The applicant of this revised K08 Mentored Clinical Scientist Development Award (MCSDA) is seeking to become an independent investigator focusing on the neurobiology of mood disorders. Research proposed for the next five years focuses on expanding my technical expertise in designing, executing and interpreting PET imaging research with radioligands developed for molecular targets in the brain. In order to achieve independence in the field of molecular imaging as it applies to the study of mental illness, I will work with my Sponsor who conducts many PET radioligand studies in psychiatric patient populations. The research project proposed together with mentoring and formal didactic coursework focuses on translation of basic discoveries to early phase clinical testing, including the expertise needed to move newly synthesized molecular imaging probes through the regulatory barriers to early phase clinical studies. The specific objective of the research proposed in this application is to characterize [11C]-MPT, our new serotonin 1A (5-HT1A) receptor agonist radioligand in baboon and then in human brain. We will test the hypothesis that [11C]-MPT will be sensitive to changes in brain intra-synaptic 5-HT levels in baboon and human (by tryptophan depletion and iv citalopram administration). We will also test the hypothesis that the ratio of antagonist (carbonyl-[11C]WAY-100635) to agonist ([11C]-MPT) receptor binding is greater than one and therefore the ratio of low versus high agonist affinity 5-HT1A binding sites can be estimated. This ratio is an important determinant of serotonergic transmission efficacy that may be altered in a variety of psychiatric conditions. The 5-HT1A receptors have been implicated in depression, anxiety, psychosis and memory disturbances. The development and characterization of a successful agonist radioligand would assist research into the role of the 5-HT1A receptor in the neurobiology of these illnesses by quantifying 5-HT1A receptors in the high agonist affinity state that can couple via G proteins to the second messenger system, and by quantifying intra-synaptic serotonin in response to therapeutic and/or experimental interventions in disease and health. There is currently no 5- HT1A agonist radioligand available for in vivo PET imaging. Training research scientists in areas of translational research such as proposed here can accelerate the translation of new PET tracers to clinical research.
