title: (+)-[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-HT2/5-HT2C) 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.
authors.affiliation: Department of PET and Nuclear Medicine, Royal Prince Alfred Hospital, NSW 2050, Camperdown, Australia. mkassiou@med.usyd.edu.au
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
authors.forename: Christian
authors.initials: C
authors.lastname: Loc'h
authors.forename: Michel
authors.initials: M
authors.lastname: Bottlaender
authors.forename: Karine
authors.initials: K
authors.lastname: Mardon
authors.forename: Michele
authors.initials: M
authors.lastname: Ottaviani
authors.forename: Christine
authors.initials: C
authors.lastname: Coulon
authors.forename: Andrew
authors.initials: A
authors.lastname: Katsifis
authors.forename: Bernard
authors.initials: B
authors.lastname: Maziere
mesh_terms: D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D001921:Brain / Q000000981:diagnostic imaging; D001923:Brain Chemistry / Q000187:drug effects; D001967:Bromine Radioisotopes; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D008297:Male; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000378:metabolism; D010208:Papaverine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010215:Papio; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: D001967:Bromine Radioisotopes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D019275:Radiopharmaceuticals; D017447:Receptors, Dopamine D1; D044005:Tetrahydroisoquinolines; C061450:A 69024; D010208:Papaverine