BRAIN DISTRIBUTION OF POTENT DOPAMINE TRANSPORT INHIBITOR O 1059

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The transporters for the monoamines dopamine, serotonin and norepinephrine are principal targets for the majority of antidepressant drugs, methylphenidate (Ritalin), the most frequently prescribed drug for treatment of Attention Deficit Hyperactivity Disorder, and the addictive drug cocaine. By blocking monoamine transporters and elevating monoamine levels, the drugs trigger a cascade of biochemical events, leading to therapeutic benefit or, in the case of cocaine, stimulant effects and abuse liability. Without exception, the molecular structure of therapeutic and other drugs that modulate monoamine transporters have been designed with an amine nitrogen in the molecular structure. We recently reported a unique series of compounds (aryloxatropanes) that bear no amine nitrogen in their structure (nonamines) yet are potent inhibitors of the dopamine transporter. The objective of the present study was to determine whether the brain distribution of a nonamine corresponds to the known distribution of the dopamine transporter in rhesus monkey brain (Macaca mulatta). Initially, parametric studies were conducted to establish appropriate pre-incubation, incubation, and buffer wash times. Subsequently, 20 mm coronal tissue sections were incubated with [3H]O-1059 (0.3 nM) to measure total binding, and cocaine (30 mM) to measure nonspecific binding. Autoradiographic analysis of the distribution of the [3H]O-1059 was subsequently performed in 9 distinct brain regions, of 6 anterior to posterior planes. Dense labelling was noted in the striatum and considerably lower levels were observed in other brain regions. The distribution pattern was similar to that obtained with the selective monoamine ligand ([3H]CFT or [3H]WIN 35,428), indicating that the absence of an amine nitrogen does affect brain distribution of potent dopamine transport inhibitors. Overall, these data support further development of nonamines, a new generation of transport inhibitors.