An understanding of the neurobiological mechanisms of cocaine action demands the proper radioligands to study the binding sites for cocaine in neuronal membranes. Although a number of studies have implicated cocaine effects at binding to dopamine transporters, cocaine itself is noteworthy because of its ability to bind to transporters for several biogenic amines, including 5-HT and norepinephrine. The most selective compounds available for each biogenic transporters (e.g. GBR analogs and mazindol for dopamine transporters; paroxetine for 5-HT transporters) do not necessarily bind at the transporters in the same manner as cocaine and related tropane derivatives of cocaine. Consequently, it has been recognized that radioligands based on the tropane structure are the most appropriate for studying cocaine action. Over the past three years, we have developed a new approach to the synthesis of 3-naphthyl tropane derivatives and these are the most potent cocaine analogs known. These analogs also demonstrate significant levels of selectivity between the biogenic amine transporters. The goal of the research described in this application is to systematically characterize in vivo and in vitro three labeled derivatives of these new tropanes: 2beta-propanoyl-3beta(2-naphthyl)-8-aza[3.2.1]bicyclooctane (WF-23), a non-selective analog; 2beta-methylpropanoyl-3beta-tolyl-8- aza[3.2.1]bicyclooctane (WF-33), a dopamine selective analog; and 2beta- propanoyl-3beta(4-isopropylphenyl)-8-aza[3.2.1]bicyclooctane (WF-39), a 5HT-selective analog. Each of these compounds will be labeled with tritium and binding experiments will examine the ability of each compound to bind to rat brain membranes. These studies will examine the pharmacological specificity, binding kinetics, and preliminary brain regional distribution of each radiolabeled compound. In vitro autoradiography experiments will determine the localization of binding sites for each radiolabeled compound in rat brain. Each compound will be labelled with [11C] for in vivo experiments which will determine the pharmacokinetics of binding into various rat tissues and for preliminary PET studies in monkeys. The pharmacological and neuroanatomical characterization of these three novel tropane analogs will not only help to explore the relative contribution of 5-HT and dopamine transporters to cocaine actions, but also provide the means for effective in vivo labelling of biogenic amine transporters.
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