Di-acetyl creatine ethyl ester, a new creatine derivative for the possible treatment of creatine transporter deficiency

Neurosci Lett. 2018 Feb 5:665:217-223. doi: 10.1016/j.neulet.2017.12.020. Epub 2017 Dec 8.


Creatine is pivotal in energy metabolism of the brain. In primary creatine deficiency syndromes, creatine is missing from the brain. Two of them (AGAT and GAMT deficiency) are due to impaired creatine synthesis, and can be treated by creatine supplementation. By contrast, creatine transporter deficiency cannot be treated by such supplementation, since creatine crossing of biological membranes (plasma membrane and blood-brain barrier) is dependent on its transporter. This problem might be overcome by modifying the creatine molecule to allow it to cross biological membranes independently of its transporter. Thus, we designed and synthesized di-acetyl creatine ethyl ester (DAC), a compound that should cross biological membranes independently of the transporter due to its very high lipophilicity. We investigated its ability to increase intracellular creatine levels even after block of creatine transporter, and to counter cell damage induced by transporter block. In our experiments after block of the creatine transporter, DAC was able both to prevent electrophysiological failure and to increase intracellular creatine. Interestingly, it did so in micromolar concentrations, at variance with all the other creatine derivatives that we know of.

Keywords: Creatine; Creatine derivatives; Creatine transporter deficiency; Di-acetyl creatine ethyl ester.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain Diseases, Metabolic, Inborn
  • Creatine / analogs & derivatives*
  • Creatine / deficiency*
  • Creatine / metabolism
  • Creatine / pharmacology
  • Guanidinoacetate N-Methyltransferase / deficiency*
  • Guanidinoacetate N-Methyltransferase / drug effects
  • Language Development Disorders
  • Membrane Transport Proteins / drug effects*
  • Mental Retardation, X-Linked
  • Mice
  • Movement Disorders / congenital*
  • Plasma Membrane Neurotransmitter Transport Proteins / deficiency*
  • Plasma Membrane Neurotransmitter Transport Proteins / pharmacology


  • Membrane Transport Proteins
  • Plasma Membrane Neurotransmitter Transport Proteins
  • creatine transporter
  • Guanidinoacetate N-Methyltransferase
  • creatine ethyl ester
  • Creatine

Supplementary concepts

  • Creatine deficiency, X-linked
  • Guanidinoacetate methyltransferase deficiency