PET studies of binding competition between endogenous dopamine and the D-1radiotracer [C-11]NNC 756

NNC 756 ((+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3 ,4,5-tetrahydro-1H-3-benzazepine) is a new high affinity dopamine (DA) D-1 receptor antagonist. Labeled with C-11, it has been used as a PET radiotrac er to visualize D-1 receptors both in striatal and extrastriatal areas, suc h as the prefrontal cortex. The goal of this study was to evaluate several methods for derivation of D-1 receptor binding potential (BP) with [C-11]NN C 756 in baboons, and to use these methods to assess the vulnerability of [ C-11]NNC 756 binding to competition by endogenous DA. A three-compartment m odel provided a good fit to PET data acquired following a single bolus inje ction. BP values obtained with this analysis were in good agreement with va lues derived from in vitro studies. BP values measured following injection of the potent DA releaser amphetamine (1 mg/kg, n = 2) were similar to valu es measured under control conditions. Kinetic parameters derived from singl e bolus experiments were used to design a bolus plus continuous infusion ad ministration protocol aimed at achieving a state of sustained binding equil ibrium. injection of amphetamine during sustained equilibrium did not affec t [C-11]NNC 156 binding. Similar results were observed with another D-1 rad iotracer, [C-11]SCH 23390. Doses of amphetamine used in this study are know n to reduce by 20-40% the binding potential of several D-2 receptors radiot racers. Therefore, the absence of displacement of [C-11]NNC 756 by an endog enous DA surge may indicate important differences between D-1 and D-2 recep tors in vivo, such as differences in proportion of high affinity states not occupied by DA at baseline. These findings may also imply that a simple bi nding competition model is inadequate to account for the effects of manipul ation of endogenous DA levels on the in vivo binding of radiolabeled antago nists. Synapse 32:93-109, 1999, (C) 1999 Wiley-Liss, Inc.