High Affinity Dopamine D2 Receptor Radioligands. 1. Regional Rat Brain Distribution

Five 12Sl-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isore-moxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. "lodo-pride " (Ko 0.88 nM), an iodine substituted benzamide struc-turally related to sulpiride, displayed a maximal stria-tum:cerebellar uptake ratio of 7.6. Demonstration of satura-tion of the receptor with [12Sl]iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands struc-turally related to eticlopride, "iclopride " (KD 0.23 riM) and "itopride " (Ko 0.16 nM), displayed maximal striatal:cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, "epidepride " (KD 0.057 nM) and "ioxipride " (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios correlated poorly with the affinity constants for the dopamine D2 receptor alone, but were highly correlated (r = 0.92) with the product of the receptor dissociation constant (Ko) and the apparent lipophil-icity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared ependent on lipophilicity, with maximal uptake occurring for ligands having log kw 2.4