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
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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Available from: Yin-Cheng Huang
- "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 . Promising imaging results  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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ABSTRACT: This study is concerned with the development of an agent for single photon emission computer tomography (SPECT) for imaging inflammation and tumor progression. [(123)I]Iodooctyl fenbufen amide ([(123)I]IOFA) was prepared from the precursor N-octyl-4-oxo-4-(4'-(trimethylstannyl)biphenyl-4-yl)butanamide with a radiochemical yield of 15%, specific activity of 37 GBq/μmol, and radiochemical purity of 95%. Analysis of the binding of [(123)I]IOFA to COX-1 and COX-2 enzymes by using HPLC and a gel filtration column showed a selectivity ratio of 1:1.3. An assay for the competitive inhibition of substrate transfer showed that IOFA exhibited a comparable IC(50) value compared to fenbufen. In the normal rat liver, a lower level and homogeneous pattern of [(123)I]IOFA radioactivity was observed by SPECT. In contrast, in the rat liver with thioacetamide-induced cholangiocarcinoma, a higher uptake and heterogeneous pattern of [(123)I]IOFA radioactivity was seen as hot spots in tumor lesions by SPECT imaging. Importantly, elevated COX-1 and COX-2 expressions from immunostaining were found in the bile ducts of tumor rats but not of normal rats. Therefore, [(123)I]IOFA was found to exhibit the potential for imaging tumors that over-express COX.
Available from: Brian Lopresti
- "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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ABSTRACT: Neuroinflammation perpetuates neuronal damage in many neurological disorders. Activation of resident microglia and infiltration of monocytes/macrophages contributes to neuronal injury and synaptic damage. Noninvasive imaging of these cells in vivo provides a means to monitor progression of disease as well as assess efficacies of potential therapeutics. This review provides an overview of positron emission tomography (PET) and magnetic resonance (MR) imaging of microglia/macrophages in the brain. We describe the rationale behind PET imaging of microglia/macrophages with ligands that bind to translocator protein-18 kDa (TSPO). We discuss the prototype TSPO radioligand [(11) C]PK11195, its limitations, and the development of newer TSPO ligands as PET imaging agents. PET imaging agents for targets other than TSPO are emerging, and we outline the potential of these agents for imaging brain microglia/macrophage activity in vivo. Finally, we briefly summarize advances in MR imaging of microglia/macrophages using iron oxide nanoparticles and ultra-small super paramagnetic particles that are phagocytosed. Despite many technical advances, more sensitive agents are required to be useful indicators of neuroinflammation in brain. © 2012 Wiley Periodicals, Inc.
Available from: Andreas H. Jacobs
- "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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ABSTRACT: Inflammation is a highly dynamic and complex adaptive process to preserve and restore tissue homeostasis. Originally viewed as an immune-privileged organ, the central nervous system (CNS) is now recognized to have a constant interplay with the innate and the adaptive immune systems, where resident microglia and infiltrating immune cells from the periphery have important roles. Common diseases of the CNS, such as stroke, multiple sclerosis (MS), and neurodegeneration, elicit a neuroinflammatory response with the goal to limit the extent of the disease and to support repair and regeneration. However, various disease mechanisms lead to neuroinflammation (NI) contributing to the disease process itself. Molecular imaging is the method of choice to try to decipher key aspects of the dynamic interplay of various inducers, sensors, transducers, and effectors of the orchestrated inflammatory response in vivo in animal models and patients. Here, we review the basic principles of NI with emphasis on microglia and common neurologic disease mechanisms, the molecular targets which are being used and explored for imaging, and molecular imaging of NI in frequent neurologic diseases, such as stroke, MS, neurodegeneration, epilepsy, encephalitis, and gliomas.
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