Our first study indicated that serotonin synthesis rates determined by the use of alpha-methyltryptophan (MTP) and PET imaging were found to be highly correlated to free plasma tryptophan concentrations, a parameter that is not well correlated to the regulation of serotonin synthesis rates under steady state conditions, and not to cerebrospinal fluid concentrations of 5- hydroxy- indole-3-acetic acid, long considered a measure of central serotonin turnover.(Paper in press). In order to determine what is actually being measured by alpha-MTP uptake, 11-C and 14-C compound were co-administered to four rhesus monkeys. After a one hour PET scan, animals were euthanized and brain tissues were taken and frozen at -80 degrees C. HPLC analysis with flourometric detection and fraction collection indicates that alpha- MTP is not converted to alpha- methylserotonin in most brain tissues and therefore acts primarily as a tracer of tryptophan uptake. A paper is currently being written. Development of ligands for detection of serotonin receptors continues. Dosimetry studies of [11-C]MDL-100907 are being performed. Toxicity testing of fluorine derivatives of WAY-100635 are being conducted. Metabolism studies indicate that they have fewer metabolites that cross the blood brain barrier. Binding studies indicated that they were silent antagonists.
