Sustainable Chemistry and Preclinical Characterization of RC-106·HCl: A Brain-Penetrant Pan Sigma Receptor Modulator for Glioblastoma

• Eco-sustainable and scalable synthesis of high-purity RC-106·HCl enables preclinical evaluation. • Solid-state analyses (XRPD, DSC, TGA, FT-IR, SEM) confirm a crystalline and thermally stable form. • RC-106·HCl shows consistent cytotoxic and pro-apoptotic effects in commercial and patient-derived GBM cells (IC₅₀ = 44–54 μM). • In vivo, RC-106·HCl penetrates the brain and reduces intracranial tumor burden in PDOX mice. • Excellent tolerability and favorable ADMET properties support further pharmacokinetic optimization. RC-106 is a Sigma receptor modulator under investigation as a potential therapeutic agent for glioblastoma (GBM). Here, we report a multigram-scale synthesis based on green chemistry principles, its comprehensive solid-state characterization, and its preclinical evaluation in vitro and in vivo . ADMET prediction indicated good drug-likeness, absence of PAINS features, compliance with Lipinski criteria, favorable metabolic stability, and the ability to cross the blood–brain barrier. The optimized synthetic process to obtain RC-106· HCl (>99% purity) for solid-state characterization performed by TGA, DSC, FT-IR, XRPD, and SEM, confirming the compound crystalline nature and appropriate thermal behavior. in vivo , RC-106 consistently reduced cell viability in both commercial (U87, A172) and patient-derived GBM cell lines (G34, G48) under hypoxic conditions, inducing apoptosis and neurosphere disaggregation with IC₅₀ values between 44 and 54 μM. In vivo , using a patient-derived orthotopic xenograft (PDOX) mouse model, daily administration of RC-106 ·HCl (20 mg/kg) was well tolerated, with no observable systemic or neurological toxicity, as evidenced by stable body weight and preserved motor performance. Intraperitoneal administration of RC-106 ·HCl, although it did not definitively arrest tumor growth, resulted in a time-dependent reduction in intracranial GBM burden in our patient-derived orthotopic xenograft (PDOX) model. Pharmacokinetic and biodistribution analyses supported rapid absorption and distribution to the brain and spinal cord. Overall, RC-106 ·HCl shows promising in vitro anti-GBM activity and an excellent safety profile in vivo , while further optimization is needed to enhance its pharmacokinetic properties and therapeutic effectiveness.