In vivo binding of [11C]SKF 75670 and [11C]SKF 82957 in rat brain: two dopamine D-1 receptor agonist ligands

The high affinity benzazepine D1 agonists SKF 75670 and SKF 82957 labeled with C-11 were evaluated in vivo in rats as potential radioligands for imaging dopamine D1 receptors with positron emission tomography (PET). Their in vivo pharmacological profile revealed selective binding for both tracers in rat brain regions rich in D1 receptors such as the caudate-putamen. The more lipophilic [11C]SKF 82957 (6-chloro-[11C]SKF 75670) showed a higher brain uptake (more than 2-fold up to 30 min), higher specific uptake in the striatum and higher signal-to-noise ratio (striatum-to-cerebellum = 3.2 +/- 0.4 for [11C]SKF 75670 and 9.7 +/- 2.5 for [11C]SKF 82957 at 60 min post-injection) as compared to [11C]SKF 75670. Both radiotracers exhibited high specificity and selectivity for D1 receptors, since only D1 competitors but not the D2 antagonist sulpiride or the 5-HT2 antagonist ritanserin reduced significantly their binding the striatum with [11C]SKF 75670 or the striatum and olfactory tubercles with [11C]SKF 82957. Previous reports have shown that only D1 agonists can recognize the functional high-affinity state from the low-affinity state of D1 receptors. [11C]SKF 75670 and especially [11C]SKF 82957 are D1 agonist radioligands that can potentially be used to study in vivo the functional high-affinity state of D1 receptors using PET.