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

The ligands N-methylspiperone and haloperidol both bind to D-2-live dopamin e receptors. The competitive nature of the binding over a wide range of hal operidol concentrations and the effect on dopamine release have never been tested in vivo. We determined the competitive interaction between 3-N-[C-11 ] methylspiperone ([C-11]NMSP) and haloperidol binding to striatal dopamine D-2-like receptors with positron emission tomography (PET) of pig brain. [ C-11]NMSP tomography was performed with haloperidol at five different plasm a concentrations maintained constant by programmed infusion. Kinetic parame ters of ligand competition for binding in the striatum were determined by d econvolving time-activity curves of the striatum and cerebellum from metabo lite-corrected arterial plasma [C-11]NMSP and haloperidol concentrations. T wo types of [C-11]NMSP-binding sites were evident in the striatum, both sat urable by haloperidol administration. The preponderant or primary sites bou nd [C-11]NMSP irreversibly, as dopamine DB-like receptors, while the second ary sites bound [C-11]NMSP reversibly, as do serotonin S2 receptors. Woolf- Hanes plots revealed the predicted approximately linear relationships betwe en the binding indices and the haloperidol plasma concentration. For the ir reversible binding sites, this relationship indicated a 50% inhibitory conc entration of haloperidol of 2 nM in plasma and a maximum binding capacity o f 64 pmol cm(-3) in striatum. For the reversible binding sites, the relatio nship indicated a 50% inhibitory plasma concentration of haloperidol of 1 n M and a maximum binding capacity of 4.5 pmol cm(-3). Second-order polynomia l Eadie-Hofstee-Scatchard plots were consistent with increased competition from an endogenous ligand of the irreversibly binding sites only with incre asing doses of haloperidol. At the highest haloperidol dose, this hypotheti cal endogenous ligand had risen 6-7-fold. We contend that this reveals the release of dopamine by high concentrations of haloperidol. Synapse 38:87-10 1, 2000, (C) 2000 Wiley Liss, Inc.