Rescue of Cognitive Deficits in a Mouse Model of Alzheimer’s Disease with a Novel Brominated P2 × 7 Receptor Antagonist

P2 × 7 receptor (P2 × 7R) represents a promising therapeutic target for Alzheimer’s disease (AD), given its marked upregulation in neuroinflammation and involvement in amyloid-β (Aβ) and tau pathology. Although several P2 × 7R antagonists with high central nervous system (CNS) penetration and cross-species activity have been developed, none have yet reached clinical use, underscoring the need for optimized agents suitable for chronic neurological conditions. In this study, we designed a series of brominated P2 × 7R antagonists based on a prominent antagonist Lu AF27139, among which the lead compound YH1 exhibited favorable lipophilicity, brain penetration, plasma stability, and receptor binding. In transgenic AD mice, YH1 treatment significantly alleviated cognitive deficits, reduced cerebral P2 × 7R expression, and decreased Aβ load. Using 18 F-GSK1482160 positron emission tomography (PET) imaging, we observed a significant decline of P2 × 7R binding, indicating that YH1-mediated cognitive improvement involves targeted suppression of P2 × 7R-driven neuroinflammation. These results establish a precision AD-oriented optimization of the Lu AF27139 scaffold, demonstrate measurable PK improvements, and provide the first PET-verified P2 × 7R target engagement in an AD model, supporting translational relevance.