PET Quantification in Healthy Humans of Cyclooxygenase-2, a Potential Biomarker of Neuroinflammation
Cyclooxygenase-2 (COX-2) is present in a healthy brain at low densities but can be markedly upregulated by excitatory input and by inflammogens. This study evaluated the sensitivity of the PET radioligand [ C]-6-methoxy-2-(4-(methylsulfonyl)phenyl)- -(thiophen-2-ylmethyl)pyrimidin-4-amine ([ C]MC1)...
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| Vydané v: | The Journal of nuclear medicine (1978) Ročník 66; číslo 3; s. 398 |
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| Hlavní autori: | , , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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United States
01.03.2025
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| ISSN: | 1535-5667, 1535-5667 |
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| Abstract | Cyclooxygenase-2 (COX-2) is present in a healthy brain at low densities but can be markedly upregulated by excitatory input and by inflammogens. This study evaluated the sensitivity of the PET radioligand [
C]-6-methoxy-2-(4-(methylsulfonyl)phenyl)-
-(thiophen-2-ylmethyl)pyrimidin-4-amine ([
C]MC1) to detect COX-2 density in a healthy human brain.
The specificity of [
C]MC1 was confirmed using lipopolysaccharide-injected rats and transgenic mice expressing the human
gene, with 120-min baseline and blocked scans using COX-1 and COX-2 selective agents. Twenty-seven healthy participants were injected with [
C]MC1. Ten of these participants received 2 PET scans: a baseline study followed by blockade with celecoxib (600 mg orally), a preferential COX-2 inhibitor. Seventeen participants underwent test-retest imaging. All scans included concurrent arterial sampling. The tissue-to-plasma ratio at equilibrium (i.e., total distribution volume) was determined using a 2-tissue compartment model (2TCM).
In humanized transgenic COX-2 mice, 70%-90% of [
C]MC1 brain uptake was blocked by nonradioactive MC1 and celecoxib (a COX-2 selective inhibitor) but not by PS13 (a COX-1 selective inhibitor), thereby confirming specific binding to human COX-2. Radioactivity in the human brain peaked at a concentration of about 4.0 SUV, indicating good passage through the blood-brain barrier. Values for the total distribution volume achieved stability after 80 min, indicating no radiometabolite contamination. Celecoxib reduced radioligand binding in neocortical areas by 25% but had little or no effect in subcortical regions and the cerebellum, which correlated with COX-2 messenger RNA expression levels. Binding site occupancy by celecoxib was virtually complete, as determined by the Lassen plots. Test-retest reliability was moderate (intraclass correlation coefficient, 0.65) but had relatively large variability (absolute retest variability, 20%). Reference tissue methods yielded results comparable to those of 2TCM but reduced retest variability by up to 75% and reduced intersubject variability (coefficient of variation) by about half. Thus, compared with 2TCM, which requires arterial blood, the reference tissue method is expected to significantly reduce the sample sizes required to detect statistically significant differences between groups.
[
C]MC1 has adequate sensitivity to measure the low density of COX-2 in a healthy human brain, suggesting it can also quantify the COX-2 elevations expected in human disorders associated with neuroinflammation. |
|---|---|
| AbstractList | Cyclooxygenase-2 (COX-2) is present in a healthy brain at low densities but can be markedly upregulated by excitatory input and by inflammogens. This study evaluated the sensitivity of the PET radioligand [
C]-6-methoxy-2-(4-(methylsulfonyl)phenyl)-
-(thiophen-2-ylmethyl)pyrimidin-4-amine ([
C]MC1) to detect COX-2 density in a healthy human brain.
The specificity of [
C]MC1 was confirmed using lipopolysaccharide-injected rats and transgenic mice expressing the human
gene, with 120-min baseline and blocked scans using COX-1 and COX-2 selective agents. Twenty-seven healthy participants were injected with [
C]MC1. Ten of these participants received 2 PET scans: a baseline study followed by blockade with celecoxib (600 mg orally), a preferential COX-2 inhibitor. Seventeen participants underwent test-retest imaging. All scans included concurrent arterial sampling. The tissue-to-plasma ratio at equilibrium (i.e., total distribution volume) was determined using a 2-tissue compartment model (2TCM).
