First-in-human evaluation of [11C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in the brain

Kim, Min-Jeong; Lee, Jae Hoon; Anaya, Fernanda Juarez; Hong, Jinsoo; Miller, William H.; Telu, Sanjay; Singh, Prachi; Cortes, Michelle; Henry, Katharine; Tye, George; Frankland, Michael P.; Santamaria, Jose A. Montero; Liow, Jeih San; Zoghbi, Sami S.; Fujita, Masahiro; Pike, Victor W.; Innis, Robert B.

doi:10.1007/s00259-020-04855-2

Cited by 33 publications

(36 citation statements)

References 29 publications

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“…The hippocampus and occipital cortex showed the highest tracer uptake, followed by the pericentral cortex. A significant correlation was observed between COX‐1 mRNA levels provided by the Allen Human Brain Atlas and the regional distribution volumes of the tracer, suggesting that the regional uptake of [ 11 C]PS13 indeed reflected regional COX‐1 density in the human brain (Kim et al., 2020).…”

Section: Resultsmentioning

confidence: 99%

Is cyclooxygenase‐1 involved in neuroinflammation?

Ghazanfari

Waarde

Dierckx

et al. 2021

J of Neuroscience Research

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Purpose: Reactive microglia are an important hallmark of neuroinflammation. Reactive microglia release various inflammatory mediators, such as cytokines, chemokines, and prostaglandins, which are produced by enzymes like cyclooxygenases (COX). The inducible COX‐2 subtype has been associated with inflammation, whereas the constitutively expressed COX‐1 subtype is generally considered as a housekeeping enzyme. However, recent evidence suggests that COX‐1 can also be upregulated and may play a prominent role in the brain during neuroinflammation. In this review, we summarize the evidence that supports this involvement of COX‐1. Methods: Five databases were used to retrieve relevant studies that addressed COX‐1 in the context of neuroinflammation. The search resulted in 32 articles, describing in vitro, in vivo, post mortem, and in vivo imaging studies that specifically investigated the COX‐1 isoform under such conditions. Results: Reviewed literature generally indicated that the overexpression of COX‐1 was induced by an inflammatory stimulus, which resulted in an increased production of prostaglandin E2. The pharmacological inhibition of COX‐1 was shown to suppress the induction of inflammatory mediators like prostaglandin E2. Positron emission tomography (PET) imaging studies in animal models confirmed the overexpression of COX‐1 during neuroinflammation. The same imaging method, however, could not detect any upregulation of COX‐1 in patients with Alzheimer's disease. Conclusion: Taken together, studies in cultured cells and living rodents suggest that COX‐1 is involved in neuroinflammation. Most postmortem studies on human brains indicate that the concentration of COX‐1‐expressing microglial cells is increased near sites of inflammation. However, evidence for the involvement of COX‐1 in neuroinflammation in the living human brain is still largely lacking.

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Section: Resultsmentioning

confidence: 99%

Is cyclooxygenase‐1 involved in neuroinflammation?

Ghazanfari

Waarde

Dierckx

et al. 2021

J of Neuroscience Research

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“…[ 11 C]PS13 is the most potent and selective COX-1 inhibitor reported to date and has recently been translated for human PET studies of neuroinflammation (16). Repurposing this PET radiopharmaceutical to OvCa imaging can greatly accelerate the timeline for translation of a COX-1 radiopharmaceutical for oncology (22).…”

Section: Discussionmentioning

confidence: 99%

“…In OvCa, cyclooxygenase-1 (COX-1) overexpression is associated with poor prognosis, tumorigenesis, and tumor invasion (11)(12)(13). To our knowledge, the only COX-1-targeted PET imaging agent explored in preclinical oncology research is 18 PET radiopharmaceutical that is >200-fold more potent than [ 18 F]FDF, and has recently been translated for clinical neuroimaging research (15)(16)(17)(18). This study explores the potential of repurposing [ 11 C]PS13 in rodent models of OvCa via dynamic PET imaging, ex vivo biodistribution studies, and radiometabolite analysis.…”

Section: Introductionmentioning

confidence: 99%

Repurposing ¹¹C-PS13 for PET Imaging of Cyclooxygenase-1 in Ovarian Cancer Xenograft Mouse Models

et al. 2020

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Cyclooxygenase-1 (COX-1), a biomarker for neuroinflammation, is implicated in ovarian cancer (OvCa) progression and prognosis. This study considered the repurposing of [ 11 C]PS13, a COX-1 PET neuroimaging radiopharmaceutical, in OvCa xenograft mouse models. Methods: [ 11 C]PS13 was evaluated in ICRscid mice with s.c. or i.p. human OVCAR-3 OvCa xenografts by dynamic PET/MR imaging, ex vivo biodistribution and radiometabolite analysis of plasma and tumor. Results: OVCAR-3 xenografts were well visualized with [ 11 C]PS13 in xenograft mouse models.Time-activity curves revealed steady tumor radioactivity accumulation that plateaued from 40-60 min, and was significantly reduced by pre-treatment with ketoprofen (3.56 ± 0.81 and 1.30 ± 0.18 %ID/g, respectively, p=0.01). Radiometabolite analysis showed that intact [ 11 C]PS13 accounted for >80% of radioactivity in the tumor, with <20% in plasma, at 40 min post-injection.Conclusions: [ 11 C]PS13 shows promise for PET imaging COX-1 in OvCa and rapid translation for clinical cancer research should be considered.

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“…However, scans acquired post‐LPS treatment revealed significant up‐regulation of COX‐2 but not COX‐1 [ 126 , 127 ]. Nevertheless, [ 11 C]PS13 was evaluated in healthy humans, showing good test–retest reliability, and thus it would be interesting to investigate binding differences between healthy subjects and, for example, AD patients [ 129 ]. To provide a radiotracer with a longer half‐life, a [ 18 F]PS13 was developed, showing similar promising results in non‐human primates, however, optimization of the radiolabeling procedure is required to obtain [ 18 F]PS13 with sufficient molar activity [ 130 ].…”

Section: Introductionmentioning

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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First-in-human evaluation of [11C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in the brain

Cited by 33 publications

References 29 publications

Is cyclooxygenase‐1 involved in neuroinflammation?

Is cyclooxygenase‐1 involved in neuroinflammation?

Repurposing ¹¹C-PS13 for PET Imaging of Cyclooxygenase-1 in Ovarian Cancer Xenograft Mouse Models

Towards PET imaging of the dynamic phenotypes of microglia

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First-in-human evaluation of [11C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in the brain

Cited by 33 publications

References 29 publications

Is cyclooxygenase‐1 involved in neuroinflammation?

Is cyclooxygenase‐1 involved in neuroinflammation?

Repurposing 11C-PS13 for PET Imaging of Cyclooxygenase-1 in Ovarian Cancer Xenograft Mouse Models

Towards PET imaging of the dynamic phenotypes of microglia

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Product

Resources

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Repurposing ¹¹C-PS13 for PET Imaging of Cyclooxygenase-1 in Ovarian Cancer Xenograft Mouse Models