Published in:
01-12-2020 | Celecoxib | Research
PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study
Authors:
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
Published in:
Journal of Neuroinflammation
|
Issue 1/2020
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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 (BPND) 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 BPND (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.