The pur.pose of this study was to determine whether dopamine D4 receptors could be detected in the human brain striatum by means of an indirect ligandbinding method, because no dopamine 114 receptor-selective ligand presently exists. The antipsychotic clozapine is more selective for the dopamine D4 receptor than for other dopamine receptors. Although most antipsychotic drugs act in the striatum to elicit Parkinson-like side-effects, clozapine is atypical in that it does not produce Parkinsonism. To understand this atypical action of clozapine, it would be helpful to know whether the presumed target for clozapine, the dopamine D4 receptor, is or is not present in the human striatum. We measured dopamine D4 receptors indirectly, using [3H]emonapridel and [3Hlraclopride. Emonapride has a high affinity (K = 90 pM) for the dopamine D4 receptor, while raclopride has a very low affinity for this receptor (K = 240 nM); thus, any difference in the densities of these two l3H1ligands (in the absence of dopamine) could be attributed to the presence of dopamine D4 receptors. Since the binding of [3H]raclopride is sensitive to endogenous dopamine, we used Parkinson-diseased tissue which has little dopamine. We found that the densities of the two ligands were identical in Parkinson striata, indicating a low density (<X pmol/g) for dopamine D4 receptors in the human striatum. This low or undetectable density of dopamine D4 receptors in the striatum is consistent with other data indicating that clozapine does not have its major action in the human striatum. Thus, the atypical action of clozapine, insofar as clozapine does not elicit Parkinson side-effects, may be based on its ability to avoid striatal dopamine D2 receptors and to target dopamine D4 receptors in non-striatal brain regions. In schizophrenia striata the density of [3Hlemonapride was almost two-fold higher than that of [3Hlraclopride. Considering that there are few dopamine D4 receptors in the human striatum, this two-fold difference is best explained by endogenous dopamine interfering with the binding of [3Hlraclopride, but not that of L3HIemonapride. o 1993 Wiley-Liss, Inc.