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Rescue of Cognitive Deficits in a Mouse Model of Alzheimer's Disease with a Novel Brominated P2 × 7 Receptor
Yuyi Hou1, Guolong Huang1, Yongshan Liu1
1Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China.
Abstract:
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 18F-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.
Insights
Researchers developed YH1, a novel P2 × 7 receptor (P2 × 7R) antagonist, to treat Alzheimer's disease (AD). YH1 improved cognition and reduced AD pathology in mice by targeting neuroinflammation.
Area of Science:
- Neuroscience
- Pharmacology
- Drug Discovery
Background:
- P2 × 7 receptor (P2 × 7R) is upregulated in Alzheimer's disease (AD) and linked to neuroinflammation and core pathologies.
- Existing P2 × 7R antagonists lack clinical translation due to limitations in CNS penetration and suitability for chronic neurological conditions.
Purpose of the Study:
- To optimize P2 × 7R antagonists for Alzheimer's disease treatment.
- To develop a novel compound with improved pharmacokinetic properties and brain penetration.
Main Methods:
- Design and synthesis of brominated P2 × 7R antagonists based on the Lu AF27139 scaffold.
- Evaluation of lead compound YH1 in transgenic AD mice, assessing cognitive function, P2 × 7R expression, and amyloid-β (Aβ) load.
- Positron emission tomography (PET) imaging using 18F-GSK1482160 to confirm P2 × 7R target engagement in vivo.
Main Results:
- The lead compound YH1 demonstrated favorable lipophilicity, brain penetration, plasma stability, and P2 × 7R binding.
- YH1 treatment in AD mice significantly improved cognitive deficits and reduced cerebral P2 × 7R expression and Aβ load.
- PET imaging confirmed a significant reduction in P2 × 7R binding, indicating successful target engagement and suppression of neuroinflammation.
Conclusions:
- YH1 represents a precision-optimized P2 × 7R antagonist scaffold for AD.
- The study demonstrates significant pharmacokinetic improvements and provides the first PET-verified P2 × 7R target engagement in an AD model.
- These findings support the translational relevance of YH1 for treating Alzheimer's disease.
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