(+)-[ 76Br]A-69024: a non-benzazepine radioligand for studies of dopamine D1 receptors using PET

Abstract

(+)-[ 76Br]A-69024 is a specific and enantioselective dopamine D1 receptor radioligand. The Bmax of (+)-[ 76Br]A-69024 measured in vitro on rat striatum membranes was 320 ± 25 fmoles/mg protein with an apparent dissociation constant of Kd = 0.6 ± 0.1 nM. The inactive enantiomer, (−)-[ 76Br]A-69024, displayed no affinity in the same assay. In vivo, the biodistribution (+)-[ 76Br]A-69024 in rats showed a rapid and high uptake in the striatum (1% ID/g), followed by a slow wash out. The striatum/cerebellum concentration ratio (index of specific binding) reached a maximum value of 10 at 60 minutes post injection. A tissue to cerebellum ratio of 2.8 and 1.5 was also observed for frontal and posterior cortex respectively. With the pharmacologically inactive enantiomer, (−)-[ 76Br]A-69024, the brain uptake was determined to be non specific since a striatum/cerebellum ratio of approximately 1 was observed throughout the time course of the experiment. The selectivity of (+)-[ 76Br]A-69024 uptake was demonstrated in competition experiments. The specific uptake in the striatum and cortical regions was completely prevented after administration of the D1 antagonist SCH 23390. Pre-treatment of rats with unlabelled (+)A-69024 also displayed the same regional inhibition of (+)-[ 76Br]A-69024 uptake. Pre-administration of rats with spiperone (D2) and ketanserin (5-HT 2/5-HT 2C) showed no inhibitory effect on (+)-[ 76Br]A-69024 uptake in any brain region. Using (+)-[ 76Br]A-69024, PET study in baboon demonstrated a preferential accumulation of the radioactivity in the striatum, frontal and posterior cortex which was displaced to the level of the cerebellum by SCH 23390. These results suggest that (+)-[ 76Br]A-69024 may deserve further investigation as a potential radioligand for studying striatal and cortical dopamine D1 receptors using PET.