Dataset Information

The 18-kDa Translocator Protein PET Tracers as a Diagnostic Marker for Neuroinflammation: Development and Current Standing.

ABSTRACT: Translocator protein (TSPO, 18 kDa) is an evolutionary, well-preserved, and tryptophan-rich 169-amino-acid protein which localizes on the contact sites between the outer and inner mitochondrial membranes of steroid-synthesizing cells. This mitochondrial protein is implicated in an extensive range of cellular activities, including steroid synthesis, cholesterol transport, apoptosis, mitochondrial respiration, and cell proliferation. The upregulation of TSPO is well documented in diverse disease conditions including neuroinflammation, cancer, brain injury, and inflammation in peripheral organs. On the basis of these outcomes, TSPO has been assumed to be a fascinating subcellular target for early stage imaging of the diseased state and for therapeutic purposes. The main outline of this Review is to give an update on dealing with the advances made in TSPO PET tracers for neuroinflammation, synchronously emphasizing the approaches applied for the design and advancement of new tracers with reference to their structure-activity relationship (SAR).

SUBMITTER: Singh P

PROVIDER: S-EPMC9089361 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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The 18-kDa Translocator Protein PET Tracers as a Diagnostic Marker for Neuroinflammation: Development and Current Standing.

Singh Priya P Adhikari Anupriya A Singh Deepika D Gond Chandraprakash C Tiwari Anjani Kumar AK

ACS omega 20220418 17

Translocator protein (TSPO, 18 kDa) is an evolutionary, well-preserved, and tryptophan-rich 169-amino-acid protein which localizes on the contact sites between the outer and inner mitochondrial membranes of steroid-synthesizing cells. This mitochondrial protein is implicated in an extensive range of cellular activities, including steroid synthesis, cholesterol transport, apoptosis, mitochondrial respiration, and cell proliferation. The upregulation of TSPO is well documented in diverse disease c ...[more]

PMID: 35557664

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Project description: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 (SUVTh) 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 (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 (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.

Project description:UnlabelledTranslocator protein (TSPO) (18 kDa), formerly called the peripheral benzodiazepine receptor, is upregulated on activated microglia and macrophages and is, thus, a biomarker of inflammation. We previously reported that an (11)C-labeled aryloxyanilide (half-life, 20 min) was able to quantify TSPOs in the healthy human brain. Because many PET centers would benefit from a longer-lived (18)F-labeled radioligand (half-life, 110 min), the objective of this study was to evaluate the ability of a closely related aryloxyanilide ((18)F-N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline [(18)F-PBR06]) to quantify TSPOs in the healthy human brain.MethodsA total of 9 human subjects were injected with (18)F-PBR06 (approximately 185 MBq) and scanned for 5 h, with rest periods outside the camera. The concentrations of (18)F-PBR06, separated from radiometabolites, were measured in arterial plasma.ResultsModeling of regional brain and plasma data showed that a 2-tissue-compartment model was superior to a 1-tissue-compartment model. Even if data for all time points were used for the fitting, concentrations of brain activity measured with PET were consistently greater than the modeled values at late (280-300 min) but not at early time points. The greater values may have been caused by the slow accumulation of radiometabolites in the brain. To determine an adequate time for more accurate measurement of distribution volume (V(T)), which is the summation of receptor binding and nondisplaceable activity, we investigated which scan duration would be associated with maximal or near-maximal identifiability. We found that a scan of 120 min provided the best identifiability of V(T) (approximately 2%). The images showed no significant defluorination.Conclusion(18)F-PBR06 can quantify TSPOs in the healthy human brain using 120 min of image acquisition and concurrent measurements of radioligand in plasma. Although brain activity is likely contaminated with radiometabolites, the percentage contamination is thought to be small (<10%), because values of distribution volume are stable during 60-120 min and vary by less than 10%. (18)F-PBR06 is a longer-lived and promising alternative to (11)C-labeled radioligands to measure TSPOs as a biomarker of inflammation in the brain.

Dataset Information

The 18-kDa Translocator Protein PET Tracers as a Diagnostic Marker for Neuroinflammation: Development and Current Standing.

Publications

The 18-kDa Translocator Protein PET Tracers as a Diagnostic Marker for Neuroinflammation: Development and Current Standing.

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