Synthesis, preclinical evaluation and pilot clinical study of a P2Y₁₂ receptor targeting radiotracer [¹⁸F]QTFT for...

Area of Science:

• Neuroscience
• Radiochemistry
• Immunology

Background:

• Microglia, the brain's immune cells, adopt diverse phenotypes crucial for brain health and disease.
• Current imaging probes primarily target pro-inflammatory microglia, leaving anti-inflammatory phenotypes largely unvisualized.
• Dynamic imaging of microglial phenotypes is vital for understanding brain diseases and treatment efficacy.

Purpose of the Study:

• To develop and validate a novel positron emission tomography (PET) tracer for visualizing anti-inflammatory microglia.
• To assess the tracer's ability to detect neuroinflammation and brain lesions in preclinical and clinical settings.

Main Methods:

• Synthesis and characterization of an 18F-labeled PET tracer ([18F]QTFT) targeting the P2Y12 receptor.
• Evaluation of [18F]QTFT binding affinity, blood-brain barrier permeability, and specificity in vitro.
• Micro-PET imaging in mouse models of IL-4-induced neuroinflammation, epilepsy, glioma, and aging.
• Blocking studies using QTFT or a P2Y12 antagonist to confirm tracer specificity.
• Pilot clinical study in an epilepsy patient.

Main Results:

• [18F]QTFT demonstrated high binding affinity for P2Y12 and excellent blood-brain barrier penetration.
• Increased [18F]QTFT uptake was observed in lesion areas of neuroinflammatory models, specifically blocked by antagonists.
• The tracer successfully visualized brain lesions in preclinical models of epilepsy, glioma, and aging.
• A pilot clinical study confirmed [18F]QTFT's ability to locate epileptic foci in a patient.

Conclusions:

• [18F]QTFT is a novel and effective PET tracer for imaging anti-inflammatory microglia.
• The tracer shows promise for diagnosing and monitoring various brain disorders characterized by altered microglial phenotypes.
• Targeting P2Y12-expressing anti-inflammatory microglia offers a new avenue for neuroimaging diagnostics.