[18F]-DPA-714 PET as a specific in vivo marker of early microglial activation in a rat model of progressive dopaminergic degeneration

Rodríguez-Chinchilla, Tatiana; Quiroga-Varela, Ana; Molinet-Dronda, Francisco; Belloso-Iguerategui, Arantzazu; Merino-Galán, Leyre; Jiménez-Urbieta, Haritz; Gago, Belén; Rodriguez-Oroz, María C.

doi:10.1007/s00259-020-04772-4

Cited by 27 publications

(25 citation statements)

References 45 publications

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“…In addition, PET scans have demonstrated significantly increased levels of [11C] (R)-PK11195 binding in the pons, basal ganglia, and frontal and temporal cortical regions, thereby indicating the presence of extensive microglial activation. Furthermore, PET imaging reveals early and progressive dopaminergic deficits, and can be used to study the preclinical stages of PD and monitor the progression of the disease (22,23). A meta-analysis of antiinflammatory drugs used in clinical trials revealed a negative association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) with the risk of PD progression (24).…”

Section: Microglial Activation In Pdmentioning

confidence: 99%

Targeting Microglial α-Synuclein/TLRs/NF-kappaB/NLRP3 Inflammasome Axis in Parkinson’s Disease

et al. 2021

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According to emerging studies, the excessive activation of microglia and the subsequent release of pro-inflammatory cytokines play important roles in the pathogenesis and progression of Parkinson’s disease (PD). However, the exact mechanisms governing chronic neuroinflammation remain elusive. Findings demonstrate an elevated level of NLRP3 inflammasome in activated microglia in the substantia nigra of PD patients. Activated NLRP3 inflammasome aggravates the pathology and accelerates the progression of neurodegenerative diseases. Abnormal protein aggregation of α-synuclein (α-syn), a pathologically relevant protein of PD, were reported to activate the NLRP3 inflammasome of microglia through interaction with toll-like receptors (TLRs). This eventually releases pro-inflammatory cytokines through the translocation of nuclear factor kappa-B (NF-κB) and causes an impairment of mitochondria, thus damaging the dopaminergic neurons. Currently, therapeutic drugs for PD are primarily aimed at providing relief from its clinical symptoms, and there are no well-established strategies to halt or reverse this disease. In this review, we aimed to update existing knowledge on the role of the α-syn/TLRs/NF-κB/NLRP3 inflammasome axis and microglial activation in PD. In addition, this review summarizes recent progress on the α-syn/TLRs/NF-κB/NLRP3 inflammasome axis of microglia as a potential target for PD treatment by inhibiting microglial activation.

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Section: Microglial Activation In Pdmentioning

confidence: 99%

Targeting Microglial α-Synuclein/TLRs/NF-kappaB/NLRP3 Inflammasome Axis in Parkinson’s Disease

et al. 2021

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“…Nevertheless, the interplay between cytokines, neurodegeneration, and protein aggregation as cause or consequence remains largely unknown today [133,134,131]. Over the last two decades, neuroinflammation in PD has been a strongly growing research area, but only few TSPO-PET studies [135][136][137][138] or TSPOautoradiography [139][140][141] studies have been reported in preclinical models. In addition, these studies generally report on the feasibility of monitoring brain inflammation but less on the mechanistic of neuroinflammation in PD.…”

Section: Parkinson's Diseasementioning

confidence: 99%

TSPO imaging in animal models of brain diseases

Camp

Lavisse

Roost

et al. 2021

Eur J Nucl Med Mol Imaging

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Over the last 30 years, the 18-kDa TSPO protein has been considered as the PET imaging biomarker of reference to measure increased neuroinflammation. Generally assumed to image activated microglia, TSPO has also been detected in endothelial cells and activated astrocytes. Here, we provide an exhaustive overview of the recent literature on the TSPO-PET imaging (i) in the search and development of new TSPO tracers and (ii) in the understanding of acute and chronic neuroinflammation in animal models of neurological disorders. Generally, studies testing new TSPO radiotracers against the prototypic [11C]-R-PK11195 or more recent competitors use models of acute focal neuroinflammation (e.g. stroke or lipopolysaccharide injection). These studies have led to the development of over 60 new tracers during the last 15 years. These studies highlighted that interpretation of TSPO-PET is easier in acute models of focal lesions, whereas in chronic models with lower or diffuse microglial activation, such as models of Alzheimer’s disease or Parkinson’s disease, TSPO quantification for detection of neuroinflammation is more challenging, mirroring what is observed in clinic. Moreover, technical limitations of preclinical scanners provide a drawback when studying modest neuroinflammation in small brains (e.g. in mice). Overall, this review underlines the value of TSPO imaging to study the time course or response to treatment of neuroinflammation in acute or chronic models of diseases. As such, TSPO remains the gold standard biomarker reference for neuroinflammation, waiting for new radioligands for other, more specific targets for neuroinflammatory processes and/or immune cells to emerge.

