Microglia-Specific Molecular Magnetic Resonance Imaging Probe Enables Noninvasive Separation of Parkinsonian Mice...

Neuroinflammation mediated by reactive microgliosis is a central driver of Parkinson's disease (PD) pathogenesis. This inflammatory process unfolds years before clinical symptoms, creating an opportunity for early intervention. In vivo imaging technologies that could detect and quantify microglial reactivity are therefore essential for early diagnosis, patient stratification, and evaluating emerging immunomodulatory therapies that target this fundamental driver of PD progression. Yet no standardized, sensitive, and specific technology currently achieves this goal. Molecular magnetic resonance imaging (mMRI) is uniquely suitable to address this problem because it integrates inherent high spatial resolution and soft-tissue contrast of conventional MRI with molecularly targeted contrast agents, enabling simultaneous acquisition of anatomical detail and functional/biological information at submillimeter isotropic resolution. Here we present a novel mMRI probe designed to specifically target colony stimulating factor-1 receptor, expressed primarily on microglia in the brain. In silico data show that the targeting ligand binds the extracellular Ig domain of the receptor. In vitro cell uptake studies with both murine and human microglia cell lines show that the probe binds the receptor triggering active cell uptake and in vivo MRI enabled effective separation of the A53T mouse model of Parkinson's disease from control mice using radiomics-assisted MR image analysis. Ex-vivo immunohistochemical analysis showed signal from the probe largely in the cytosolic compartment of IBA-1 reactive cells, confirming that the observed in vivo MRI signal is due primarily to retention of the agent by microglia. This novel technology has the potential to interrogate the rgional presentation of microglial activation in PD.