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

The synthesis and resolution of (+/-)-7-chloro-8-hydroxy-1-(3'-iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1H-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 (> 99%) of the intermediates and the final compounds was determined. Radioiodination was achieved by an iodo-destannylation reaction with sodium [I-125]iodide and hydrogen peroxide. As expected, the R-(+)-[I-125]-8 (the active isomer) displayed high affinity and selectivity to the CNS D-1 receptor in rat striatum tissue preparation (K(d) = 0.205 nM). The rank order of potency was as follows: SCH-23390 (1a) > (+/-)-8 > (+)-butaclamol > spiperone, WB4101 > dopamine, 5-HT. After an iv injection, the R-(+)-[I-125]-8 penetrated the blood-brain barrier with ease and displayed specific regional distribution corresponding to the D-1 receptor density, while the S-(-)-[I-125]-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.