Fluoroethylnormemantine, A Novel Derivative of Memantine, Facilitates Extinction Learning Without Sensorimotor Deficits

Int J Neuropsychopharmacol. 2021 Jul 14;24(6):519-531. doi: 10.1093/ijnp/pyab007.


Background: Memantine, a noncompetitive N-methyl-D-aspartate receptor antagonist, has been approved for use in Alzheimer's disease, but an increasing number of studies have investigated its utility for neuropsychiatric disorders. Here, we characterized a novel compound, fluoroethylnormemtantine (FENM), which was derived from memantine with an extra Fluor in an optimized position for in vivo biomarker labeling. We sought to determine if FENM produced similar behavioral effects as memantine and/or if FENM has beneficial effects against fear, avoidance, and behavioral despair.

Methods: We administered saline, FENM, or memantine prior to a number of behavioral assays, including paired-pulse inhibition, open field, light dark test, forced swim test, and cued fear conditioning in male Wistar rats.

Results: Unlike memantine, FENM did not produce nonspecific side effects and did not alter sensorimotor gating or locomotion. FENM decreased immobility in the forced swim test. Moreover, FENM robustly facilitated fear extinction learning when administered prior to either cued fear conditioning training or tone reexposure.

Conclusions: These results suggest that FENM is a promising, novel compound that robustly reduces fear behavior and may be useful for further preclinical testing.

Keywords: FENM; NMDAR antagonist; PTSD; cued fear conditioning; extinction learning.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Behavior, Animal / physiology*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Extinction, Psychological / drug effects*
  • Fear / drug effects*
  • Male
  • Memantine / analogs & derivatives*
  • Memantine / pharmacology*
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*


  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • fluoroethylnormemantine
  • Memantine