PET studies of binding competition between endogenous dopamine and the D1 radiotracer [11C]NNC 756

Abstract

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) D1 receptor antagonist. Labeled with C-11, it has been used as a PET radiotracer to visualize D1 receptors both in striatal and extrastriatal areas, such as the prefrontal cortex. The goal of this study was to evaluate several methods for derivation of D1 receptor binding potential (BP) with [11C]NNC 756 in baboons, and to use these methods to assess the vulnerability of [11C]NNC 756 binding to competition by endogenous DA. A three-compartment model provided a good fit to PET data acquired following a single bolus injection. BP values obtained with this analysis were in good agreement with values derived from in vitro studies. BP values measured following injection of the potent DA releaser amphetamine (1 mg/kg, n=2) were similar to values measured under control conditions. Kinetic parameters derived from single bolus experiments were used to design a bolus plus continuous infusion administration protocol aimed at achieving a state of sustained binding equilibrium. Injection of amphetamine during sustained equilibrium did not affect [11C]NNC 756 binding. Similar results were observed with another D1 radiotracer, [11C]SCH 23390. Doses of amphetamine used in this study are known to reduce by 20-40% the binding potential of several D2 receptors radiotracers. Therefore, the absence of displacement of [11C]NNC 756 by an endogenous DA surge may indicate important differences between D1 and D2 receptors 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 binding competition model is inadequate to account for the effects of manipulation of endogenous DA levels on the in vivo binding of radiolabeled antagonists.

Effects of Endogenous Neurotransmitters on the in vivo Binding of Dopamine and 5-HT Radiotracers in Mice

“…These experiments hence suggest that, in contrast to D 2 receptors, the occupancy of D 1 receptors by dopamine under basal conditions may be relatively low. Previous studies examining the sensitivity of D 1 radiotracers to endogenous dopamine have been conducted using either SCH 23390 or NNC 756 and have given results which also indicate an insensitivity of D 1 radiotracer binding to synaptic dopamine (Inoue et al 1991;Thibaut et al 1996;Abi-Dargham et al 1999;Gifford et al 2000). For both the [ 3 H]raclopride experiments and the [ 3 H]A69024 experiments the animals were sacrificed at a 30-min time point after radiotracer administration.…”

“…For non-benzazepine compounds the only D 1 radiotracer which has been evaluated so far is [ 11 C]A69024, which was found to be effective at labeling D 1 receptors in vivo despite a relatively low affinity for the receptor (Kassiou et al 1995). With regard to the effect of endogenous dopamine on the in vivo binding of D 1 radiotracers, the few studies performed to date have been conducted using benzazepine radiotracers such as SCH 23390 and have indicated that the binding of these radiotracers appears to be relatively resistant to pharmacologically induced changes in dopamine levels (Inoue et al 1991;Thibaut et al 1996;Abi-Dargham et al 1999;Gatley et al 2000;Gifford et al 2000). However, by analogy with the high-affinity D 2 radiotracers, it may be expected that the susceptibility of these high-affinity benzazepine derivatives to competition with dopamine will be limited as a result of their non-reversible and flow-dependent binding kinetics.…”

News and views on in-vivo imaging of neurotransmission using PET and MRI

“…In contrast to the D2/D3 receptor tracers, D1 receptor antagonist tracers such as [ 11 C]SCH23390 and [ 11 C]NNC-112 have not appeared to be sensitive to acute changes in extracellular dopamine concentrations 8,9 . This might be due to the fact that dopamine has significantly lower affinity to the D1 receptor, which predominantly exist in the low-affinity state, than D2 receptor in the striatum 10,11 .…”

Combining PET Biodistribution and Equilibrium Dialysis Assays to Assess the Free Brain Concentration and BBB Transport of CNS Drugs

“…where g is constrained to equal the difference between (g CER ) the terminal rate of washout of the nondisplaceable cerebellar TAC and (g P ) the smallest elimination rate constant of the total plasma (g = g CER Àg P ; Abi-Dargham et al, 1999). P-gp, P-glycoprotein; ROI, region of interest; PET, positron emission tomography.…”