Discovery and In Vitro Characterization of SPL028: Deuterated N,N-Dimethyltryptamine

The psychedelic N,N- 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 (N,N-D₂-dimethyltryptamine, D₂-DMT) demonstrated the longest half-life and intrinsic clearance in hepatocyte mitochondrial fractions when compared with DMT. The in vitro receptor binding profile of D₂-DMT was comparable to that of DMT, with the highest affinity at the 5-HT_1A, 5-HT_2A, and 5-HT_2C receptors. D₂-DMT was therefore the preferred candidate to consider for further evaluation.