PET measurement of cyclooxygenase-2 using a novel radioligand: Upregulation in primate neuroinflammation and first-in-human study

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. ZoghbiMasahiro Fujita, James D. Katz, Victor W. Pike, Robert B. Innis

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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: NCT03912428. Registered April 11, 2019.

Original languageEnglish (US)
Article number140
Pages (from-to)140
JournalJournal of Neuroinflammation
Issue number1
StatePublished - May 2 2020


  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Inflammation
  • Lipopolysaccharide
  • Positron emission tomography
  • Rheumatoid arthritis
  • Humans
  • Middle Aged
  • Inflammation/diagnostic imaging
  • Macaca mulatta
  • Brain/diagnostic imaging
  • Pyrimidines
  • Animals
  • Cyclooxygenase 2/analysis
  • Adult
  • Female
  • Arthritis, Rheumatoid/diagnostic imaging
  • Radiopharmaceuticals
  • Positron-Emission Tomography/methods

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience
  • Neuroscience(all)
  • Immunology


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