neuroinflammation in a Mouse Model of Ischemic Stroke.

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Dataset Information

11C-DPA-713 Versus 18F-GE-180: A Preclinical Comparison of Translocator Protein 18 kDa PET Tracers to Visualize Acute and Chronic Neuroinflammation in a Mouse Model of Ischemic Stroke.

Publications

<sup>11</sup>C-DPA-713 Versus <sup>18</sup>F-GE-180: A Preclinical Comparison of Translocator Protein 18 kDa PET Tracers to Visualize Acute and Chronic Neuroinflammation in a Mouse Model of Ischemic Stroke.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

¹¹C-DPA-713 Versus ¹⁸F-GE-180: A Preclinical Comparison of Translocator Protein 18 kDa PET Tracers to Visualize Acute and Chronic Neuroinflammation in a Mouse Model of Ischemic Stroke.