Synthesis and resolution of (+-)-7-chloro-8-hydroxy-1-(3'-iodophenyl)-3-methyl-2,3,4,5-tetrahydro- 1H-3- benzazepine (TISCH): a high affinity and selective iodinated ligand for CNS D1 dopamine receptor

J Med Chem. 1991 Mar;34(3):877-83. doi: 10.1021/jm00107a002.

Abstract

The synthesis and resolution of (+-)-7-chloro-8-hydroxy-1-(3'-iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1 H-3- benzazepine, (+/-)-TISCH (8) has been achieved by resolution of intermediate 4, the O-methoxyl, 3'-bromo derivative, as the diastereomeric camphor sulfonate salt. The final products, R-(+)-8 and S-(-)-8, were prepared by treatment of R-(+)- or S-(-)-7, the 3'-tributyltin intermediates, with iodine in chloroform, followed by O-demethylation. By using HPLC with a chiral column, the optical purity (greater than 99%) of the intermediates and the final compounds was determined. Radioiodination was achieved by an iodo-destannylation reaction with sodium [125I]iodide and hydrogen peroxide. As expected, the R-(+)-[125I]-8 (the active isomer) displayed high affinity and selectivity to the CNS D-1 receptor in rat striatum tissue preparation (Kd = 0.205 nM). The rank order of potency was as follows: SCH-23390 (1a) greater than (+/-)-8 greater than (+)-butaclamol greater than spiperone, WB4101 greater than dopamine, 5-HT. After an iv injection, the R-(+)-[125I]-8 penetrated the blood-brain barrier with ease and displayed specific regional distribution corresponding to the D-1 receptor density, while the S-(-)-[125I]-8 showed no specific uptake. The data suggest that the ligand may be useful as a pharmacological tool for characterizing the D-1 dopamine receptor. When labeled with I-123, this ligand is a potential agent for in vivo imaging of CNS D-1 dopamine receptor.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzazepines / chemical synthesis*
  • Benzazepines / chemistry
  • Benzazepines / metabolism
  • Binding, Competitive
  • Brain / metabolism*
  • Cell Membrane / metabolism
  • Chemical Phenomena
  • Chemistry
  • Chromatography, High Pressure Liquid
  • Corpus Striatum / metabolism
  • Iodine Radioisotopes
  • Isotope Labeling
  • Male
  • Molecular Structure
  • Rats
  • Rats, Inbred Strains
  • Receptors, Dopamine / metabolism*
  • Receptors, Dopamine D1
  • Tissue Distribution

Substances

  • Benzazepines
  • Iodine Radioisotopes
  • Receptors, Dopamine
  • Receptors, Dopamine D1
  • 7-chloro-8-hydroxy-1-(3'-iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine