PET Imaging of Innate Immune Activation Using 11C Radiotracers Targeting GPR84
© 2023 American Chemical Society..
Chronic innate immune activation is a key hallmark of many neurological diseases and is known to result in the upregulation of GPR84 in myeloid cells (macrophages, microglia, and monocytes). As such, GPR84 can potentially serve as a sensor of proinflammatory innate immune responses. To assess the utility of GPR84 as an imaging biomarker, we synthesized 11C-MGX-10S and 11C-MGX-11Svia carbon-11 alkylation for use as positron emission tomography (PET) tracers targeting this receptor. In vitro experiments demonstrated significantly higher binding of both radiotracers to hGPR84-HEK293 cells than that of parental control HEK293 cells. Co-incubation with the GPR84 antagonist GLPG1205 reduced the binding of both radiotracers by >90%, demonstrating their high specificity for GPR84 in vitro. In vivo assessment of each radiotracer via PET imaging of healthy mice illustrated the superior brain uptake and pharmacokinetics of 11C-MGX-10S compared to 11C-MGX-11S. Subsequent use of 11C-MGX-10S to image a well-established mouse model of systemic and neuro-inflammation revealed a high PET signal in affected tissues, including the brain, liver, lung, and spleen. In vivo specificity of 11C-MGX-10S for GPR84 was confirmed by the administration of GLPG1205 followed by radiotracer injection. When compared with 11C-DPA-713-an existing radiotracer used to image innate immune activation in clinical research studies-11C-MGX-10S has multiple advantages, including its higher binding signal in inflamed tissues in the CNS and periphery and low background signal in healthy saline-treated subjects. The pronounced uptake of 11C-MGX-10S during inflammation, its high specificity for GPR84, and suitable pharmacokinetics strongly support further investigation of 11C-MGX-10S for imaging GPR84-positive myeloid cells associated with innate immune activation in animal models of inflammatory diseases and human neuropathology.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:3 |
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| Enthalten in: |
JACS Au - 3(2023), 12 vom: 25. Dez., Seite 3297-3310 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kalita, Mausam [VerfasserIn] |
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| Anmerkungen: |
Date Revised 30.12.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1021/jacsau.3c00435 |
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| Förderinstitution / Projekttitel: |
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NLM366462806 |
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| 520 | |a Chronic innate immune activation is a key hallmark of many neurological diseases and is known to result in the upregulation of GPR84 in myeloid cells (macrophages, microglia, and monocytes). As such, GPR84 can potentially serve as a sensor of proinflammatory innate immune responses. To assess the utility of GPR84 as an imaging biomarker, we synthesized 11C-MGX-10S and 11C-MGX-11Svia carbon-11 alkylation for use as positron emission tomography (PET) tracers targeting this receptor. In vitro experiments demonstrated significantly higher binding of both radiotracers to hGPR84-HEK293 cells than that of parental control HEK293 cells. Co-incubation with the GPR84 antagonist GLPG1205 reduced the binding of both radiotracers by >90%, demonstrating their high specificity for GPR84 in vitro. In vivo assessment of each radiotracer via PET imaging of healthy mice illustrated the superior brain uptake and pharmacokinetics of 11C-MGX-10S compared to 11C-MGX-11S. Subsequent use of 11C-MGX-10S to image a well-established mouse model of systemic and neuro-inflammation revealed a high PET signal in affected tissues, including the brain, liver, lung, and spleen. In vivo specificity of 11C-MGX-10S for GPR84 was confirmed by the administration of GLPG1205 followed by radiotracer injection. When compared with 11C-DPA-713-an existing radiotracer used to image innate immune activation in clinical research studies-11C-MGX-10S has multiple advantages, including its higher binding signal in inflamed tissues in the CNS and periphery and low background signal in healthy saline-treated subjects. The pronounced uptake of 11C-MGX-10S during inflammation, its high specificity for GPR84, and suitable pharmacokinetics strongly support further investigation of 11C-MGX-10S for imaging GPR84-positive myeloid cells associated with innate immune activation in animal models of inflammatory diseases and human neuropathology | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Park, Jun Hyung |e verfasserin |4 aut | |
| 700 | 1 | |a Kuo, Renesmee Chenting |e verfasserin |4 aut | |
| 700 | 1 | |a Hayee, Samira |e verfasserin |4 aut | |
| 700 | 1 | |a Marsango, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Straniero, Valentina |e verfasserin |4 aut | |
| 700 | 1 | |a Alam, Israt S |e verfasserin |4 aut | |
| 700 | 1 | |a Rivera-Rodriguez, Angelie |e verfasserin |4 aut | |
| 700 | 1 | |a Pandrala, Mallesh |e verfasserin |4 aut | |
| 700 | 1 | |a Carlson, Mackenzie L |e verfasserin |4 aut | |
| 700 | 1 | |a Reyes, Samantha T |e verfasserin |4 aut | |
| 700 | 1 | |a Jackson, Isaac M |e verfasserin |4 aut | |
| 700 | 1 | |a Suigo, Lorenzo |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Audrey |e verfasserin |4 aut | |
| 700 | 1 | |a Nagy, Sydney C |e verfasserin |4 aut | |
| 700 | 1 | |a Valoti, Ermanno |e verfasserin |4 aut | |
| 700 | 1 | |a Milligan, Graeme |e verfasserin |4 aut | |
| 700 | 1 | |a Habte, Frezghi |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a James, Michelle L |e verfasserin |4 aut | |
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