In vivo imaging of the dopaminergic system in mammalian brain with positron emission tomography (PET) and single photon emission tomography (SPECT) has been the subject of extensive studies in recent years. The dopamine receptor system in very important for normal brain function; it is also the apparent action site for various neuroleptic drugs for the treatment of schizophrenia and other mental disorders. In recent years, the application of molecular biology techniques to express receptors in cloned cells has dramatically expanded the understanding and the complexity of molecular pharmacology. Cloning of dopamine receptors has yielded at least five different dopamine receptor subtypes-D1, D2L, D2S, D3, D4 and D5, a diversity far beyond the traditional classification of two subtypes. In this competitive renewal application we propose to continue the development of new single photon emission tomography (SPECT) imaging agents for evaluation of dopaminergic function in the central nervous system. Under the sponsorship of this project several new SPECT imaging agents have been successfully developed and tested in humans: [123I]TISCH for the D1 dopamine receptor, [123I]IBZM and IBF, two iodobenzamide derivatives, for the D2/D3 dopamine receptor. Two other ligands, FIDA2 for the D2/D3 dopamine receptor receptor and IPT, a cocaine derivative, for dopamine reuptake site will be evaluated in humans in the near future. The first iodinated ligand, R-(+)-trans-7-OH-PIPAT, for the D3 dopamine receptor was synthesized and characterized with cloned cell lines expressing the D2 and D3 dopamine receptors and with rat striatal membrane preparations. Most of the known iodobenzamides displayed similar potency in binding to D2 as well as D3 dopamine receptors expressed in the cloned line cells. Initial studies performed in this laboratory appear to suggest that by fine tuning the iodobenzamide structure, it may be possible to develop agents specific for D2 or D3 receptors. It is important scientifically to investigate D2/D3 selectivity for this series of potent ligands. Based on the successful experience we have had for the past few years, we propose to continue in the development of new dopaminergic ligands.
Specific aims i nclude; a.) Synthesis of the proposed new ligands and the corresponding precursors for radiolabeling. b.) Studies of radiochemistry for preparation of I-125 and I-123 labeled target molecules. c.) Evaluation of biodistribution in rats and in vitro autoradiography as well as in vitro binding study. d.) In vivo imaging studies in monkeys. e.) Evaluation of in vivo metabolism and modeling. f.) Radiation dosimetry calculation and toxicology stud, g.) Phase I clinical trial in humans. Highly selective D2, D3 and D4 dopamine receptor ligands and dopamine reuptake site agents will provide useful in vivo imaging agents for SPECT and powerful tools to increase our understanding of the pharmacology and function roles of the dopaminergic system in normal and disease states.
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