PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study
Abstract Background Cyclooxygenase-2 (COX-2), which is rapidly upregulated by inflammation, is a key enzyme catalyzing the rate-limiting step in the synthesis of several inflammatory prostanoids. Successful positron emission tomography (PET) radioligand imaging of COX-2 in vivo could be a potentiall...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-05-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-020-01804-6 |
| _version_ | 1828453006084931584 |
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| author | Stal Shrestha Min-Jeong Kim Mark Eldridge Michael L. Lehmann Michael Frankland Jeih-San Liow Zu-Xi Yu Michelle Cortes-Salva Sanjay Telu Ioline D. Henter Evan Gallagher Jae-Hoon Lee J. Megan Fredericks Chelsie Poffenberger George Tye Yanira Ruiz-Perdomo Fernanda Juarez Anaya Jose A. Montero Santamaria Robert L. Gladding Sami S. Zoghbi Masahiro Fujita James D. Katz Victor W. Pike Robert B. Innis |
| author_facet | Stal Shrestha Min-Jeong Kim Mark Eldridge Michael L. Lehmann Michael Frankland Jeih-San Liow Zu-Xi Yu Michelle Cortes-Salva Sanjay Telu Ioline D. Henter Evan Gallagher Jae-Hoon Lee J. Megan Fredericks Chelsie Poffenberger George Tye Yanira Ruiz-Perdomo Fernanda Juarez Anaya Jose A. Montero Santamaria Robert L. Gladding Sami S. Zoghbi Masahiro Fujita James D. Katz Victor W. Pike Robert B. Innis |
| author_sort | Stal Shrestha |
| collection | DOAJ |
| description | Abstract Background Cyclooxygenase-2 (COX-2), which is rapidly upregulated by inflammation, is a key enzyme catalyzing the rate-limiting step in the synthesis of several inflammatory prostanoids. Successful positron emission tomography (PET) radioligand imaging of COX-2 in vivo could be a potentially powerful tool for assessing inflammatory response in the brain and periphery. To date, however, the development of PET radioligands for COX-2 has had limited success. Methods The novel PET tracer [11C]MC1 was used to examine COX-2 expression [1] in the brains of four rhesus macaques at baseline and after injection of the inflammogen lipopolysaccharide (LPS) into the right putamen, and [2] in the joints of two human participants with rheumatoid arthritis and two healthy individuals. In the primate study, two monkeys had one LPS injection, and two monkeys had a second injection 33 and 44 days, respectively, after the first LPS injection. As a comparator, COX-1 expression was measured using [11C]PS13. Results COX-2 binding, expressed as the ratio of specific to nondisplaceable uptake (BP ND) of [11C]MC1, increased on day 1 post-LPS injection; no such increase in COX-1 expression, measured using [11C]PS13, was observed. The day after the second LPS injection, a brain lesion (~ 0.5 cm in diameter) with high COX-2 density and high BP ND (1.8) was observed. Postmortem brain analysis at the gene transcript or protein level confirmed in vivo PET results. An incidental finding in an unrelated monkey found a line of COX-2 positivity along an incision in skull muscle, demonstrating that [11C]MC1 can localize inflammation peripheral to the brain. In patients with rheumatoid arthritis, [11C]MC1 successfully imaged upregulated COX-2 in the arthritic hand and shoulder and apparently in the brain. Uptake was blocked by celecoxib, a COX-2 preferential inhibitor. Conclusions Taken together, these results indicate that [11C]MC1 can image and quantify COX-2 upregulation in both monkey brain after LPS-induced neuroinflammation and in human peripheral tissue with inflammation. Trial registration ClinicalTrials.gov NCT03912428. Registered April 11, 2019. |
| first_indexed | 2024-12-11T00:01:02Z |
| format | Article |
