IN-VIVO BINDING OF [C-11] SKF-75670 AND [C-11] SKF-82957 IN RAT-BRAIN- 2 DOPAMINE D-1 RECEPTOR AGONIST LIGANDS

The high affinity benzazepine D-1 agonists SKF 75670 and SKF 82957 lab eled with C-11 were evaluated in vivo in rats as potential radioligand s for imaging dopamine D-1 receptors with positron emission tomography (PET). Their in vivo pharmacological profile revealed selective bindi ng 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-noi se 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 si gnificantly their binding in the striatum with [C-11]SKF 75670 or the striatum and olfactory tubercles with [C-11]SKF 82957. Previous report s 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 tha t can potentially be used to study in vivo the functional high-affinit y state of D, receptors using PET.