Design and Development of a Novel BET Protein-Targeted PET Imaging Probe for In Vivo Characterization 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.