RT Journal Article SR Electronic T1 Evaluation of a novel positron emission tomographic radioligand to measure cyclooxygenase-2 in a model of neuroinflammation in rhesus macaque JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 71 OP 71 VO 59 IS supplement 1 A1 Michael Frankland A1 Stal Shrestha A1 Mark Eldridge A1 Michael Lehmann A1 Zu Xi Yu A1 Michelle Cortes A1 Prachi Singh A1 Min-Jeong Kim A1 Jeih-San Liow A1 Masahiro Fujita A1 Sami Zoghbi A1 Evan Gallagher A1 Megan Fredericks A1 Robert Gladding A1 George Tye A1 Victor Pike A1 Robert Innis YR 2018 UL http://jnm.snmjournals.org/content/59/supplement_1/71.abstract AB 71Background: The cyclooxygenase (COX) isozymes, COX-1 and COX-2, mediate inflammatory responses, and are targets for nonsteroidal anti-inflammatory drugs (NSAIDs). To study the distribution and function of these COX isozymes in vivo, our laboratory developed two novel PET radioligands: 11C-PS13 and 11C-MC1. PS13 demonstrated potent selectivity for COX-1 (IC50 = 1 nM) compared to COX-2 (IC50 > 1,000 nM). Conversely, MC1 was potent and selective for COX-2 (IC50 = 1 nM) compared to COX-1 (IC50 > 1,000 nM). Previously, we showed that 11C-PS13, but not 11C-MC1 shows specific uptake in normal monkey brain. Whether 11C-MC1 exhibits specific binding in conditions that elicit significant densities of COX-2 has yet to be studied. This study sought to examine whether 11C-MC1 could image COX-2 in a model of neuroinflammation via intracerebral injection of lipopolysaccharide (LPS). As a control, we measured COX-1 using 11C-PS13 before and after LPS. Methods: To elicit an inflammatory response in monkey brain, LPS (from Escherichia coli O26:B6), was injected into the right putamen of monkeys (n=4). Prior to injection, a T1-weighted MRI was obtained to guide the insertion of the needle. In total, 10 µg of LPS was injected at a concentration of 1 µg/µL and an infusion rate of 0.5 µL/min. Dynamic brain PET scans were acquired for two hours both pre- and post-LPS injection. Approximately 220 MBq of radioligand was injected intravenously into the monkey before each scan. Blocking studies were also conducted with non-radioactive PS13 or MC1 (0.3-1 mg/kg) to confirm the specific uptake of the radioligands in the brain. Full quantitation with arterial sampling was done to measure volume of distribution (VT) before and after LPS injection. Results: In this LPS model of neuroinflammation, 11C-MC1 measured specific binding to COX-2. After the first injection, a widespread, 60% increase of 11C-MC1 uptake was observed in the brain that was displaced by non-radioactive MC1. Following the second injection, there was an even more dramatic increase (>200%) in 11C-MC1 uptake at the site of injection (Figure 1). As a comparator, we found no increase in COX-1 after LPS injection. 11C-PBR28, a radioligand for translocator protein (TSPO), showed increased uptake, as expected, at the site of injection. Conclusions: 11C-MC1 is useful for imaging COX-2 upregulation in rhesus macaque brain from basal levels to 60% after a single injection and >200% after a second injection. We show that in monkey brain, COX-2 but not COX-1 is upregulated after inflammation, which is consistent with the general notion that expression of COX-1 is constitutive and COX-2 is inducible. Of interest, COX-2 was primarily in neurons. Ongoing first in-human studies will measure COX-1 in healthy conditions, and COX-2 in inflammatory disorders, and can also be used to evaluate the selectivity of NSAIDs, and delivery to brain for the two COX isozymes.Figure 1. The effect of inflammogen on 11C-MC1 uptake in a monkey brain shown as volume of distribution (VT). In normal brain (pre-LPS), there was no detectable uptake. After the second injection of LPS into right putamen, 11C-MC1 uptake increased by >200% in the area of lesion, and blocked by non-radioactive MC1 (1 mg/kg i.v.).