Fluorinated benzazepines: 1. Synthesis, radiosynthesis and biological evaluation of a series of substituted benzazepines as potential radiotracers for positron emission tomographic studies of dopamine D-1 receptors

Abstract

We have prepared N-alkyl, aryl, fluoroalkyl, fluoroaryl and iodoaryl derivatives of 7-chloro-8-hydroxy-3-methyl-1-(3′-aminophenyl)-2, 3,4,5-tetrahydro-1H-3-benzazepine (SCH 38548) as high-affinity ligands for the dopamine D 1 receptor. Binding affinities of the compounds for dopamine D 1, D 2, and serotonin 5-HT 2 receptor sites in rat brain homogenates were measured. The affinity of SCH 38548 for dopamine D 1 receptors was found to be 0.53 ± 0.46 nM, whereas lower affinities (in the micromolar range) for dopamine D 2 and serotonin 5-HT 2 receptors were found. Alkylation (ethyl, n-propyl and benzyl) and acylation (benzoyl) of the amino group of SCH 38548 did not decrease affinities for the D 1 receptors significantly. The fluoroethyl, fluoropropyl, and fluorobenzyl derivatives showed approximately an 8-fold, 9-fold, and 3-fold decrease in affinity for the D 1 sites compared to SCH 38548. The N-4-fluorobenzoyl derivative, however, showed a similar affinity for the D 1 sites as for SCH 38548. All four fluorinated derivatives exhibited weak binding at D 2 and serotonin 5-HT 2 receptors. The N-(4- 18F-fluorobenzoyl)SCH 38548 was prepared by reacting SCH 38548 with 4- 18F-fluorobenzoyl fluoride in 2–5% radiochemical yield with a specific radioactivity of ~600–700 Ci/mmol. The N-(3- 18F-fluoropropyl)SCH 38548 was prepared by reacting SCH 38548 with 18F-fluoropropyl iodide in 2–5% radiochemical yield with a specific radioactivity of ~600–700 Ci/mmol. N-(4- 18F-fluorobenzoyl)SCH 38548 failed to localize in the dopaminergic sites in the rat and rhesus monkey brain. Biodistribution of N-(3- 18F-fluoropropyl) SCH 38548 in rats showed specific uptake and retention (0.64% injected dose/g at 30 min) of the radiotracer in the striata, with striata-to-cerebellum ratios reaching 12 at 2 h postinjection (p.i.). Positron emission tomography scans in rheusus monkeys indicate selective uptake of the radiotracer in the striata. After IV injection of N-(3- 18F-fluoropropyl)SCH 38548, a rapid brain uptake of the tracer from blood was observed. Initial uptake in the striata and cerebellum was ~0.02% of injected dose/cc. Nonspecific uptake from the tissue surrounding the striata cleared slowly. The striata-to-cerebellum ratio increased from 1.20 to 3.5 min postinjection to ~2.5 at 120 min p.i. The specific uptake of N-(3- 18F-fluoropropyl)SCH 38548 in the striata was displaced by IV administration of SCH 24518 (2 mg/kg).