Dopamine D2 receptors selectively labeled by a benzamide neuroleptic: [3H]-YM-09151-2

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Abstract
In order to label dopamine D2 receptors selectively we tritiated the potent benzamide neuroleptic, YM-09151-2 (26.7 Ci/mmol). The binding of [3H]-YM-09151-2 to canine striatal membranes was saturable and specific with a K D of 57 pmol/l and B max of 36 pmol/g tissue as determined by Scatchard analysis. The K D, but not the B max, of [3H]-YM-09151-2 increased 6-fold in the absence of sodium chloride. [3H]-YM-09151-2 labeled 40% more sites than [3H]-spiperone in the same tissue homogenate. [3H]-YM-09151-2 binding was inhibited by dopaminergic drugs in a concentration and stereoselective manner with the appropriate dopamine D2 receptor profile. Thus, dopamine agonists inhibited [3H]-YM-09151-2 binding to canine striatal membranes with the following rank order of potency: (−)-N-n-propylnorapomorphine > apomorphine > (±)-6,7-dihydroxy-2-aminotetralin > (+)-N-n-propylnorapomorphine > dopamine > (−)-noradrenaline > serotonin > (−)-isoprenaline. Dopaminergic antagonists competed for [3H]-YM-09151-2 binding with the following order of potency: spiperone > (+)-butaclamol > haloperidol > clebopride > (−)-sulpiride > SCH-23390 > (−)-butaclamol. Furthermore, dopamine agonists recognized 2 states of the receptor labeled by [3H]-YM-09151-2, D 2 high and D 2 low . The D 2 high state of the receptor could be converted to D 2 low by guanine nucleotides and sodium ions as is the case for [3H]-spiperone binding to D2 receptors. [3H]-YM-09151-2 appears to be a more selective ligand for dopamine D2 receptors than [3H]-spiperone, since YM-09151-2 displays approximately 9-fold lower affinity than spiperone for cortical serotonergic (S2) receptors. [3H]-YM-09151-2 may become a useful tool for the selective characterization of dopamine D2 receptors.