| id | doaj.art-549fdcb2b5f34261b797487884d7bade |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-11T00:01:02Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-549fdcb2b5f34261b797487884d7bade2022-12-22T01:28:28ZengBMCJournal of Neuroinflammation1742-20942020-05-0117111710.1186/s12974-020-01804-6PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human studyStal Shrestha0Min-Jeong Kim1Mark Eldridge2Michael L. Lehmann3Michael Frankland4Jeih-San Liow5Zu-Xi Yu6Michelle Cortes-Salva7Sanjay Telu8Ioline D. Henter9Evan Gallagher10Jae-Hoon Lee11J. Megan Fredericks12Chelsie Poffenberger13George Tye14Yanira Ruiz-Perdomo15Fernanda Juarez Anaya16Jose A. Montero Santamaria17Robert L. Gladding18Sami S. Zoghbi19Masahiro Fujita20James D. Katz21Victor W. Pike22Robert B. Innis23National Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Heart, Lung, and Blood Institute Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNational Institute of Mental Health Intramural Research ProgramNational Institute of Mental Health Intramural Research ProgramAbstract Background Cyclooxygenase-2 (COX-2), which is rapidly upregulated by inflammation, is a key enzyme catalyzing the rate-limiting step in the synthesis of several inflammatory prostanoids. Successful positron emission tomography (PET) radioligand imaging of COX-2 in vivo could be a potentially powerful tool for assessing inflammatory response in the brain and periphery. To date, however, the development of PET radioligands for COX-2 has had limited success. Methods The novel PET tracer [11C]MC1 was used to examine COX-2 expression [1] in the brains of four rhesus macaques at baseline and after injection of the inflammogen lipopolysaccharide (LPS) into the right putamen, and [2] in the joints of two human participants with rheumatoid arthritis and two healthy individuals. In the primate study, two monkeys had one LPS injection, and two monkeys had a second injection 33 and 44 days, respectively, after the first LPS injection. As a comparator, COX-1 expression was measured using [11C]PS13. Results COX-2 binding, expressed as the ratio of specific to nondisplaceable uptake (BP ND) of [11C]MC1, increased on day 1 post-LPS injection; no such increase in COX-1 expression, measured using [11C]PS13, was observed. The day after the second LPS injection, a brain lesion (~ 0.5 cm in diameter) with high COX-2 density and high BP ND (1.8) was observed. Postmortem brain analysis at the gene transcript or protein level confirmed in vivo PET results. An incidental finding in an unrelated monkey found a line of COX-2 positivity along an incision in skull muscle, demonstrating that [11C]MC1 can localize inflammation peripheral to the brain. In patients with rheumatoid arthritis, [11C]MC1 successfully imaged upregulated COX-2 in the arthritic hand and shoulder and apparently in the brain. Uptake was blocked by celecoxib, a COX-2 preferential inhibitor. Conclusions Taken together, these results indicate that [11C]MC1 can image and quantify COX-2 upregulation in both monkey brain after LPS-induced neuroinflammation and in human peripheral tissue with inflammation. Trial registration ClinicalTrials.gov NCT03912428. Registered April 11, 2019.http://link.springer.com/article/10.1186/s12974-020-01804-6Cyclooxygenase 2Cyclooxygenase 1Positron emission tomographyInflammationLipopolysaccharideRheumatoid arthritis |
| spellingShingle | Stal Shrestha Min-Jeong Kim Mark Eldridge Michael L. Lehmann Michael Frankland Jeih-San Liow Zu-Xi Yu Michelle Cortes-Salva Sanjay Telu Ioline D. Henter Evan Gallagher Jae-Hoon Lee J. Megan Fredericks Chelsie Poffenberger George Tye Yanira Ruiz-Perdomo Fernanda Juarez Anaya Jose A. Montero Santamaria Robert L. Gladding Sami S. Zoghbi Masahiro Fujita James D. Katz Victor W. Pike Robert B. Innis PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study Journal of Neuroinflammation Cyclooxygenase 2 Cyclooxygenase 1 Positron emission tomography Inflammation Lipopolysaccharide Rheumatoid arthritis |
| title | PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study |
| title_full | PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study |
| title_fullStr | PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study |
| title_full_unstemmed | PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study |
| title_short | PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study |
| title_sort | pet measurement of cyclooxygenase 2 using a novel radioligand upregulation in primate neuroinflammation and first in human study |
| topic | Cyclooxygenase 2 Cyclooxygenase 1 Positron emission tomography Inflammation Lipopolysaccharide Rheumatoid arthritis |
| url | http://link.springer.com/article/10.1186/s12974-020-01804-6 |
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