High affinity dopamine D2 receptor radioligands. 2. ( sup 125 I)epidepride, a potent and specific radioligand for the characterization of striatal and extrastriatal dopamine D2 receptors

Journal Article · Tue Jan 01 04:00:00 EST 1991 · Life Sciences; (United States)

DOI:https://doi.org/10.1016/0024-3205(91)90261-9· OSTI ID:5699089

Kessler, R M; Ansari, M S; Schmidt, D E; de Paulis, T; Clanton, J A; Manning, R G; Gillespie, D ^[1]; Innis, R; Al-Tikriti, M ^[2]

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1. Vanderbilt Univ., Nashville, TN (United States)
2. Yale Univ., New Haven, CT (United States)

Epidepride, (S)-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-iodo-2,3-dimethoxybenzamide, the iodine analogue of isoremoxipride (FLB 457), was found to be a very potent dopamine D2 receptor antagonist. Optimal in vitro binding required incubation at 25C for 4 h at pH 7.4 in a buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl{sub 2} and 1 nM MgCl{sub 2}. Scatchard analysis of in vitro binding to striatal, medical frontal cortical, hippocampal and cerebellar membranes revealed a K{sub D} of 24 pM in all regions, with Bmax's of 36.7, 1.04, 0.85, and 0.37 pmol/g tissue, respectively. The Hill coefficients ranged from 0.91-1.00 in all four regions. The IC{sub 50}'s for inhibition of ({sup 125}I)epidepride binding to striatal, medial frontal cortical, and hippocampal membranes for SCH 23390, SKF 83566, serotonin, ketanserin, mianserin, naloxone, QNB, prasozin, clonidine, alprenolol, and norepinephrine ranged from 1 {mu}M to >10 {mu}M. Partial displacement of ({sup 125}I)epidepride by nanomolar concentrations of clonidine was noted in the frontal cortex and hippocampus, but not in the striatum. Scatchard analysis of epidepride binding to {alpha}{sub 2} noradrenergic receptors in the frontal cortex and hippocampus revealed an apparent K{sub D} of 9 nM. At an epidepride concentration equal to the K{sub D} for the D2 receptor, i.e., 25 pM, no striatal {alpha}{sub 2} binding was seen and only 7% of the specific epidepride binding in the cortex or hippocampus was due to binding at the {alpha}{sub 2} site. Correlation of inhibition of ({sup 3}H)spiperone and ({sup 125}I)epidepride binding to striatal membranes by a variety of D2 ligands revealed a correlation coefficient of 0.99, indicating that epidepride labels a D2 site.

• OSTI ID: 5699089
• Journal Information: Life Sciences; (United States), Journal Name: Life Sciences; (United States) Vol. 49:8; ISSN 0024-3205; ISSN LIFSA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINES
AROMATICS
AUTONOMIC NERVOUS SYSTEM AGENTS
BETA DECAY RADIOISOTOPES
BIOCHEMICAL REACTION KINETICS
BODY
BRAIN
CARDIOTONICS
CARDIOVASCULAR AGENTS
CELL CONSTITUENTS
CELL MEMBRANES
CENTRAL NERVOUS SYSTEM
CHEMICAL COMPOSITION
DAYS LIVING RADIOISOTOPES
DOPAMINE
DRUGS
ELECTRON CAPTURE RADIOISOTOPES
HYDROXY COMPOUNDS
INTERMEDIATE MASS NUCLEI
INTERNAL CONVERSION RADIOISOTOPES
IODINE 125
IODINE ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
KINETICS
LIGANDS
MEMBRANE PROTEINS
MEMBRANES
NERVOUS SYSTEM
NEUROREGULATORS
NUCLEI
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
ORGANS
PHENOLS
POLYPHENOLS
PROTEINS
RADIOISOTOPES
REACTION KINETICS
RECEPTORS
SYMPATHOMIMETICS
TRACER TECHNIQUES