Cyclooxygenases as Potential PET Imaging Biomarkers to Explore Neuroinflammation in Dementia

Abstract

The most frequently studied target of neuroinflammation using PET is 18-kDa translocator protein, but its limitations have spurred the molecular imaging community to find more promising targets. This article reviews the development of PET radioligands for cyclooxygenase (COX) subtypes 1 and 2, enzymes that catalyze the production of inflammatory prostanoids in the periphery and brain. Although both isozymes produce the same precursor compound, prostaglandin H 2 , they have distinct functions based on their differential cellular localization in the periphery and brain. For example, COX-1 is located primarily in microglia, a resident inflammatory cell in the brain whose role in producing inflammatory cytokines is well documented. In contrast, COX-2 is located primarily in neurons and can be markedly upregulated by inflammatory and excitatory stimuli, but its functions are poorly understood. This article reviews these 2 isozymes as biomarkers of neuroinflammation, as well as the radioligands that have recently been developed to image them in animals and humans. To place this work into context, the properties of COX-1 and COX-2 are compared with 18-kDa translocator protein, with special consideration of their application in Alzheimer disease as a representative neurodegenerative disorder.

A Fast-Binding, Functionally Reversible, COX-2 Radiotracer for CNS PET Imaging

“…This is a complex landscape, and research approaches are currently limited to preclinical models and post-mortem tissue analyses. Given potential species differ-ences in COX-2 brain function and pathology 30 and the exceptional complexity of COX-2's involvement in underlying pathological mechanisms, there is great need for tools that will enable in vivo research of COX-2 in the human brain.…”

“…25 Adding to the complexity, research indicates that COX-2 is expressed constitutively in neurons in the healthy brain where it has been suggested to play a role in some synaptic functions; 26−28 additionally, neuronal COX-2 can also be elevated in some instances of inflammation and neurodegeneration. 29,30 Although the connection of COX-2 with inflammation and neurodegeneration is well-established, the impacts of COX-2 activity during inflammatory processes and of changing COX-2 expression during disease progression are still very unclear. 6,31 COX inhibition (COXib), both of COX-1 and COX-2, has been associated with and evaluated clinically for treating various neurological and neurodegenerative diseases 32−34 and psychiatric disorders, including schizophrenia and depression.…”

“…Research in aging mice found that (i) prostaglandin signaling impacts the metabolic state of microglia in aging mice, and (ii) ablation of the EP2 receptor of PGE 2 not only restores metabolic phenotypes in these cells, but also reduces the expression of inflammatory cytokines, increases synaptic protein levels, and restores cognitive ability . Adding to the complexity, research indicates that COX-2 is expressed constitutively in neurons in the healthy brain where it has been suggested to play a role in some synaptic functions; − additionally, neuronal COX-2 can also be elevated in some instances of inflammation and neurodegeneration. , Although the connection of COX-2 with inflammation and neurodegeneration is well-established, the impacts of COX-2 activity during inflammatory processes and of changing COX-2 expression during disease progression are still very unclear. , …”

“…To address this need, COX-2 positron emission tomography (PET) radiotracers for human neuroimaging have been pursued for several years. ,, Imaging with PET allows researchers and clinicians to measure how critical targets, such as proteins or enzymes, change in the living brain at disease onset and throughout disease progression. More importantly, PET can measure how a target changes following therapeutic intervention, a critical step in assessing treatment efficacy.…”

m-Terphenylamines, Acting as Selective COX-1 Inhibitors, Block Microglia Inflammatory Response and Exert Neuroprotective Activity

“…COX-1 has also been shown to mediate neuroinflammation and neurotoxicity in a mouse model of retinitis pigmentosa [ 17 ]. In summary, the pharmacological modulation of microglial activation via selective COX-1 inhibition [ 18 ] is an attractive, if little explored, approach to therapy [ 2 ] and diagnosis [ 19 ] in CNS inflammatory diseases, and also to other inflammation-connected diseases, including cancer [ 20 ]. In the context of the therapeutic use of COX-1 inhibitors, it must be stressed that, in spite of previous misconceptions, animal studies suggest that the total extent of COX inhibition is more important for gastric toxicity than the extent of the inhibition of the individual COX-1 and COX-2 enzymes and for this reason highly selective COX-1 inhibitors do not exhibit particularly high gastrointestinal toxicity, behaving similarly to highly selective COX-2 inhibitors [ 21 , 22 , 23 ].…”