[C]5-Hydroxy-tryptophan model for quantitative assessment of in vivo serotonin biosynthesis, retention and degradation in the endocrine pancreas.

[C]5-Hydroxy-tryptophan ([C]5-HTP) is a Positron Emission Tomography marker for serotonergic biosynthesis and degradation, with use in imaging of neuroendocrine tumors and recently also the endocrine pancreas in diabetes. In order to further develop [C]5-HTP as a quantitative in vivo tool for understanding the mechanisms of serotonin signaling in human pancreas, we aimed to develop a kinetic modeling approach sensitive for changes in serotonin biosynthesis, retention and degradation. Cynomolgus monkeys were examined by [C]5-HTP PET/CT, either at baseline (n=9) or following intravenous pretreatment with 3 mg/kg carbidopa (Dopa Decarboxylase inhibitor, n=3) or 2 mg/kg clorgyline (Monoamine Oxidase-A inhibitor, n=5). The dynamic tissue uptake was analysed by a 2-tissue compartment model including an efflux mechanism from the second tissue compartment (2TC k), which theoretically reproduces the known processing of 5-HTP in neuroendocrine cells. The 2TC k model could accurately describe all three modes of tissue kinetics depending on the pretreatment regiment. Rate constant k (corresponding to DDC activity) and the macro-parameter Flux (K) was decreased (P<0.05) by carbidopa pretreatment, while k (corresponding to cellular washout of intact [C]5-HTP) was increased (P<0.05). The efflux parameter k (corresponding to MAO-A activity) was decreased (P<0.05) by pretreatment of clorgyline, while the macro-parameter Flux/Efflux ratio (K/k) was increased (P<0.0001). We present a compartment model analysis method that can quantitatively assess in vivo pharmacological interactions with several of the key enzymatic steps of the serotonergic biosynthesis in pancreas.