In humanized transgenic COX-2 mice, 70%-90% of [
C]MC1 brain uptake was blocked by nonradioactive MC1 and celecoxib (a COX-2 selective inhibitor) but not by PS13 (a COX-1 selective inhibitor), thereby confirming specific binding to human COX-2. Radioactivity in the human brain peaked at a concentration of about 4.0 SUV, indicating good passage through the blood-brain barrier. Values for the total distribution volume achieved stability after 80 min, indicating no radiometabolite contamination. Celecoxib reduced radioligand binding in neocortical areas by 25% but had little or no effect in subcortical regions and the cerebellum, which correlated with COX-2 messenger RNA expression levels. Binding site occupancy by celecoxib was virtually complete, as determined by the Lassen plots. Test-retest reliability was moderate (intraclass correlation coefficient, 0.65) but had relatively large variability (absolute retest variability, 20%). Reference tissue methods yielded results comparable to those of 2TCM but reduced retest variability by up to 75% and reduced intersubject variability (coefficient of variation) by about half. Thus, compared with 2TCM, which requires arterial blood, the reference tissue method is expected to significantly reduce the sample sizes required to detect statistically significant differences between groups.
[
C]MC1 has adequate sensitivity to measure the low density of COX-2 in a healthy human brain, suggesting it can also quantify the COX-2 elevations expected in human disorders associated with neuroinflammation. Cyclooxygenase-2 (COX-2) is present in a healthy brain at low densities but can be markedly upregulated by excitatory input and by inflammogens. This study evaluated the sensitivity of the PET radioligand [11C]-6-methoxy-2-(4-(methylsulfonyl)phenyl)-N-(thiophen-2-ylmethyl)pyrimidin-4-amine ([11C]MC1) to detect COX-2 density in a healthy human brain. Methods: The specificity of [11C]MC1 was confirmed using lipopolysaccharide-injected rats and transgenic mice expressing the human COX-2 gene, with 120-min baseline and blocked scans using COX-1 and COX-2 selective agents. Twenty-seven healthy participants were injected with [11C]MC1. Ten of these participants received 2 PET scans: a baseline study followed by blockade with celecoxib (600 mg orally), a preferential COX-2 inhibitor. Seventeen participants underwent test-retest imaging. All scans included concurrent arterial sampling. The tissue-to-plasma ratio at equilibrium (i.e., total distribution volume) was determined using a 2-tissue compartment model (2TCM). Results: In humanized transgenic COX-2 mice, 70%-90% of [11C]MC1 brain uptake was blocked by nonradioactive MC1 and celecoxib (a COX-2 selective inhibitor) but not by PS13 (a COX-1 selective inhibitor), thereby confirming specific binding to human COX-2. Radioactivity in the human brain peaked at a concentration of about 4.0 SUV, indicating good passage through the blood-brain barrier. Values for the total distribution volume achieved stability after 80 min, indicating no radiometabolite contamination. Celecoxib reduced radioligand binding in neocortical areas by 25% but had little or no effect in subcortical regions and the cerebellum, which correlated with COX-2 messenger RNA expression levels. Binding site occupancy by celecoxib was virtually complete, as determined by the Lassen plots. Test-retest reliability was moderate (intraclass correlation coefficient, 0.65) but had relatively large variability (absolute retest variability, 20%). Reference tissue methods yielded results comparable to those of 2TCM but reduced retest variability by up to 75% and reduced intersubject variability (coefficient of variation) by about half. Thus, compared with 2TCM, which requires arterial blood, the reference tissue method is expected to significantly reduce the sample sizes required to detect statistically significant differences between groups. Conclusion: [11C]MC1 has adequate sensitivity to measure the low density of COX-2 in a healthy human brain, suggesting it can also quantify the COX-2 elevations expected in human disorders associated with neuroinflammation.Cyclooxygenase-2 (COX-2) is present in a healthy brain at low densities but can be markedly upregulated by excitatory input and by inflammogens. This study evaluated the sensitivity of the PET radioligand [11C]-6-methoxy-2-(4-(methylsulfonyl)phenyl)-N-(thiophen-2-ylmethyl)pyrimidin-4-amine ([11C]MC1) to detect COX-2 density in a healthy human brain. Methods: The specificity of [11C]MC1 was confirmed using lipopolysaccharide-injected rats and transgenic mice expressing the human COX-2 gene, with 120-min baseline and blocked scans using COX-1 and COX-2 selective agents. Twenty-seven healthy participants were injected with [11C]MC1. Ten of these participants received 2 PET scans: a baseline study followed by blockade with celecoxib (600 mg orally), a preferential COX-2 inhibitor. Seventeen participants underwent test-retest imaging. All scans included concurrent arterial sampling. The tissue-to-plasma ratio at equilibrium (i.e., total distribution volume) was determined using a 2-tissue compartment model (2TCM). Results: In humanized transgenic COX-2 mice, 70%-90% of [11C]MC1 brain uptake was blocked by nonradioactive MC1 and celecoxib (a COX-2 selective inhibitor) but not by PS13 (a COX-1 selective inhibitor), thereby confirming specific binding to human COX-2. Radioactivity in the human brain peaked at a concentration of about 4.0 SUV, indicating