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

Area of Science:

• Neuroscience
• Immunology
• Radiochemistry

Background:

• Chronic innate immune activation is central to neurological diseases.
• GPR84 is upregulated in myeloid cells during inflammation, serving as a potential imaging biomarker.
• Existing imaging methods for innate immune activation have limitations.

Purpose of the Study:

• To synthesize and evaluate novel positron emission tomography (PET) tracers targeting GPR84.
• To assess the specificity and efficacy of these tracers for imaging GPR84 in inflammatory conditions.
• To compare the performance of the novel tracers with existing imaging agents.

Main Methods:

• Synthesis of carbon-11 labeled tracers (C-MGX-10S and C-MGX-11S) via carbon-11 alkylation.
• In vitro binding assays using GPR84-expressing cells and a GPR84 antagonist (GLPG1205).
• In vivo PET imaging in healthy mice and a mouse model of systemic and neuro-inflammation.

Main Results:

• Both tracers demonstrated high specificity for GPR84 in vitro.
• C-MGX-10S exhibited superior brain uptake and pharmacokinetics compared to C-MGX-11S in mice.
• C-MGX-10S successfully visualized inflammation in various tissues, including the brain, with high signal and low background.
• C-MGX-10S showed advantages over the existing tracer C-11-DPA-713.

Conclusions:

• C-MGX-10S is a highly specific and effective PET tracer for imaging GPR84.
• Its favorable properties support its use for detecting GPR84-positive myeloid cells in inflammatory diseases.
• C-MGX-10S holds promise for preclinical and clinical imaging of neuro-inflammation and other inflammatory conditions.