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 H₂, 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.

Keywords: COX-1; COX-2; PET; biomarkers; neuroinflammation.

FIGURE 1.

Distinct functions of COX-1 and COX-2 derive from their cellular location. Both COX-1 and COX-2 convert arachidonic acid into prostaglandin H₂ (PGH₂), which is later enzymatically converted into several bioactive prostanoids with different and sometimes opposing functions. The specific prostanoid depends on the enzymes in a given cell. Platelets contain primarily COX-1 and produce thromboxane A₂ (TXA₂), which promotes clotting. Vascular endothelium primarily contains COX-2 and produces prostaglandin I₂ (PGI₂), which inhibits clotting. Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit COX isomers, either nonselectively (e.g., naproxen) or selectively (e.g., aspirin for COX-1 and rofecoxib for COX-2). Thus, the pharmacological effect of inhibiting COX-1 is to inhibit clotting and that of inhibiting COX-2 is to promote clotting.

FIGURE 2.

Imaging of COX-1 with ¹¹C-PS13 in monkey at baseline and after blocking with nonradioactive PS13, which is highly selective for COX-1. High specific binding (i.e., blockable) was shown in brain (percentage blockade, 35%), spleen (86%), gastrointestinal tract (61%), and kidney (∼75%). (Reprinted from (24).)

FIGURE 3.

Distribution of COX-1 in healthy human brain. After ¹¹C-PS13 injection, enzyme density was calculated on the pixel level as distribution volume (V_T). The MRI is from a representative participant, and PET images of COX-1 are an average from 10 participants. Notable ¹¹C-PS13 binding (arrows) was detected in hippocampus (HC), occipital cortex (OC), and pericentral cortex (PC). The third row shows images fused from MRI and PET scans. (Reprinted from (19).)

FIGURE 4.

COX-2 was increased after a lesion in the brain of a rhesus macaque was found. The inflammatory agent lipopolysaccharide (LPS) was injected into the right putamen and initially caused edema and, later, a hemorrhage. (A) The coronal T2-weighted magnetic resonance image (MRI) scan of a rhesus macaque showing poorly visualized edema (blue arrow) and hematoma (purple arrow) around the injection site. (B) The PET image after ¹¹C-MC1 injection showed markedly elevated COX-2, especially overlying the hematoma. (C) The COX-2 selective compound MC1 (1 mg/kg intravenously) blocked uptake in the lesion area, confirming the existence of both specific (i.e., blockable) and non-specific (i.e., residual) binding of the radioligand. (Adapted from (6).)

FIGURE 5.

PET images of COX-2 and TSPO in a patient with RA and a healthy volunteer. The red arrows indicate symptomatic joints, and the blue arrows indicate asymptomatic joints. Increased COX-2 in the hands reflected currently symptomatic joints, whereas increased TSPO binding reflected both currently symptomatic and previously symptomatic joints. Celecoxib (400 mg orally) blocked only ∼25% of the ¹¹C-MC1 uptake in the joints of the patient, confirming uptake selectivity for COX-2 compared to COX-1. Animal studies suggest that higher doses of celecoxib are required for complete blockade. Adapted from (6).