Assessment of Peripheral Serotonin Synthesis Using Stable Isotope-Labeled Tryptophan

Serotonin (5-HT) is synthesized from dietary tryptophan (Trp) and plays an important role in numerous diseases of the central nervous system and periphery. Stable isotope tracers enable safe monitoring of metabolic rates. Here we demonstrate measurement of peripheral 5-HT synthesis in healthy subjects by monitoring the produced [¹³ C₁₀ ]-5-HT (h-5-HT) in EDTA-whole blood from three doses of orally administered [¹³ C₁₁ ]-Trp (h-Trp) tracer. h-Trp was rapidly absorbed and distributed in a multiphasic manner, followed by a slower terminal elimination phase. The h-5-HT synthesis rate was dependent on h-Trp dose, appeared linear up to 12 hours postdose, and could be reliably assessed for the two highest doses. The human data was compared to similar studies in rats and dogs, finding larger interspecies differences in the h-5-HT synthesis rate than in 5-HT levels. In future studies, the h-5-HT synthesis rate can be used to assess disease-dysregulated 5-HT synthesis or quantify the pharmacodynamics of 5-HT synthesis inhibitors.