Synthesis and Initial In Vivo Evaluation of [11C]AZ683—A Novel PET Radiotracer for Colony Stimulating Factor 1 Receptor (CSF1R)

Tanzey, Sean; Shao, Xia; Stauff, Jenelle; Arteaga, Janna; Sherman, Phillip; Scott, Peter J. H.; Mossine, Andrew V.

doi:10.3390/ph11040136

Cited by 29 publications

(31 citation statements)

References 33 publications

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“…[ 11 C]5 showed high specific binding in vitro, but selectivity for CSF-1R was limited [123]. In healthy rats, [ 11 C]5 did not cross the showed low brain uptake and retention in both rats and non-human primates [114], but [ 11 C]CPPC showed increased tracer uptake in mouse and baboon brains after LPS-induced neuroinflammation [115]. Transgenic AD and EAE mice also showed an increase in PET signal, which correlated with disease severity in the EAE mice.…”

Section: Colony Stimulating Factor 1 Receptor (Csf-1r)mentioning

confidence: 99%

Towards PET imaging of the dynamic phenotypes of microglia

Beaino

Janssen

Vugts

et al. 2021

Clinical and Experimental Immunology

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There is increasing evidence showing the heterogeneity of microglia activation in neuroinflammatory and neurodegenerative diseases. It has been hypothesized that pro-inflammatory microglia are detrimental and contribute to disease progression, while anti-inflammatory microglia play a role in damage repair and remission. The development of therapeutics targeting the deleterious glial activity and modulating it into a regenerative phenotype relies heavily upon a clearer understanding of the microglia dynamics during disease progression and the ability to monitor therapeutic outcome in vivo. To that end, molecular imaging techniques are required to assess microglia dynamics and study their role in disease progression as well as to evaluate the outcome of therapeutic interventions. Positron emission tomography (PET) is such a molecular imaging technique, and provides unique capabilities for noninvasive quantification of neuroinflammation and has the potential to discriminate between microglia phenotypes and define their role in the disease process. However, several obstacles limit the possibility for selective in vivo imaging of microglia phenotypes mainly related to the poor characterization of specific targets that distinguish the two ends of the microglia activation spectrum and lack of suitable tracers. PET tracers targeting translocator protein 18 kDa (TSPO) have been extensively explored, but despite the success in evaluating neuroinflammation they failed to discriminate

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Section: Colony Stimulating Factor 1 Receptor (Csf-1r)mentioning

confidence: 99%

Towards PET imaging of the dynamic phenotypes of microglia

Beaino

Janssen

Vugts

et al. 2021

Clinical and Experimental Immunology

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“…Genetic and pharmacological strategies to eliminate or reduce CSF1R kinase activity, and thus decrease microglial proliferation, have been shown to promote beneficial effects in preclinical models of AD, ALS, tauopathies, and MS (Asai et al, 2015;Bruttger et al, 2015;Dagher et al, 2015;Borjini et al, 2016;Martínez-Muriana et al, 2016;Olmos-Alonso et al, 2016;Spangenberg et al, 2016Spangenberg et al, , 2019El-Gamal et al, 2018;Elmore et al, 2018;Sosna et al, 2018;Spiller et al, 2018;Mancuso et al, 2019;Zhong et al, 2019). Of note, a number of PET tracers have recently been developed to monitor response to CSF1R inhibitors which we believe reflects the broad level of interest in this mechanism (Tanzey et al, 2018;Horti et al, 2019;Janssen and Mach, 2019;Mason et al, 2019). Colony stimulating factor 1 receptor has two known ligands, CSF1 (colony stimulating factor 1) which is also expressed in microglia and IL-34 predominantly expressed in neurons (Lin et al, 2008;Wei et al, 2010;Mizuno et al, 2011;Nandi et al, 2012;Wang et al, 2012;Chitu et al, 2016).…”

Section: Csf1r (Colony Stimulating Factor 1 Receptor)mentioning

confidence: 99%

Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease

Benn¹,

Dawson

2020

Front. Aging Neurosci.

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Kinases are an intensively studied drug target class in current pharmacological research as evidenced by the large number of kinase inhibitors being assessed in clinical trials. Kinase-targeted therapies have potential for treatment of a broad array of indications including central nervous system (CNS) disorders. In addition to the many variables which contribute to identification of a successful therapeutic molecule, drug discovery for CNS-related disorders also requires significant consideration of access to the target organ and specifically crossing the blood-brain barrier (BBB). To date, only a small number of kinase inhibitors have been reported that are specifically designed to be BBB permeable, which nonetheless demonstrates the potential for success. This review considers the potential for kinase inhibitors in the context of unmet medical need for neurodegenerative disease. A subset of kinases that have been the focus of clinical investigations over a 10-year period have been identified and discussed individually. For each kinase target, the data underpinning the validity of each in the context of neurodegenerative disease is critically evaluated. Selected molecules for each kinase are identified with information on modality, binding site and CNS penetrance, if known. Current clinical development in neurodegenerative disease are summarized. Collectively, the review indicates that kinase targets with sufficient rationale warrant careful design approaches with an emphasis on improving brain penetrance and selectivity.

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“…However, 11 C-CPPC binding is increased in whole brain regions, and is not limited to regions with lesions as exemplified by cerebellum in AD model and intracranial LPS injection model, and immunohistochemistry for active microglia and CSF1R expression to support imaging results was not provided. Another reported CSF1R imaging tracer, 11 C-AZ683, showed high affinity for CSF1R (Ki = 8 nM) and >250-fold selectivity over other kinases tested, but low brain uptake in rodents and nonhuman primates limited its utility in living brains [ 89 ]. Further examinations and improvements will be required for their clinical application.…”

Section: Alternative Molecular Targets For Microglia Imagingmentioning

confidence: 99%

Basic Science of PET Imaging for Inflammatory Diseases

Kubota

Ogawa

et al. 2019

PET/CT for Inflammatory Diseases

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FDG-PET/CT has recently emerged as a useful tool for the evaluation of inflammatory diseases too, in addition to that of malignant diseases. The imaging is based on active glucose utilization by inflammatory tissue. Autoradiography studies have demonstrated high FDG uptake in macrophages, granulocytes, fibroblasts, and granulation tissue. Especially, activated macrophages are responsible for the elevated FDG uptake in some types of inflammation. According to one study, after activation by lipopolysaccharide of cultured macrophages, the [ 14 C]2DG uptake by the cells doubled, reaching the level seen in glioblastoma cells. In activated macrophages, increase in the expression of total GLUT1 and redistributions from the intracellular compartments toward the cell surface have been reported. In one rheumatoid arthritis model, following stimulation by hypoxia or TNF-α, the highest elevation of the [ 3 H]FDG uptake was observed in the fibroblasts, followed by that in macrophages and neutrophils. As the fundamental mechanism of elevated glucose uptake in both cancer cells and inflammatory cells, activation of glucose metabolism as an adaptive response to a hypoxic environment has been reported, with transcription factor HIF-1α playing a key role. Inflammatory cells and cancer cells seem to share the same molecular mechanism of elevated glucose metabolism, lending support to the notion of usefulness of FDGPET/CT for the evaluation of inflammatory diseases, besides cancer.

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Synthesis and Initial In Vivo Evaluation of [11C]AZ683—A Novel PET Radiotracer for Colony Stimulating Factor 1 Receptor (CSF1R)

Cited by 29 publications

References 33 publications

Towards PET imaging of the dynamic phenotypes of microglia

Towards PET imaging of the dynamic phenotypes of microglia

Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease

Basic Science of PET Imaging for Inflammatory Diseases

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