Peripheral serotonin synthesis as a new drug target

The first step in serotonin (5-HT) biosynthesis is catalyzed by tryptophan hydroxylase (TPH). There are two independent sources of the monoamine that have distinct functions: first, the TPH1-expressing enterochromaffin cells (ECs) of the gut; second, TPH2-expressing serotonergic neurons. TPH1-deficient mice revealed that peripheral 5-HT plays important roles in platelet function and in inflammatory and fibrotic diseases of gut, pancreas, lung, and liver. Therefore, TPH inhibitors were developed which cannot pass the blood–brain barrier to specifically block peripheral 5-HT synthesis. They showed therapeutic efficacy in several rodent disease models, and telotristat ethyl is the first TPH inhibitor to be approved for the treatment of carcinoid syndrome. We review this development and discuss further therapeutic options for these compounds.