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Characterization of Radioiodinated TISCH: A High‐Affinity and Selective Ligand for Mapping CNS D 1 Dopamine Receptor
Author(s) -
Billings Jeffrey J.,
Kung MeiPing,
Chumpradit Sumalee,
Mozley David,
Alavi Abass,
Kung Hank F.
Publication year - 1992
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1992.tb09300.x
Subject(s) - dopamine , ligand (biochemistry) , characterization (materials science) , chemistry , neuroscience , receptor , dopamine receptor , biophysics , biochemistry , biology , materials science , nanotechnology
In developing CNS D 1 dopamine receptor‐imaging agents with improved specificity and longer brain retention, an iodinated D 1 ligand was synthesized. In vitro and in vivo radiolabeling studies of a new iodinated benzazepine, TISCH [7‐chloro‐8‐hydroxy‐1‐(3′‐iodophenyl)‐3‐methyl‐2,3,4,5‐tetrahydro‐1 H ‐3‐benzazepine], an analog of SCH 23390 (7‐chloro‐8‐hydroxy‐3‐methyl‐1‐phenyl‐2,3,4,5‐tetrahydro‐1 H ‐3‐benzazepine), were investigated. After an intravenous injection, the R (+) isomer of TISCH showed high brain uptake in rats (2.20 and 0.57% dose per whole brain at 2 and 60 min, respectively). The striatum/cerebellum ratio increased progressively with time (12 at 60 min). Ex vivo autoradiography of rat brain sections, after intravenous injection of R (+)‐[ 125 I]TISCH, displayed the highest uptake in striatum and substantia nigra, regions known to have a high concentration of D 1 receptors, whereas the S (–) isomer displayed no specific uptake. Furthermore, the specific uptake can be blocked by pretreatment with SCH 23390. In vitro binding studies using the rat striatum tissue preparation showed high specific and low nonspecific bindings ( K D = 0.21 ± 0.03 n M ). The rank order of potency exhibiting high specificity to the D 1 receptor was SCH 23390 > (±)‐TISCH > (+)‐butaclamol = (±)‐FISCH [7‐chloro‐8‐hydroxy‐1‐(4′‐iodophenyl)‐3‐methyl‐2,3,4,5‐tetrahydro‐1 H ‐3‐benzazepine] ≥ WB4101 = spiperone > dopamine, serotonin, (±)‐propranolol, and naloxone. Imaging studies in a monkey with the resolved isomer, R (+)‐[ 123 I]TISCH, demonstrated a high uptake in the basal ganglia and prolonged retention. The preliminary data suggest that R (+)‐TISCH is selective for the CNS D 1 receptor and is potentially useful for in vivo and in vitro pharmacological studies. When labeled with iodine‐123, it may be suitable for noninvasive imaging in humans.