Cyclooxygenase-2 (COX-2) is a prostaglandin-generating enzyme that exhibits low basal expression levels and is upregulated in the central nervous system (CNS) in response to inflammatory stimuli. COX-2 has been implicated in the microglial-mediated neuroinflammatory and neurodegenerative processes of multiple sclerosis (MS), a demyelinating autoimmune disease. To study COX-2 activity and the role it may play in demyelination, a novel PET radiotracer specific for COX-2, [11C]BRD1158, was developed and evaluated in the lysolecithin rodent model of focal demyelination with PET-MR imaging. Preliminary results of this pilot pre-clinical study confirmed our hypothesis that the properties of [11C]BRD1158 enable visualization and monitoring of COX-2 activity under pathological conditions induced by LPC. Radiotracer uptake correlated positively with disease progression at the site of LPC injection in male rats, peaking at day 7 and resolving by day 28. Treatment with an FDA-approved MS therapy, Siponimod, diminished the increase in COX-2 activity and tracer uptake at the lesion site and throughout the brain in both male and female rats. The results from the present study will inform future pre-clinical and translational work that validates the use of [11C]BRD1158 to image COX-2 activity as a marker of underlying inflammation in MS, leading to a better understanding of pathological and inflammatory processes in MS development and progression.