Design and Developmentof a Novel BET Protein-TargetedPET Imaging Probe for In VivoCharacterization of Alzheimer’s Disease Pathophysiology

BET proteins are essential epigenetic regulators involved in gene transcription and have been linked to neurodegenerative disorders, such as Alzheimer’s disease (AD). In vivo imaging of BET proteins may provide insights into disease pathophysiology and help identify potential therapeutic targets. We developed a carbon-¹¹-labeled radiotracer, [¹¹C]YL9, which exhibits high binding affinity for BET proteins. It was synthesized via standard methylation and evaluated for brain uptake, binding specificity, and pharmacokinetics in wild-type and AD mouse models using PET imaging and autoradiography. [¹¹C]YL9 demonstrated excellent blood-brain barrier penetration, prolonged retention, and strong BET protein binding. In AD mice, [¹¹C]YL9 uptake was significantly higher than in wild-type mice, suggesting increased BET protein availability. These findings suggest that [¹¹C]YL9 is a promising PET radioligand for noninvasive BET protein imaging. Its high specificity and favorable pharmacokinetics make it a valuable tool for studying BET protein involvement in neurodegeneration.