This project is designed to develop new and selective [I-123] labeled 5-HT1A receptor agonists and antagonists as single photon emission computed tomography (SPECT) imaging agents for evaluation of this serotonin (5-HT) receptor subtype in brain. The serotonin neurotransmission system is an important CNS network regulating various normal neurological functions and psychological behavior including anxiety and affective states. The serotonin receptor subtype 5-HT1A plays an important function as somatodendritic autoreceptor (presynaptic) in the dorsal raphe nucleus and as a postsynaptic receptor in 5-HT terminal fields. Development of SPECT imaging agents will facilitate the study of the basic pharmacology of 5-HT1A receptors. Moreover their interactions with various agents may improve our understanding of normal CNS function as well as in disease states. In this project, the design of 5-HT1A ligands will be based on the agonist, (R)-(+)-8-OH-PIPAT (Kd=0.09nM), and the antagonist, p-MPPI (Kd=0.3nM), which were both developed by the applicant. Because of the failure of these two agents to show desired localization in human SPECT studies despite promising in vitro characteristics, new ligands with high affinity and extended in vivo stability will be prepared and evaluated. Ultimately, the best imaging agent for quantitative SPECT will be selected from these new ligands.