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

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.