Discovery and Characterization of SPL028: Deuterated ,-Dimethyltryptamine.

The psychedelic ,- dimethyltryptamine (DMT) is in clinical development for the treatment of major depressive disorder. However, when administered via intravenous infusion, its effects are short-lived due to rapid clearance. Here we describe the synthesis of deuterated analogues of DMT with the aim of prolonging the half-life and decreasing the clearance rate while maintaining similar pharmacological effects. The molecule with the greatest degree of deuteration at the α-carbon (,-D-dimethyltryptamine, D-DMT) demonstrated the longest half-life and intrinsic clearance in hepatocyte mitochondrial fractions when compared with DMT. The receptor binding profile of D-DMT was comparable to that of DMT, with the highest affinity at the 5-HT, 5-HT, and 5-HT receptors. D-DMT was therefore the preferred candidate to consider for further evaluation.