Targeted delivery of mGluR1 ligand RMGOH via lipid nanoparticles: a novel approach for enhancing CNS drug accessibility

Abstract

Delivery of pharmaceuticals to the brain is challenging due to the presence of the blood–brain barrier (BBB), which limits the entry of unwanted substances. This study focuses on developing effective targeting strategies for the central nervous system (CNS). The selective mGluR1 receptor ligand, RMGOH (4-hydroxy-N-(4-(6-(isopropylamino)pyrimidin-4-yl)thiazol-2-yl)-N-methylbenzamide), was identified using computational tools like ADMET analysis, molecular docking and molecular dynamics simulations. RMGOH demonstrated promising binding affinity with a glide score of −4.13 kJ mol⁻¹ and favorable pharmacokinetic properties for the BBB and CNS permeability. The synthesis of RMGOH-lipid nanoparticles (LNs) was conducted with DSPC cationic lipids, followed by in vitro and in vivo studies. The nanoparticles exhibited an average size of 179 nm and controlled drug release over 72 hours. Hemolysis tests indicated RMGOH's safety for in vivo applications. The compound achieved over 95% radiolabelling efficiency with ^99mTc and biodistribution studies with ^99mTcRMGOH-LNs showed significant brain uptake. Overall RMGOH-LNs are promising for evaluating mGluR1 in specific brain regions.