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

The high affinity benzazepine D-1 agonists SKF 75670 and SKF 82957 labeled with C-11 were evaluated in vivo in rats as potential radioligands for imaging dopamine D-1 receptors with positron emission tomography (PET). Their in vivo pharmacological profile revealed selective binding for both tracers in rat brain regions rich in D-1 receptors such as the caudate-putamen. The more lipophilic [C-11]SKF 82957 (6-chloro-[C-11]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 [C-11]SKF 75670 and 9.7 +/- 2.5 for [C-11]SKF 82957 at 60 min post-injection) as compared to [C-11]SKF 75670. Both radiotracers exhibited high specificity and selectivity for D-1 receptors, since only D-1 competitors but not the D-2 antagonist sulpiride or the 5-HT2 antagonist ritanserin reduced significantly their binding in the striatum with [C-11]SKF 75670 or the striatum and olfactory tubercles with [C-11]SKF 82957. Previous reports have shown that only D-1 agonists can recognize the functional high-affinity state from the low-affinity state of D-1 receptors. [C-11]SKF 75670 and especially [C-11]SKF 82957 are D-1 agonist radioligands that can potentially be used to study in vivo the functional high-affinity state of D, receptors using PET.