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

Boyle, Amanda J.; Tong, Junchao; Zoghbi, Sami S.; Pike, Victor W.; Innis, Robert B.; Vasdev, Neil

doi:10.2967/jnumed.120.249367

Cited by 5 publications

(9 citation statements)

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“…Additional proof for the target specificity of [ 11 C]PS13 was acquired in a PET study in mice bearing ovarian cancer xenografts (Boyle et al., 2021). COX‐1 overexpression in ovarian cancer is associated with tumor progression (Malerba et al., 2020).…”

Section: Resultsmentioning

confidence: 99%

“…ICRscid mice with xenografts were scanned at baseline and after pretreatment with 2 mg of ketoprofen in 20 µl dimethylsulfoxide (i.p). The tracer could visualize all tumors, and tumor uptake was 2.7‐fold decreased after pretreatment with ketoprofen, which indicated significant engagement of [ 11 C]PS13 with its COX‐1 target (Boyle et al., 2021).…”

Section: Resultsmentioning

confidence: 99%

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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%

Section: Resultsmentioning

confidence: 99%

Is cyclooxygenase‐1 involved in neuroinflammation?

Ghazanfari

Waarde

Dierckx

et al. 2021

J of Neuroscience Research

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“…PET/MR image acquisition and analysis were performed as previously described [9]. Tumor-bearing mice were anesthetized by isoflurane in O 2 (4 %, 2 l/min induction; 1-2 %, 1 l/min maintenance) for lateral tail-vein catheterization then transferred to a nanoScan™ PET/MRI 3T scanner (Mediso).…”

Section: Dynamic Pet/mr Imaging and Biodistribution Studiesmentioning

confidence: 99%

“…Description of the radiochemical synthesis of [ 11 C]MC1 is available in Supplementary Material [9,15].…”

Section: Radiosynthesismentioning

confidence: 99%

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Repurposing [11C]MC1 for PET Imaging of Cyclooxygenase-2 in Colorectal Cancer Xenograft Mouse Models

et al. 2021

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Cyclooxygenase-2 (COX-2) is a target for inflammation and colorectal cancer (CRC). This study evaluated the COX-2 neuro-PET radiopharmaceutical, [ 11 C]MC1, in CRC xenograft mice. Procedures: [ 11 C]MC1 was evaluated in ICRscid mice with HT-29 and HCT-116 CRC xenografts, with high and low COX-2 expression, respectively, by immunohistochemistry, cellular uptake, dynamic PET/MR imaging, ex vivo biodistribution, and radiometabolite analysis. Results: HT-29 xenografts were well visualized with [ 11 C]MC1 using PET/MR. Time-activity curves revealed steady tumor radioactivity accumulation in HT-29 xenografts that plateaued from 40 to 60 min (3.07 ± 0.65 %ID/g) and was significantly reduced by pre-treatment with MC1 or celecoxib (1.62 ± 0.29 and 1.18 ± 0.21 %ID/g, respectively, p = 0.045 and p = 0.005). Radiometabolite analysis showed that [ 11 C]MC1 accounted for >90 % of tumor radioactivity, with <10 % in plasma, at 40 min post-injection of the radiotracer. Conclusions: [ 11 C]MC1 is a promising PET imaging agent for COX-2 in CRC and translation for cancer research should be considered.

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Synthesis of [¹⁸F]PS13 and Evaluation as a PET Radioligand for Cyclooxygenase-1 in Monkey

Taddei

Morse

Kim

et al. 2021

ACS Chem. Neurosci.

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Cyclooxygenase-1 (COX-1) and its isozyme COX-2 are key enzymes in the syntheses of prostanoids. Imaging of COX-1 and COX-2 selective radioligands with positron emission tomography (PET) may clarify how these enzymes are involved in inflammatory conditions and assist in the discovery of improved anti-inflammatory drugs. We have previously labeled the selective high-affinity COX-1 ligand, 1,5-bis(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-1,2,4-triazole (PS13), with carbon-11 (t 1/2 = 20.4 min). This radioligand ([11C]PS13) has been successful for PET imaging of COX-1 in monkey and human brain and in periphery. [11C]PS13 is being used in clinical investigations. Alternative labeling of PS13 with fluorine-18 (t 1/2 = 109.8 min) is desirable to provide a longer-lived radioligand in high activity that might be readily distributed among imaging centers. However, labeling of PS13 in its 1,1,1-trifluoroethoxy group is a radiochemical challenge. Here we assess two labeling approaches based on nucleophilic addition of cyclotron-produced [18F]fluoride ion to gem-difluorovinyl precursors, either to label PS13 in one step or to produce [18F]2,2,2-trifluoroethyl p-toluenesulfonate for labeling a hydroxyl precursor. From the latter two-step approach, we obtained [18F]PS13 ready for intravenous injection in a decay-corrected radiochemical yield of 7.9% and with a molar activity of up to 7.9 GBq/μmol. PET imaging of monkey brain with [18F]PS13 shows that this radioligand can specifically image and quantify COX-1 without radiodefluorination but with some radioactivity uptake in skull, ascribed to red bone marrow. The development of a new procedure for labeling PS13 with fluorine-18 at a higher molar activity is, however, desirable to suppress occupancy of COX-1 by carrier at baseline.

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

Cited by 5 publications

References 23 publications

Is cyclooxygenase‐1 involved in neuroinflammation?

Is cyclooxygenase‐1 involved in neuroinflammation?

Repurposing [11C]MC1 for PET Imaging of Cyclooxygenase-2 in Colorectal Cancer Xenograft Mouse Models

Synthesis of [¹⁸F]PS13 and Evaluation as a PET Radioligand for Cyclooxygenase-1 in Monkey

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

Cited by 5 publications

References 23 publications

Is cyclooxygenase‐1 involved in neuroinflammation?

Is cyclooxygenase‐1 involved in neuroinflammation?

Repurposing [11C]MC1 for PET Imaging of Cyclooxygenase-2 in Colorectal Cancer Xenograft Mouse Models

Synthesis of [18F]PS13 and Evaluation as a PET Radioligand for Cyclooxygenase-1 in Monkey

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

Synthesis of [¹⁸F]PS13 and Evaluation as a PET Radioligand for Cyclooxygenase-1 in Monkey