New Dopamine D1 Agonists as PET Imaging Agents

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DESCRIPTION (provided by applicant): Dopamine is a neurochemical involved in many critical brain functions including movement, cognition, neuroendocrine and reward. There are two families of dopamine receptors, dopamine D1 subtypes and dopamine D2 subtypes. Positron emission tomography (PET) imaging has been very useful in understanding the roles of dopamine receptors in health and disease. While PET imaging agents targeted to dopamine D2 receptors are well developed, the same can not be said for dopamine D1 PET imaging agents. Both dopamine receptor subtypes exist in two binding states- high affinity states and low affinity states. Dopamine has nanomolar affinity for high affinity states and micromolar affinity for low affinity states. Because the high Affinity state is the physiologically functional state, dopamine agonists are preferred as PET imaging agents since they can discriminate between high and low affinity states. In contrast dopamine antagonists bind both high and low affinity states with equal avidity. The understanding of dopamine D2 receptors is more mature than the understanding of dopamine D1 receptors due in part to the paucity of dopamine D1 PET imaging agents. The goal of this proposal is to develop high affinity and highly selective dopamine D1 agonists as PET imaging agents based on a group of 6-chloro-phenylbenzazepines with promising affinities and selectivities. We plan to label these agonists with a novel PET isotope, Cl-34m (tVz = 32 min, 53%.{3+). The specific aims of this project are (1) develop routine Cl-34m production methods using a small 11 Mev proton cyclotron, (2) prepare cold authentic samples of 6-chloro-phenylbenzazepines and their derivatives suitable as precursors for positron labeling, (3) develop routine radiosynthesis of high affinity Cl-34m dopamine D1 agonists and (4) perform preliminary microPET imaging to evaluate and validate Cl-34m-labeled dopamine D1 agonists as PET imaging agents in rhesus macaques. There is currently no reliable Cl-34m production method. Successful development of Cl-34m production methods will allow the evaluation of many chlorinated Pharmaceuticals. In addition, new dopamine D1 agonists labeled with Cl-34m will extend the utility of PET rnaging toward better understanding of the role of dopamine D1 receptors in neuropsychiatric disorders. PET imaging with dopamine D1 agonists will facilitate the understanding and treatment of dopamine D1- related neuropsychiatric disorders.