Dopamine displaces [3H]domperidone from high‐affinity sites of the dopamine D2 receptor, but not [3H]raclopride or [3H]spiperone in isotonic medium: Implications for human positron emission tomography

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Abstract
Because the high-affinity state of the dopamine D2 receptor, D2High, is the functional state of the receptor, has a role in demarcating typical from atypical antipsychotics, and is markedly elevated in amphetamine-sensitized rats, it is important to have a method for the convenient detection of this state by a ligand. The present data show that, in contrast to [3H]spiperone or [3H]raclopride, [3H]domperidone labels D2High sites in the presence of isotonic NaCl in either striatum or cloned D2Long receptors, yielding a dopamine dissociation constant (1.75 nM) in agreement with that found with [3H]dopamine. Increased labeling of D2High sites occurred with [3H]domperidone after severe disruption of the cells, suggesting that [3H]domperidone has better access to the D2 receptor from the cytoplasmic aspect of the cell membrane. The density of the [3H]domperidone-labeled D2 receptors was the same as that of the [3H]raclopride-labeled D2 receptors, but twice the density of [3H]spiperone sites for human cloned D2Long receptors, compatible with the monomer-dimer concept of the D2 receptor. [3H]domperidone readily labels the D2High sites in postmortem human brain homogenates. Although [3H]spiperone or [3H]raclopride can occupy D2High sites, the inability of 1–10 nM dopamine to displace these ligands under isotonic conditions suggests that these ligands may not be suitable for monitoring the physiological high-affinity state of the dopamine D2 receptor by means of [11C]methylspiperone or [11C]raclopride in humans. Synapse 49:209–215, 2003.

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