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“…Labeled with 18 F, 18 F-DPA-714 has a longer half-time (110 min) than 11 C-PK11195 (20 min). It is widely used in TSPO PET imaging to dynamically monitor the brain in ammatory response and disease progression, and showed improved bioavailability, lower nonspeci c binding, and higher nondisplaceable binding potential (BP ND ) [13,14]. Clinical studies using 18 F-DPA-714 have been performed on patients with ALS [15] [16], AD [16] [17], as well as in post-stroke studies [18], with great promise demonstrated in neuroimaging studies.…”

Section: Introductionmentioning

confidence: 99%

“…Although TSPO PET imaging has been performed in a variety of neuroin ammatory diseases, it still has some drawbacks, including relatively low neuroin ammatory uptake, low SNR and insensitivity to the small variance of TSPO expression when quanti ed with the semi-quantitative parameters (%ID/cc or SUV) [26]. In order to overcome these limitations, macro parameters like V T , BP ND and DVR were often introduced to TSPO imaging, with the aim to fully characterize radiotracer pharmacokinetics, TSPO expression level, as well as to increase SNR and to improve imaging visual effects [13] [26][27][28][29]. In practice, radiotracers featuring higher binding speci city often demonstrate higher macro parameter values (like BP ND ), higher SNR and thus better visual effects in PET imaging as well as the higher sensitivity to TSPO density variance.…”

Section: Introductionmentioning

confidence: 99%

18F-VUIIS1009B Features a Superior Imaging Performance to 18F-DPA-714 in TSPO Density Characterization for Neuroinflammatory PET Imaging

Huang¹,

Fan²,

Hao³

et al. 2020

Preprint

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Abstract Purpose Translocator protein (TSPO), an out-mitochondrial membrane protein, is regarded as a key biomarker for neuroinflammation in a variety of neurodegenerative diseases. In this study, we aim to evaluate two highly specific TSPO radiotracers 18F-VUIIS1009A and 18F-VUIIS1009B in a mild cerebral ischemic rat model, and to compare their in vivo performance to the well-established TSPO probe 18F-DPA-714 for neuroinflammation imaging. With multiple graphic analytical methods tested and macro parameters determined, we propose to find a suitable and best quantification method to profile neuroinflammation and measure TSPO density with the three TSPO radiotracers. Methods Cerebral ischemia rat model was created and imaged using 18F-VUIIS1009A, 18F-VUIIS1009B and 18F-DPA-714. Displacement studies using cold analogs were performed to evaluate the binding specificities of 18F-VUIIS1009A and 18F-VUIIS1009B individually. Imaging analysis using arterial plasma input functions (AIFs) was employed to generate Logan plots and parametric images of total distribution volume (VT) for each radiotracer. Reference Logan model using healthy brain as a reference region was introduced to generate parametric images for binding potential (BPND). Results When compared to 18F-DPA-714, 18F-VUIIS1009B demonstrated higher in vitro binding specificity, binding potential (BPND) and distribution volume ratio (DVR). Parameter images of BPND and VT also indicate 18F-VUIIS1009B has a superior imaging profile when compared with other two radiotracers in TSPO imaging. Correlation analysis between BPND for 18F-VUIIS1009B and 18F-DPA-714 also indicates 18F-VUIIS1009B is more sensitive than 18F-DPA-714 in TSPO density measurement. Conclusions This study demonstrates the superiority of 18F-VUIIS1009B to 18F-VUIIS1009A and 18F-DPA-714 in the neuroinflammation imaging. It also demonstrates that 18F-VUIIS1009B PET imaging coupled with parameter mapping (VT and BPND) and graphic analysis holds great promise for neuroinflammation characterization and TSPO density measurement.

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[18F]-DPA-714 PET as a specific in vivo marker of early microglial activation in a rat model of progressive dopaminergic degeneration

Cited by 27 publications

References 45 publications

Targeting Microglial α-Synuclein/TLRs/NF-kappaB/NLRP3 Inflammasome Axis in Parkinson’s Disease

Targeting Microglial α-Synuclein/TLRs/NF-kappaB/NLRP3 Inflammasome Axis in Parkinson’s Disease

TSPO imaging in animal models of brain diseases

18F-VUIIS1009B Features a Superior Imaging Performance to 18F-DPA-714 in TSPO Density Characterization for Neuroinflammatory PET Imaging

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