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

Journal Article · Fri Mar 01 04:00:00 EST 1991 · Journal of Medicinal Chemistry; (USA)

DOI:https://doi.org/10.1021/jm00107a002· OSTI ID:5944009

Chumpradit, S; Kung, M P; Billings, J J; Kung, H F ^[1]

---

1. Univ. of Pennsylvania, Philadelphia (USA)

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.

• OSTI ID: 5944009
• Journal Information: Journal of Medicinal Chemistry; (USA), Journal Name: Journal of Medicinal Chemistry; (USA) Vol. 34:3; ISSN JMCMA; ISSN 0022-2623
• Country of Publication: United States
• Language: English

Related Subjects

550601* -- Medicine-- Unsealed Radionuclides in Diagnostics
62 RADIOLOGY AND NUCLEAR MEDICINE
AMINES
AROMATICS
AUTONOMIC NERVOUS SYSTEM AGENTS
BETA DECAY RADIOISOTOPES
CARDIOTONICS
CARDIOVASCULAR AGENTS
CELL CONSTITUENTS
CELL MEMBRANES
CHEMICAL PREPARATION
CHROMATOGRAPHY
DAYS LIVING RADIOISOTOPES
DISTRIBUTION
DOPAMINE
DRUGS
ELECTRON CAPTURE RADIOISOTOPES
HOURS LIVING RADIOISOTOPES
HYDROXY COMPOUNDS
INTERMEDIATE MASS NUCLEI
IODINE 123
IODINE 125
IODINE ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
LABELLED COMPOUNDS
LIGANDS
LIQUID COLUMN CHROMATOGRAPHY
MEMBRANE PROTEINS
MEMBRANES
MOLECULAR STRUCTURE
NEUROREGULATORS
NUCLEI
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
PHENOLS
POLYPHENOLS
PROTEINS
RADIOISOTOPES
RADIOPHARMACEUTICALS
RECEPTORS
SEPARATION PROCESSES
SYMPATHOMIMETICS
SYNTHESIS
TISSUE DISTRIBUTION
TRACER TECHNIQUES