Neuroreceptor imaging techniques using positron emission tomography allow the in vivo investigation of the neurotransmitter systems in psychiatric disease. As a result, radioligand imaging can provide direction for targeted treatment strategies. This is of critical importance in developing future pharmacotherapy for substance abuse. Both preclinical and clinical studies indicate that the "direct pathway" plays a critical role in relapse. The direct pathway consists of the GABAergic neurons of the striatum that project back to the substantial nigra/VTA, and which contain the D1 receptor and dynorphin. We have currently begun studies in cocaine dependence with a D1radioligand. Therefore the goal oft his application is the development of a radioligand for the kappa receptor, which can be employed in future studies of substance dependence. In the R21 portion of this application, we propose to develop both an agonist (GR103545) and antagonist (JDTic) radiotracer, as well as their analogs, for the kappa receptor. The development of these radiotracers will begin with the optimization of their synthesis, in order to ensure the most effective and reliable chemistry. These compounds will be evaluated in vitro in order to measure their affinity for the receptor and to establish their selectivity for the kappa receptor. Those ligands shown to have a high affinity and selectivity will then be evaluated in vivo in biodistribtuion studies in rodents, followed by studies in non-human primates. The studies in baboons will be used to establish the selectivity for the kappa receptor in vivo, the susceptibility of the radioligand to endogenous dynorphin, and to develop the imaging analysis of the radioligands. The candidate radioligands that meet the criteria outlined in the milestones will be chosen for the R33 portion of this application, which includes toxicology studies and test/retest studies in healthy human volunteers. The studies in human subjects will be performed in order to establish the selectivity for the kappa receptor in humans and to determine optimal scanning protocol. At the end of the award period, we expect to have developed both a kappa agonist and antagonist, which will be available for a wide range of research centers.