Illuminating proinflammatory myeloid cells with PET tracers targeting GPR84

Area of Science:

• Neuroscience
• Immunology
• Radiochemistry

Background:

• Chronic activation of myeloid cells contributes to tissue damage and neurodegeneration.
• Current positron emission tomography (PET) tracers for neuroinflammation often lack specificity for activated myeloid cells.
• G protein-coupled receptor 84 (GPR84) is selectively upregulated on activated microglia and macrophages, making it a promising biomarker.

Purpose of the Study:

• To develop and validate novel fluorine-18-labeled GPR84 tracers for molecular imaging of myeloid cell activation.
• To assess the specificity, affinity, and performance of [18F]MGX-110S and [18F]MGX-111S in detecting inflammation.

Main Methods:

• Synthesis and radiolabeling of two GPR84 tracers: [18F]MGX-110S and [18F]MGX-111S.
• In vitro validation of tracer binding to GPR84-expressing cells.
• In vivo PET imaging studies in mouse models of systemic and neuroinflammation (LPS-treated and 5xFAD mice).
• Comparison with a translocator protein 18 kDa (TSPO) radiotracer.

Main Results:

• Both [18F]MGX-110S and [18F]MGX-111S showed specific binding to GPR84.
• [18F]MGX-110S demonstrated superior affinity, selectivity, and signal-to-background ratio compared to [18F]MGX-111S.
• In vivo, [18F]MGX-110S successfully detected systemic and neuroinflammation in mice and outperformed a TSPO tracer in visualizing pathology-correlated myeloid cell activation in the 5xFAD model.

Conclusions:

• [18F]MGX-110S is a highly sensitive and specific PET tracer for visualizing maladaptive myeloid cell activation.
• Clinical translation of [18F]MGX-110S could enhance the detection, staging, and therapeutic monitoring of neurodegenerative and other inflammatory diseases.