In Vivo Expression of Cyclooxygenase-1 in Activated Microglia and Macrophages During Neuroinflammation Visualized by PET with C-11-Ketoprofen Methyl Ester

RIKEN Center for Molecular Imaging Science, Hyogo, Japan.
Journal of Nuclear Medicine (Impact Factor: 6.16). 06/2011; 52(7):1094-101. DOI: 10.2967/jnumed.110.084046
Source: PubMed


Cyclooxygenase (COX)-1 and -2 are prostanoid-synthesizing enzymes that play important roles in the regulation of neuroinflammation and in the development of neurodegenerative disorders. However, the specific functions of these isoforms are still unclear. We recently developed (11)C-labeled ketoprofen methyl ester as a PET probe that targets the COXs for imaging neuroinflammation, though its responsible isoform is yet to be determined. In the present study, we performed ex vivo and in vivo imaging studies with (11)C-ketoprofen methyl ester and determined the contributions of the COX isoforms during the neuroinflammatory process.
To identify the COX isoform responsible for (11)C-ketoprofen methyl ester in the brain, we examined the ex vivo autoradiography of (11)C-ketoprofen methyl ester using COX-deficient mice. Time-dependent changes in accumulation of (11)C-ketoprofen methyl ester during the neuroinflammatory process were evaluated by PET in rats with hemispheric neuroinflammation induced by intrastriatal injection of lipopolysaccharide or quinolinic acid. In both rat models, cell-type specificity of COX isoform expression during neuroinflammation was identified immunohistochemically.
Ex vivo autoradiographic analysis of COX-deficient mice revealed a significant reduction of (11)C-ketoprofen methyl ester accumulation only in COX-1-deficient mice, not COX-2-deficient mice. PET of rats after intrastriatal injection of lipopolysaccharide showed a significant increase in accumulation of (11)C-ketoprofen methyl ester in the inflamed area. This increase was evident at the early phase of 6 h, peaked at day 1, and then returned to basal levels by day 7. In addition, immunohistochemical analysis revealed that the population of activated microglia and macrophages was elevated at the early phase with COX-1 expression but not COX-2. A significant increase in (11)C-ketoprofen methyl ester accumulation was also observed at day 1 after intrastriatal injection of quinolinic acid, with increased COX-1-expressing activated microglia and macrophages.
We have identified (11)C-ketoprofen methyl ester as a COX-1-selective PET probe, and using this, we have also demonstrated a time-dependent expression of COX-1 in activated microglia and macrophages during the neuroinflammatory process in the living brain. Thus, COX-1 may play a crucial role in the pathology of neuroinflammation and might be a critical target for the diagnosis and therapy of neurodegenerative disorders.

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    • "Because the designs of these radiolabeled COX-2 inhibitors are mainly based on a triphenyl ring scaffold or biaryl scaffold that specifically target the COX-2 enzyme, other types of radiopharmaceuticals that target the COX-1 enzyme have been reinvestigated [38]. Promising imaging results [39] encouraged us to prepare octyl fenbufen amide (OFA) [40e42], which are members of the NSAID family that do not exhibit COX selectivity (Fig. 1). "
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    Biomaterials 02/2013; 34(13). DOI:10.1016/j.biomaterials.2013.01.050 · 8.56 Impact Factor
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    • "s arachidonic acid to prostaglandin in the prostaglandin pathway . [ 11 C ] ketoprofen methyl ester targets COX - 1 and showed increased uptake in rats injected with LPS but not COX - 1 deficient rats . Further , temporal changes in [ 11 C ] ketoprofen methyl ester uptake paralleled immuno - histochemical assessment of M / l in rat brain tissues ( Shukuri et al . , 2011 ) . Other non - TSPO binding agents used in imaging neuroinflammation include 2 - [ 18 F ] - fluo - roacetate targeted at the citric acid cycle in glial metab - olism and [ 11 C ] - L - deprenyl labeling monoamine oxidase B are hypothesized to be enriched in astrocytes ( Gulyas et al . , 2010 ; Marik et al . , 2009 ) . While these appro"
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    Glia 01/2013; 61(1). DOI:10.1002/glia.22357 · 6.03 Impact Factor
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    • "Further microglial targets: Further microglial targets currently being explored for imaging include the P2X7 receptor (Monif et al, 2009; Yiangou et al, 2006), the cannabinoid CB2 receptor (Evens et al, 2009; Horti et al, 2010; Turkman et al, 2011; Vandeputte et al, 2011), the cyclooxygenase-1 and -2 enzyme (de Vries et al, 2008; Shukuri et al, 2011), and matrix metalloproteinases (Iwama et al, 2011; Pinas et al, 2009; Wagner et al, 2007). The CB2 receptors can be targeted by both radiolabeled and paramagnetic imaging probes (te Boekhorst et al, 2010). "
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