Do Brain Extracellular Fluid Concentrations Predict PET-Inferred Receptor Occupancy in Human CNS? A Mechanistic...

We previously developed a mechanistic model framework integrating physiologically based pharmacokinetic model (LeiCNS-PK3.0), binding kinetics, and receptor dynamics, to predict regional human central nervous system (CNS) receptor occupancy (RO), using brain extracellular fluid (brain_ECF) concentrations. Positron emission tomography (PET)-RO is a non-invasive biomarker to estimate, and validate human CNS RO. However, for highly lipophilic drug buprenorphine brain_ECF concentrations-based RO predictions deviated substantially from PET-RO. This mismatch and the lipophilicity driven brain cell membrane (brain_M) accumulation motivated us to investigate relevance of brain_ECF vs. brain_M concentrations for PET-RO. We identified human studies reporting plasma PK and CNS PET-RO for D2 receptor ligands spanning lipophilicities. Population PK parameters, derived via model fitting, served as inputs to the mechanistic framework to simulate brain_ECF and brain_M-based regional RO and compared with PET-RO. We systematically assessed the impact of lipophilicity, receptor dynamics, endogenous ligands, and schizophrenia-related physiological changes on simulations accuracy. Brain_M concentrations showed better agreement with PET-RO than brain_ECF for five of eight D2 ligands. However, neither improvement nor brain_M partitioning showed a clear trend with logP; $K_p^M$ substitution yielded modest improvement. Receptor internalization reduced simulated RO and enhanced PET agreement (remoxipride/haloperidol), independent of lipophilicity. Endogenous dopamine and schizophrenia-related changes had negligible effects. This study demonstrated that brain_M concentrations offer improved PET-RO alignment for a subset of compounds, independent of lipophilicity suggesting role of other drug-specific factors in brain_M accumulation or lack thereof. The integrated mechanistic framework offers potential to enhance CNS drug treatment, subject to further development via qMRI, hMRI, MRS, and controlled clinical studies.