good passage through the blood-brain barrier. Values for the total distribution volume achieved stability after 80 min, indicating no radiometabolite contamination. Celecoxib reduced radioligand binding in neocortical areas by 25% but had little or no effect in subcortical regions and the cerebellum, which correlated with COX-2 messenger RNA expression levels. Binding site occupancy by celecoxib was virtually complete, as determined by the Lassen plots. Test-retest reliability was moderate (intraclass correlation coefficient, 0.65) but had relatively large variability (absolute retest variability, 20%). Reference tissue methods yielded results comparable to those of 2TCM but reduced retest variability by up to 75% and reduced intersubject variability (coefficient of variation) by about half. Thus, compared with 2TCM, which requires arterial blood, the reference tissue method is expected to significantly reduce the sample sizes required to detect statistically significant differences between groups. Conclusion: [11C]MC1 has adequate sensitivity to measure the low density of COX-2 in a healthy human brain, suggesting it can also quantify the COX-2 elevations expected in human disorders associated with neuroinflammation. |
| Author | Morse, Cheryl L Usdin, Ted B Liow, Jeih-San Jenkins, Madeline Yan, Xuefeng Zhang, Andrea Wu, Shawn Pike, Victor W Hong, Jinsoo Kim, Min-Jeong Feng, Ningping Zanotti-Fregonara, Paolo Zoghbi, Sami S Innis, Robert B Montero Santamaria, Jose A Williams Avram, Sarah K Greve, Douglas Galassi, Anthony Van Buskirk, Maia Noergaard, Martin Lee, Adrian Telu, Sanjay Manly, Lester S |
| Author_xml | – sequence: 1 givenname: Xuefeng surname: Yan fullname: Yan, Xuefeng organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 2 givenname: Martin surname: Noergaard fullname: Noergaard, Martin organization: Department of Computer Science, University of Copenhagen, Copenhagen, Denmark; and – sequence: 3 givenname: Cheryl L surname: Morse fullname: Morse, Cheryl L organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 4 givenname: Jeih-San surname: Liow fullname: Liow, Jeih-San organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 5 givenname: Jinsoo surname: Hong fullname: Hong, Jinsoo organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 6 givenname: Douglas surname: Greve fullname: Greve, Douglas organization: Laboratory for Computational Neuroimaging, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts – sequence: 7 givenname: Sanjay surname: Telu fullname: Telu, Sanjay organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 8 givenname: Min-Jeong surname: Kim fullname: Kim, Min-Jeong organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 9 givenname: Jose A surname: Montero Santamaria fullname: Montero Santamaria, Jose A organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 10 givenname: Anthony surname: Galassi fullname: Galassi, Anthony organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 11 givenname: Ningping surname: Feng fullname: Feng, Ningping organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 12 givenname: Sarah K surname: Williams Avram fullname: Williams Avram, Sarah K organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 13 givenname: Ted B surname: Usdin fullname: Usdin, Ted B organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 14 givenname: Shawn surname: Wu fullname: Wu, Shawn organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 15 givenname: Andrea surname: Zhang fullname: Zhang, Andrea organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 16 givenname: Lester S surname: Manly fullname: Manly, Lester S organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 17 givenname: Madeline surname: Jenkins fullname: Jenkins, Madeline organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 18 givenname: Maia surname: Van Buskirk fullname: Van Buskirk, Maia organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 19 givenname: Adrian surname: Lee fullname: Lee, Adrian organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 20 givenname: Sami S surname: Zoghbi fullname: Zoghbi, Sami S organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 21 givenname: Victor W surname: Pike fullname: Pike, Victor W organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 22 givenname: Paolo surname: Zanotti-Fregonara fullname: Zanotti-Fregonara, Paolo organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland – sequence: 23 givenname: Robert B surname: Innis fullname: Innis, Robert B email: robert.innis@nih.gov organization: Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland; robert.innis@nih.gov |
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| Snippet | Cyclooxygenase-2 (COX-2) is present in a healthy brain at low densities but can be markedly upregulated by excitatory input and by inflammogens. This study... |
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| SubjectTerms | Adult Animals Biomarkers - metabolism Brain - diagnostic imaging Brain - metabolism Celecoxib Cyclooxygenase 2 - metabolism Female Healthy Volunteers Humans Male Mice Mice, Transgenic Middle Aged Neuroinflammatory Diseases - diagnostic imaging Neuroinflammatory Diseases - enzymology Neuroinflammatory Diseases - metabolism Positron-Emission Tomography - methods Rats Young Adult |
| Title | PET Quantification in Healthy Humans of Cyclooxygenase-2, a Potential Biomarker of Neuroinflammation |
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