Summary:
Researchers at the University of Eastern Finland (UEF) have identified the sodium-dependent multivitamin transporter (SMVT) as a viable pathway to deliver creatine derivatives across the blood-brain barrier (BBB).
Published in ACS Chemical Neuroscience, the study demonstrates an alternative method for restoring cerebral energy metabolism in Creatine Transporter Deficiency Syndrome (CTDS), a serious genetic disorder in which the native creatine transporter is nonfunctional. By exploiting the brain’s own nutrient-uptake systems rather than disrupting vascular defenses, this strategy offers a promising platform to transport a range of therapeutics into the central nervous system (CNS).
Key Facts:
- Alternative Gateway Identified: The sodium-dependent multivitamin transporter (SMVT), which normally mediates uptake of water-soluble vitamins, can recognize and transport chemically modified creatine derivatives across the blood-brain barrier.
- Overcoming Genetic Transport Blocks: This approach addresses Creatine Transporter Deficiency Syndrome (CTDS), an X-linked metabolic disorder caused by mutations in the SLC6A8 gene that render the primary creatine transporter inactive and leave the brain chronically low in creatine.
- Broad CNS Drug Delivery Platform: Leveraging SMVT’s native carrier mechanisms provides a modular chemical framework to improve the brain availability of neurotherapeutics that otherwise cannot cross brain capillary endothelial cells.
Source: University of Eastern Finland
The blood-brain barrier is the central nervous system’s most selective gatekeeper. Built from tightly joined capillary endothelial cells and supported by astrocytic end-feet, it protects neural tissue from toxins and systemic fluctuations but also excludes most drugs—roughly 98% of small molecules and nearly all biologics—from entering the brain.
Instead of attempting to breach this delicate barrier, which raises the risk of inflammation and systemic side effects, neuroscientists have been developing targeted “Trojan horse” approaches: chemically modifying therapeutic compounds so they can be carried across the BBB by endogenous nutrient transporters.
In the reported study, investigators in UEF’s School of Pharmacy tested whether SMVT could act as such a carrier, successfully demonstrating that engineered creatine prodrugs are taken up by SMVT and transported across cerebral microvessels.
Rescuing Brain Bioenergetics in CTDS
Creatine is central to rapid cellular energy transfer, buffering ATP production through the creatine kinase circuit. Because the brain’s own creatine synthesis is limited, neural tissue depends on circulating creatine imported by dedicated membrane transporters.
In Creatine Transporter Deficiency Syndrome (CTDS), caused by loss-of-function mutations in the SLC6A8 gene that encodes the CRT1 transporter, the primary route for cerebral creatine uptake is blocked. Affected individuals exhibit profound brain creatine deficiency and severe neurodevelopmental symptoms, including intellectual disability, speech impairment, early-onset epilepsy, and autistic-like traits. Oral creatine supplements are ineffective for CTDS because creatine cannot cross the BBB without a functioning CRT1.
To bypass this obstacle, the UEF team evaluated whether SMVT—a solute carrier that normally transports vitamins such as biotin and pantothenic acid—could recognize synthetic creatine conjugates and mediate their uptake into the brain.
Through a combination of in silico analyses, in vitro transport assays, and molecular studies conducted during doctoral projects by Adéla Králová and Ville Kuorikoski, the group designed creatine prodrugs that mimic SMVT substrates. They confirmed SMVT-mediated recognition and transport of these derivatives in cultured cells, demonstrating that the brain’s multivitamin transporter can act as a secondary uptake route when native creatine transport is impaired.
Turning the Barrier Into a Carrier
The implications of this work extend well beyond treating CTDS. SMVT is stably expressed along human brain capillary endothelium, which means conjugating neuroactive molecules to SMVT-recognized chemical motifs could consistently improve brain penetration for many therapeutic classes, from neuroprotective agents to anticonvulsants.
Associate Professor Kristiina Huttunen, who led the team, summarizes the significance: SMVT is not only a nutrient channel but also a practical gateway for drug delivery into the brain. Rather than attempting to overcome or disrupt the BBB, using its own transport systems provides a safer and potentially more effective route to deliver therapies to neural tissue.
Supported by a Proof of Concept award from the Jane and Aatos Erkko Foundation, the researchers are advancing their most promising synthesized derivatives into preclinical pharmacokinetic studies to confirm sustained brain uptake and functional restoration of ATP levels in vivo.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by staff.
About this Neuroscience Research:
- Media Contact: Kristiina Huttunen
- Source: University of Eastern Finland
- Image Credit: Image credited to Neuroscience News
- Original Research (Open Access): ACS Chemical Neuroscience (Oct 1, 2026). Title: “Sodium-Dependent Multivitamin Transporter Facilitates Brain and Neuronal Uptake of a Creatine Analogue.” Authors: Adéla Králová, Ville Kuorikoski, Landry Anamea, Janne Tampio, Arun Kumar Tonduru, Hengjing Cui, Henri Leinonen, Jaana Rysä, Antti Poso, Tetsuya Terasaki, Aaro Jalkanen, Thales Kronenberger, and Kristiina M. Huttunen.
- DOI: 10.1021/acschemneuro.6c00484
Abstract
Sodium-Dependent Multivitamin Transporter Facilitates Brain and Neuronal Uptake of a Creatine Analogue
Creatine transporter 1 (CRT1, SLC6A8) is essential for transporting creatine across the blood–brain barrier into neurons and glia. Loss-of-function mutations in CRT1 cause creatine transporter deficiency syndrome (CTDS), a severe X-linked neurological condition lacking effective therapies.
To identify alternative routes for creatine delivery, this study deployed a carrier-mediated strategy targeting the sodium-dependent multivitamin transporter (SMVT) as a potential neuronal uptake pathway. SMVT was characterized using in silico modeling and in vitro assays to reveal substrate-binding residues and functional activity in human glioblastoma (U-87MG) and mouse neuronal cells.
Four novel creatine derivatives designed to engage SMVT were synthesized and tested in vitro. The lead compound, COMP 1, displayed SMVT-mediated uptake at concentrations below 100 μM and was taken up by both human glioblastoma cells and mouse neurons. In vivo studies showed COMP 1 accumulation in mouse brain tissue, and biochemical assays indicated interactions with the creatine kinase system relevant to ATP/ADP dynamics. Molecular dynamics simulations supported the proposed transporter–substrate interactions.
Together, these results identify SMVT as a promising route for brain uptake of creatine analogues and justify further evaluation of SMVT-targeted derivatives in animal models of CTDS and other conditions where enhanced brain delivery is needed.
