PET Imaging of Innate Immune Activation Using ¹¹C Radiotracers Targeting GPR84

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 ^<b>11</b><b>C-MGX-10S</b> and ^<b>11</b><b>C-MGX-11S</b> <i>via</i> carbon-11 alkylation for use as positron emission tomography (PET) tracers targeting this receptor. <i>In vitro</i> 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 <i>in vitro</i>. <i>In vivo</i> assessment of each radiotracer <i>via</i> PET imaging of healthy mice illustrated the superior brain uptake and pharmacokinetics of ^<b>11</b><b>C-MGX-10S</b> compared to ^<b>11</b><b>C-MGX-11S</b>. Subsequent use of ^<b>11</b><b>C-MGX-10S</b> 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. <i>In vivo</i> specificity of ^<b>11</b><b>C-MGX-10S</b> 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^<b>11</b><b>C-MGX-10S</b> 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 ^<b>11</b><b>C-MGX-10S</b> during inflammation, its high specificity for GPR84, and suitable pharmacokinetics strongly support further investigation of ^<b>11</b><b>C-MGX-10S</b> for imaging GPR84-positive myeloid cells associated with innate immune activation in animal models of inflammatory diseases and human neuropathology.