Synthesis and evaluation of NLRP3-inhibitory sulfonylurea [11C]MCC950 in healthy animals

Hill, J. R.; Shao, Xia; Massey, Nicholas L.; Stauff, Jenelle; Sherman, Phillip; Robertson, Avril A. B.; Scott, Peter J. H.

doi:10.1016/j.bmcl.2020.127186

Cited by 17 publications

(11 citation statements)

References 33 publications

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“…The commonly used dose in these studies was 10 mg/kg, relatively high compared to its low nanomolar potency. Recent studies of radio-labeled MCC950 PET tracer demonstrate its low CNS penetration, which may limit its development and use as a CNS agent (Hill et al, 2020).…”

Section: Mcc950mentioning

confidence: 99%

The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases

Blevins

Biby

et al. 2022

Front. Aging Neurosci.

205

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The NLRP3 inflammasome is a multiprotein complex that plays a pivotal role in regulating the innate immune system and inflammatory signaling. Upon activation by PAMPs and DAMPs, NLRP3 oligomerizes and activates caspase-1 which initiates the processing and release of pro-inflammatory cytokines IL-1β and IL-18. NLRP3 is the most extensively studied inflammasome to date due to its array of activators and aberrant activation in several inflammatory diseases. Studies using small molecules and biologics targeting the NLRP3 inflammasome pathway have shown positive outcomes in treating various disease pathologies by blocking chronic inflammation. In this review, we discuss the recent advances in understanding the NLRP3 mechanism, its role in disease pathology, and provide a broad review of therapeutics discovered to target the NLRP3 pathway and their challenges.

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Section: Mcc950mentioning

confidence: 99%

The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases

Blevins

Biby

et al. 2022

Front. Aging Neurosci.

205

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“…CRID3/MCC950 (Figure 2), the best-known and prevalently applied NLRP3 inflammasome inhibitor, constitutes a sulfonylurea with a hexahydro-s-indacen-4-yl group at the terminal nitrogen and a furan moiety at the sulfur atom (Vande Walle et al, 2019;Chauhan et al, 2020;Wu et al, 2020). 11 C-labeled CRID3/MCC950 was developed for non-invasive PET imaging studies (Hill et al, 2020a). CRID3/MCC950 was chosen as the template for the NLRP3 binding moiety for all of our probes.…”

Section: Resultsmentioning

confidence: 99%

Development of Fluorescent and Biotin Probes Targeting NLRP3

et al. 2021

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Extracellular signals drive the nucleation of the NLRP3 inflammasome which leads to the release of cytokines and causes inflammatory events. Hence, the inflammasome has gained enormous momentum in biomedical basic research. The detailed mechanisms of inflammasome generation and regulation remain to be elucidated. Our study was directed toward the design, convergent synthesis, and initial biochemical evaluation of activity-based probes addressing NLRP3. For this purpose, probes were assembled from a CRID3/MCC950-related NLRP3-binding unit, a linker portion and a coumarin 343 fluorophore or biotin. The affinity of our probes to NLRP3 was demonstrated through SPR measurements and their cellular activity was confirmed by reduction of the interleukin 1β release from stimulated bone marrow-derived macrophages. The initial characterizations of NLRP3-targeting probes highlighted the coumarin probe 2 as a suitable tool compound for the cellular and biochemical analysis of the NLRP3 inflammasome.

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“…In 2020, [ 11 C] 107 ([ 11 C]MCC950) was disclosed as the first potential NLRP3 PET radioligand, with a favorable binding affinity (IC 50 = 8 nM) (Figure ). However, PET imaging studies indicated no brain uptake and rapid washout in several species, such as mice (SUV max = 0.06), rats (SUV max = 0.06), and rhesus monkeys (SUV max = 0.48), impeding its further investigation. Soon after, another radioligand [ 11 C] 108 was prepared and evaluated in mice .…”

Section: Emerging Biological Targets In Neuroinflammatory Processes F...mentioning

confidence: 99%

The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO

et al. 2021

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Neuroinflammation is an adaptive response of the central nervous system to diverse potentially injurious stimuli, which is closely associated with neurodegeneration and typically characterized by activation of microglia and astrocytes. As a noninvasive and translational molecular imaging tool, positron emission tomography (PET) could provide a better understanding of neuroinflammation and its role in neurodegenerative diseases. Ligands to translator protein (TSPO), a putative marker of neuroinflammation, have been the most commonly studied in this context, but they suffer from serious limitations. Herein we present a repertoire of different structural chemotypes and novel PET ligand design for classical and emerging neuroinflammatory targets beyond TSPO. We believe that this Perspective will support multidisciplinary collaborations in academic and industrial institutions working on neuroinflammation and facilitate the progress of neuroinflammation PET probe development for clinical use.

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Synthesis and evaluation of NLRP3-inhibitory sulfonylurea [11C]MCC950 in healthy animals

Cited by 17 publications

References 33 publications

The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases

The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases

Development of Fluorescent and Biotin Probes Targeting NLRP3

The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO

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