Positron emission tomography of radioligand binding in porcine striatum in vivo: Haloperidol inhibition linked to endogenous ligand release

The ligands N‐methylspiperone and haloperidol both bind to D2‐like dopamine receptors. The competitive nature of the binding over a wide range of haloperidol concentrations and the effect on dopamine release have never been tested in vivo. We determined the competitive interaction between 3‐N‐[11C]methylspiperone ([11C]NMSP) and haloperidol binding to striatal dopamine D2‐like receptors with positron emission tomography (PET) of pig brain. [11C]NMSP tomography was performed with haloperidol at five different plasma concentrations maintained constant by programmed infusion. Kinetic parameters of ligand competition for binding in the striatum were determined by deconvolving time–activity curves of the striatum and cerebellum from metabolite‐corrected arterial plasma [11C]NMSP and haloperidol concentrations. Two types of [11C]NMSP‐binding sites were evident in the striatum, both saturable by haloperidol administration. The preponderant or primary sites bound [11C]NMSP irreversibly, as dopamine D2‐like receptors, while the secondary sites bound [11C]NMSP reversibly, as do serotonin S2 receptors. Woolf‐Hanes plots revealed the predicted approximately linear relationships between the binding indices and the haloperidol plasma concentration. For the irreversible binding sites, this relationship indicated a 50% inhibitory concentration of haloperidol of 2 nM in plasma and a maximum binding capacity of 64 pmol cm−3 in striatum. For the reversible binding sites, the relationship indicated a 50% inhibitory plasma concentration of haloperidol of 1 nM and a maximum binding capacity of 4.5 pmol cm−3. Second‐order polynomial Eadie‐Hofstee‐Scatchard plots were consistent with increased competition from an endogenous ligand of the irreversibly binding sites only with increasing doses of haloperidol. At the highest haloperidol dose, this hypothetical endogenous ligand had risen 6–7‐fold. We contend that this reveals the release of dopamine by high concentrations of haloperidol. Synapse 38:87–101, 2000. © 2000 Wiley‐Liss, Inc.