Synthesis of Psilocin, Psilocybin and 5‐MeO‐DMT Succinate, All Labelled With Carbon‐14 at the Indole 2‐Position

Three new radiolabelled versions of the psychedelic compounds psilocin, psilocybin, and 5-MeO-DMT were synthesized, each with carbon-14 at the 2-position of the indole ring. The synthesis used a common route: attaching the dimethylaminoethyl side chain to substituted indole intermediates via oxalyl chloride, dimethylamine, and lithium aluminium hydride reduction. Psilocybin-2-14C at 234 μCi/mg showed limited stability, but a 5.5-fold dilution with unlabelled psilocybin maintained >97.5% radiochemical purity after one month at ≤−70°C. 5-MeO-DMT-2-14C succinate at 173 μCi/mg remained 98.0% pure after six months at ≤−70°C, supporting long-term studies. These labelled compounds enable in vivo pharmacokinetic and metabolic studies of psychedelic tryptamines, aiding ADME and mass balance research for potential regulatory approval in treating depression, anxiety, and PTSD.

Study at a glance

Abstract

ABSTRACT Three novel 14 C‐labelled isotopologues of the psychoactive agents psilocin, psilocybin and 5‐methoxy‐ N , N ‐dimethyltryptamine (5‐MeO‐DMT) were synthesised, all labelled at the 2‐position of the indole. The syntheses involved incorporating the 3‐dimethylaminoethyl substituent common to all three substances onto a 4‐ or 5‐substituted indole intermediate via successive treatments with oxalyl chloride, dimethylamine and reduction with lithium aluminium hydride. Psilocybin‐ 2 ‐ 14 C with a specific activity of 234 μCi/mg exhibited limited stability, but a 5.5‐fold radio dilution with unlabelled psilocybin afforded material that maintained a radiochemical purity exceeding 97.5% after 1‐month storage at ≤ −70°C. The stability of 5‐MeO‐DMT‐ 2 ‐ 14 C succinate salt with a specific activity of 173 μCi/mg was assessed over a more extended storage period, and after 6 months at ≤ −70°C the radiochemical purity was 98.0%, supporting its use in long‐term studies. The radiolabelled psilocybin‐ 2 ‐ 14 C and 5‐MeO‐DMT‐ 2 ‐ 14 C succinate represent new tools for in vivo pharmacokinetic and metabolic studies with psychedelic tryptamines. These novel derivatives may offer enhanced metabolic stability and facilitate more precise ADME and mass balance studies. Future research will explore their behaviour in biological systems to support necessary studies toward regulatory approval of both psilocybin and 5‐MeO‐DMT for treating mental health disorders such as depression, anxiety and post‐traumatic stress disorder.