Pharmacological characterization of SYT-510, a first-in class selective endocannabinoid reuptake inhibitor and clinical candidate for stress- and anxiety-related disorders[

Background

The endocannabinoid system (ECS) exerts a key neuromodulatory role in the central nervous system [1]. On a functional level it is involved in regulating neurotransmitter release of major neuronal circuits [2]. Its dysfunction has been implicated in a variety of neuropsychiatric diseases such as anxiety disorders, post-traumatic stress disorder and obsessive compulsive disorder [3]. While ECS modulators have been tested in humans with some therapeutic benefits, more effective ECS modulators with better specificity and efficacy are needed.

Objectives

Here, we present the preclinical pharmacological characterization of SYT-510, the first clinical candidate of a new class of ECS modulators called Selective Endocannabinoid Reuptake Inhibitors (SERIs).

Methods

In vitro assays were employed to characterize SYT-510’s mode of action and specificity. Ex vivo electrophysiological recordings in rodent brain slices were used to gain insight on the neuromodulatory function of SYT-510. In vivo rodent animal models were utilized to study the efficacy of SYT-510 on symptoms relevant to CNS disorders (Elevated zero maze, elevated plus maze, open field test, marble burying test, tetrad test). All data are presented as mean values ± SD or mean values ± SEM. Data was tested for outliers using either Grubbs test (alpha = 0.05) or ROUT test (Q=5%). Data as analyzed using non-parametrical methods. However, if a data set followed normal distribution (D’Agostino & Pearson test, the Anderson Darling Test, the Shapiro-Wilk test, or the Kolmogorov-Smirnov test), parametrical methods for analysis were applied. A confidence level of p<0.05 was considered statistically significant.

Results

SYT-510 binds to the newly identified endocannabinoid (eCB) membrane transporter ACSL4 isoform 2 and selectively and reversibly inhibits the uptake of both major eCBs anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in immune and neuronal cells. The compound shows high selectivity against the other components of the ECS (CB1R, CB2R, FAAH, MAGL, ABHD6, ABHD12) as well as against a panel of CNS-related targets (receptors and ion channels). In brain slices, SYT-510 elicits CB1 receptor-mediated, ACSL4-dependent short-term synaptic plasticity in regions relevant to anxiety as well as learning and memory. SYT-510 is effective in animal models of anxiety and compulsive behavior. The pharmacological effect is evident after a single administration as well as upon chronic treatment without any signs of tolerance. It correlates with moderate increases in eCB levels, which are sufficient to fully activate the ECS without eliciting sedation, abuse potential and the typical psychotropic effects associated with exogenous activation of CB1 receptor. These results support SYT-510’s neuromodulatory potential via elevation of the endogenous cannabinoid tone.

Conclusions

Taken together, SYT-510 is the first candidate of SERIs, a novel class of ECS modulators that potently and selectively inhibits eCB reuptake, thereby rebalancing and gently enhancing the homeostatic eCB tone ultimately restoring normal brain function under disease conditions. SERIs show broad therapeutic potential across psychiatric disorders. SYT-510 is in clinical development for neuropsychiatric disorders and currently in Phase 2 for Generalized Anxiety Disorder.

References

Iannotti, F.A., Di Marzo, V., 2025. The endocannabinoidomes: Pharmacological redundancy and promiscuity, and multi-kingdom variety of sources and molecular targets. Pharmacol Rev 77, 100070. https://doi.org/10.1016/j.pharmr.2025.100070
Mechoulam, R., Parker, L.A., 2013. The Endocannabinoid System and the Brain. Annual Review of Psychology 64, 21–47. https://doi.org/10.1146/annurev-psych-113011-143739
Lutz, B., Marsicano, G., Maldonado, R., Hillard, C.J., 2015. The endocannabinoid system in guarding against fear, anxiety and stress. Nat Rev Neurosci 16, 705–718. https://doi.org/10.1038/nrn4036