The development of effective central nervous system (CNS) drugs has been hampered by the lack of robust strategies to mimic the blood-brain barrier (BBB) and cerebrovascular impairments in vitro. Recent technological advancements in BBB modeling using induced pluripotent stem cells (iPSCs) allowed to overcome some of these obstacles, nonetheless the pertinence for their use in drug permeation study remains to be established. This mandatory information requires a cross comparison of in vitro and in vivo pharmacokinetic data in the same species to avoid failure in late clinical drug development. Here, we measured the BBB permeabilities of 8 clinical positron emission tomography (PET) radioligands with known pharmacokinetic parameters in human brain in vivo with a newly developed in vitro iPSC-based human BBB (iPSC-hBBB) model. Our findings showed a good correlation between in vitro and in vivo drug brain permeability (R2 = 0.83; P = 0.008) which contrasted with the limited correlation between in vitro apparent permeability for a set of 18 CNS/non-CNS compounds using the in vitro iPSCs-hBBB model and drug physicochemical properties. Our data suggest that the iPSC-hBBB model can be integrated in a flow scheme of CNS drug screening and potentially used to study species differences in BBB permeation.

Creatine transporter (CrT) deficiency is an X-linked intellectual disability caused by mutations of CrT. Aim: This work focus on the preclinical development of a new therapeutic approach based on a microemulsion (ME) as drug delivery system for dodecyl creatine ester (DCE). Materials & methods: DCE-ME was prepared by titration method. Novel object recognition (NOR) tests were performed before and after DCE-ME treatment on Slc6a8-/y mice. Results: Intranasal administration with DCE-ME improved NOR performance in Slc6a8-/y mice. Slc6a8-/y mice treated with DCE-ME had increased striatal ATP levels mainly in the striatum compared with vehicle-treated Slc6a8-/y mice which was associated with increased expression of synaptic markers. Conclusion: These results highlight the potential value of DCE-ME as promising therapy for creatine transporter deficiency.