{"doi":"10.1021/jacsau.3c00435","title":"PET Imaging of Innate Immune Activation Using <sup>11</sup>C Radiotracers Targeting GPR84","abstract":"High Resolution Image Download MS PowerPoint Slide 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 11 C-MGX-10S and 11 C-MGX-11S via 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 11 C-MGX-10S compared to 11 C-MGX-11S . Subsequent use of 11 C-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 11 C-MGX-10S for GPR84 was confirmed by the administration of GLPG1205 followed by radiotracer injection. When compared with 11 C-DPA-713─an existing radiotracer used to image innate immune activation in clinical research studies─ 11 C-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 11 C-MGX-10S during inflammation, its high specificity for GPR84, and suitable pharmacokinetics strongly support further investigation of 11 C-MGX-10S for imaging GPR84-positive myeloid cells associated with innate immune activation in animal models of inflammatory diseases and human neuropathology.","journal":"JACS Au","year":2023,"id":330603,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9658,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":380270,"name":"Jun Hyung Park","orcid":"0009-0000-6903-2500","position":1,"is_corresponding":false},{"id":976848,"name":"Renesmee Kuo","orcid":"0000-0002-9309-2914","position":2,"is_corresponding":false},{"id":1055495,"name":"Samira Hayee","orcid":null,"position":3,"is_corresponding":false},{"id":1034899,"name":"Sara Marsango","orcid":"0000-0002-0590-7942","position":4,"is_corresponding":false},{"id":429738,"name":"Valentina Straniero","orcid":"0000-0002-5089-0879","position":5,"is_corresponding":false},{"id":588503,"name":"Israt S. 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Nagy","orcid":"0000-0002-1837-8955","position":14,"is_corresponding":false},{"id":429739,"name":"Ermanno Valoti","orcid":"0000-0002-5608-3875","position":15,"is_corresponding":false},{"id":679803,"name":"Graeme Milligan","orcid":"0000-0002-6946-3519","position":16,"is_corresponding":false},{"id":260488,"name":"Frezghi Habte","orcid":"0000-0002-9488-3427","position":17,"is_corresponding":false},{"id":344315,"name":"Bin Shen","orcid":"0000-0002-9632-7221","position":18,"is_corresponding":false},{"id":227499,"name":"Michelle L. 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