Mechanosensitive Piezo1 channel is highly expressed in the eukaryotic central nervous system and involved in many important physiological functions that maintain cell homeostasis. This membrane ion channel is opened by different forms of mechanical and chemical stimulation. However, pharmacological tools for Piezo1 channel manipulations and in vivo application are limited. In the present study, to address this need, 12 L-type amino acid transporter 1 (LAT1)-utilizing brain-targeted conjugates of Piezo1 activators, Jedi1 and Jedi2, were synthesized and evaluated for their physicochemical and pharmaceutical properties. As a result, the novel compounds were more effectively transported via LAT1 into mouse BV2 microglia cells. Moreover, compared to their parent compounds, they had a higher ability to activate Piezo1 measured by a fluorescent live calcium imaging assay. Furthermore, the pharmacokinetic study revealed that the compounds were delivered into the mouse brain and were distributed to other peripheral tissues to a lesser extent than their parent compound, Jedi2. Therefore, these novel conjugates can be considered as potential compounds to achieve brain- and microglia-targeted delivery and potential neuroprotective effects via Piezo1 ion channel activation, being beneficial in the treatment of neurodegenerative disorders.
