Numerous lines of evidence reviewed in the introduction of this CCNMD suggest that alterations of serotonin (5-HT) neurotransmission in discrete brain areas confer vulnerability to suicidal behavior. Recent development of methods to assess 5-HT neurotransmission in vivo with PET allows direct testing of this hypothesis in patients. The brain imaging core is an integrated team of scientists from various disciplines (chemistry, pharmacology, physics, mathematics), covering the range of expertise needed to develop and support PET neuroreceptor studies. The services provided to the Center by the brain imaging core fall into four general categories: 1) To provide logistical support and technical expertise to brain imaging projects of the Center. The core provides expertise at the level of study design, implementation, and analysis. In addition, these studies benefit from the general infrastructure maintained by the core, such as radiochemistry laboratories and image analysis workstations. 2) To provide chemistry and radiochemistry services to other cores, such as tritiated ligands or other compounds not available commercially. 3) To provide training in brain imaging to young investigators. These include PGF-IV to VI residents, who are completing a fellowship in the Brain Imaging Division, as well as other investigators in the Center, interested in applying brain imaging techniques to the study of mood disorders and suicide. 4) To develop new imaging modalities that are pertinent to suicide research. Over the next five years, our development effort will be targeted at the serotonin (5-HT) system with PET. The choice of these objectives is guided by a general model of neurochemical imbalance associated with suicide vulnerability provided in the background section. 1) To develop and validate a measure of 5HT/2A receptors binding potential in humans using the radiolabeled antagonist [11C],DL 100907; 2) To develop a new radiotracer to measure 5-HT/1B receptors with PET ([11C]GR127935); 3) To develop a new radiolabeled agonist to measure the agonist high affinity state of the 5-HT/1A receptors ([11C]MHA) and to develop with this ligand a measure of 5-HT release based on endogenous competition techniques; 4) To develop a radiolabeled agonist to measure high affinity state of 5HT/2A receptors ([123I]/[11C]DOI). Together, these projects should provide new and sophisticated tools for the in vivo characterization of 5-HT neurotransmission in patients with history of suicidal attempts. The radiotracers developed during this funding cycle of the Center will be used in clinical studies in the next funding cycle.
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