Inhibition of serotonin transport by (+)McN5652 is noncompetitive.

INTRODUCTION: Imaging of the serotonergic innervation of the brain using positron emission tomography (PET) with the serotonin transporter (SERT) ligand [11C] (+)McN5652 might be affected by serotonin in the synaptic cleft if there is relevant interaction between [11C] (+)McN5652 and serotonin at the SERT. The aim of the present study therefore was to pharmacologically characterize the interaction of [11C] (+)McN5652 and serotonin at the SERT. METHODS: In vitro saturation analyses of [3H]serotonin uptake into HEK293 cells stably expressing the human SERT were performed in the absence and presence of unlabelled (+)McN5652. Data were evaluated assuming Michaelis-Menten kinetics. RESULTS: Unlabelled (+)McN5652 significantly reduced the maximal rate of serotonin transport V(max) of SERT without affecting the Michaelis-Menten constant K(M). CONCLUSIONS: This finding indicates that (+)McN5652 inhibits serotonin transport through the SERT in a noncompetitive manner. This might suggest that [11C] (+)McN5652 PET is not significantly affected by endogenous serotonin.

Discovery of biomarkers in human urine and cerebrospinal fluid by capillary electrophoresis coupled to mass spectrometry: towards new diagnostic and therapeutic approaches.

We report on our results using capillary electrophoresis coupled to mass spectrometry (CE-MS) to examine human bodyfluids. To demonstrate the versatility of this approach, data on two different bodyfluids, urine and cerebrospinal fluid, are shown. CE-MS analysis of human urine enables the identification of a series of polypeptides which serve as biomarkers for a variety of different renal diseases. The polypeptides are utilized to generate disease-specific polypeptide patterns. Diagnosis of these diseases is possible based on these polypeptide patters. Further, due to the high mass accuracy, polypeptides of interest can subsequently be identified using tandem MS (MS/MS) analysis. The patterns, which are based on distinct polypeptides, allow differentiation of even similar diseases like focal-segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). We present preliminary data suggesting that the indicative polypeptides also enable to evaluate therapy success. Initial data obtained on human cerebrospinal fluid strongly suggest that CE-MS analysis of low-molecular-weight proteins and peptides reveals several potential biomarkers for schizophrenia as well as Alzheimer's disease. In conclusion, the data presented here indicate that CE-MS analysis, applied towards different human bodyfluids, holds the promise to allow diagnosis, staging, and evaluation of therapy success of a large number of diseases, due to its ability to display ca. 1000 individual native polypeptides within ca. 60 min.