Background/Objectives: GL-II-73 is a positive allosteric modulator that is selective for α5GABA_A receptors and has physicochemical properties that favor nanocarrier formulations when parenteral delivery to the central nervous system is desired. Our aim was to develop an optimized nanoemulsion containing GL-II-73 and subsequently test whether this would improve permeation across the blood–brain barrier (BBB) and availability in the brain. Methods: The nanoemulsions were formulated and subjected to detailed physiochemical characterization. The optimized formulation was tested in comparison to a solution of GL-II-73 in the appropriate solvent in an in vitro model of the blood–brain barrier based on human induced pluripotent stem cell-derived microvascular endothelial cells, astrocytes, and pericytes. Plasma and brain exposure to GL-II-73 and its metabolite MP-III-022 was investigated in an in vivo neuropharmacokinetic study in rats exposed to the selected nanoemulsion and the conventional solution formulation. Results: The selected biocompatible nanoemulsion exhibited satisfactory physicochemical properties for parenteral administration, with a Z-ave of 122.0 ± 1.5, PDI of 0.123 ± 0.009 and zeta potential of −40.7 ± 1.5, pH of 5.16 ± 0.04, and adequate stability after one year of storage, and allowed the localization of GL-II-73 in the stabilization layer. The permeability of GL-II-73 through the BBB was twice as high with the selected nanoemulsion as with the solution. The availability of GL-II-73 and MP-III-022 (also a positive allosteric modulator selective for α5GABA_A receptors) in the brain was 24% and 61% higher, respectively, after intraperitoneal administration of the nanoemulsion compared to the solution; the former increase was statistically significant. Conclusions: The increased permeability in vitro proved to be a good predictor for the improved availability of GL-II-73 in brain tissue in vivo from the formulation obtained by encapsulation in a nanoemulsion. The putative additive effect of the parent molecule and its metabolite MP-III-022 could lead to enhanced and/or prolonged modulation of α5GABA_A receptors in the brain.

Background/Objectives: The novel pyrazoloquinolinone ligand CW-02-79 shows a unique profile of selective binding to σ2 receptors, but its poor solubility in both water and lipids makes its research and development a burdensome task. We aimed to develop a phospholipid-complex-based nanoemulsion formulation containing CW-02-79 suitable for intravenous administration in preclinical research. Methods: The decorated and undecorated nanoemulsions were formulated and subjected to detailed physiochemical characterization. The delivery and exposure to CW-02-79 from selected nanoemulsions were examined in the in vitro blood–brain barrier model based on human-induced pluripotent stem-cell-derived microvascular endothelial cells, astrocytes, and pericytes, and in vivo neuropharmacokinetic study in rats, respectively. Results: The developed biocompatible nanoemulsions loaded with a CW-02-79—phospholipid complex at a mass ratio of 1:10 exhibited a small droplet size and narrow size distribution, with satisfactory physicochemical stability during steam sterilization and short-term storage at 25 °C. The analysis of protein binding interactions revealed that the PEGylated nanoemulsions had fewer observable interactions compared to the undecorated nanoemulsions, especially when 0.2% DSPE-PEG2000 and 0.1% DSPE-PEG2000-mannose were combined. An in vitro BBB study demonstrated that a substantial part of CW-02-79 present in the applied nanoemulsion is able to permeate the barrier. The quantification of CW-02-79 in plasma/brain homogenate and calculated pharmacokinetic parameters confirmed good systemic and brain availability after intravenous administration. There were subtle differences in the pharmacokinetic parameters in favor of a dual surface-functionalized nanoemulson containing the glucose transporter-1-targeting ligand (mannose). Conclusions: The developed and characterized nanoemulsions enable substantial brain exposure to CW-02-79 as a prerequisite for a pharmacologically and clinically relevant selective modulation of σ2 receptors.