NNC 22-0010 is a new dopamine antagonist with a high affinity and selectivity for D1 receptors in vitro. NNC 22-0010 has both an N-methyl group and a bromine, which allows radiolabelling with either 11C or 76Br. We labelled [11C]NNC 22-0010 by N-methylation of the free base of the secondary amine with [11C]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/mumol. The [76Br]NNC 22-0010 was synthesized from the iodine precursor by an exchange reaction with 76Br 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/mumol. In PET experiments with [11C]NNC 22-0010 and [76Br]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 D1 receptors selectively in the human brain.

01 Jan 1995·XenobioticaQ4 · MEDICINE

Characterization of benzazepine UDP-glucuronosyl-transferases in laboratory animals and man

Q4 · MEDICINE

Article

Author: K. T. Hansen ; K. Stentoft

1. The O-glucuronidation of two dopamine D1 receptor antagonists, Odapipam and Berupipam, were studied in hepatic microsomal fractions from mouse, rat, rabbit, dog, pig, and man using 14C-UDP-glucuronic acid. 2. The influence of pH, detergent, gender, drug-metabolizing enzyme inducers, and age were examined. Detergents like the zwitterionic CHAPS and non-ionic Tween 20, Triton X-100, and Brij 35 stimulated the glucuronidation rate by up to 600% of native activity with the latter being most effective. Both apparent Km and Vmax increased following detergent treatment in rat hepatic microsomes. Less marked activation of UDP glucuronosyltransferase activity was observed with Brij 35 in mouse, rabbit, dog, and pig compared with rat. In contrast, human hepatic microsomes were not stimulated by detergent treatment. 3. Marked species-dependent UDP-glucuronosyltransferase activity were observed for the two compounds. In general, Odapipam exhibited higher Vmax and Km compared with Berupipam with the exception of rabbit where the reverse was true. Similar kinetic parameters were, however, observed in human hepatic microsomes. Highest glucuronidation rate (in general) was observed in mouse followed by dog, pig, rabbit, man, and rat. 4. UGT activity in human livers showed up to a seven-fold variation. Conjugation of each compound were highly correlated (r = 0.92; n = 20) suggesting that identical isoform(s) were involved in this reaction. A significant age-related decrease in UDP-glucuronosyltranferase activity was observed, which partly could be explained by a preponderance in elderly female donor liver samples.

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Psychotic Disorders	Phase 1	US	Novo Nordisk A/S	-

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