C-11- and Br-76-labelled NNC 22-0010, selective dopamine D-1 receptor radioligands for PET

NNC 22-0010 is a new dopamine antagonist with a high affinity and selectivity for D-1 receptors in vitro. NNC 22-0010 has both an N methyl group and a bromine, which allows radiolabelling with either C-11 or Br-76. We labelled [C-11]NNC 22-0010 by N methylation of the free base of the secondary amine with [C-11]methyl iodide in a total radiochemical yield of 40%. The total synthesis time was 30 min. The specific radioactivity at time of injection of the radioligand was 48 to 55 GBq/mu mol. The [Br-76]NNC 22-0010 was synthesized from the iodine precursor by an exchange reaction with Br-76 using a Cu+-assisted nucleophilic substitution reaction. The radiochemical yield was 60% after purification. Specific radioactivity at time of injection of the radioligand was 6 to 20 GBq/mu mol. In PET experiments with [C-11]NNC 22-0010 and [Br-76]NNC 22-0010 there was a rapid uptake of radioactivity in the monkey brain. The striatum to cerebellum ratio was 2-2.5 after 1 h. Binding in the striatum was displaced by SCH 23390, whereas binding in the cerebellum was not reduced. Metabolite studies showed that 1 h after injection about 20% of the radioactivity in plasma represented unchanged radioligand. This value was on the same level for at least 6 h. The results indicate that radiolabelled NNC 22-0010 has potential for imaging dopamine D-1 receptors selectively in the human brain.