Characterization of 125I-IABN, a novel azabicyclononane benzamide selective for D2-like dopamine receptors

Robert T. Luedtke, Rebekah A. Freeman, Virginia A. Boundy, Michael W. Martin, Yunsheng Huang, Robert H. Mach

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

The properties of an 125I-labeled structural analog of 2,3-dimethoxy-N-[9-(4-fluorobenzyl)-9-azabicyclo[3.3.1]nonan-3β-yl]benzamide (MABN), 125I-IABN, are described. 125I-IABN was developed as a high-affinity radioligand selective for the D2-like (D2, D3, and D4) dopamine receptor subtypes. 125I-IABN binds with picomolar affinity and nonselectively to rat D2 and D3 dopamine receptors expressed in Sf9 and HEK 293 cells. 125I-IABN binds with 7- to 25-fold lower affinity to human D4.4 dopamine receptors expressed in HEK 293 cells. Dissociation constants (Kd) calculated from kinetic experiments were in agreement with equilibrium Kd values obtained from saturation binding studies. Saturation plots of the binding of 125I-IABN with rat caudate membrane preparations were monophasic and exhibited low nonspecific binding. The pharmacologic profile of the binding of 125I-IABN to rat caudate was consistent with a D2-like receptor, suggesting that the ligand binds primarily to D2 dopamine receptors. In addition, IABN was found to bind with low affinity to D1 dopamine receptors, as well as to the σ1 and σ2 receptor subtypes. Quantitative autoradiographic studies using rat brain slices indicate that 125I-IABN selectively labels the striatum and the olfactory tubercle area, which is consistent with the labeling of D2-like receptors. IABN blocks dopamine-dependent inhibition of adenylyl cyclase activity at D2 or D4.4 receptors expressed in HEK cells. Therefore, 125I-IABN appears to be a high-affinity, selective antagonist at D2-like dopamine receptors. Finally, a unique property of the azabicyclononane benzamide 125I-IABN compared to previously studied substituted benzamides is that the binding of this radioligand is not effected by variations in Na+ concentration. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)438-449
Number of pages12
JournalSynapse
Volume38
Issue number4
DOIs
StatePublished - 15 Dec 2000

Keywords

  • Benzamides
  • D2 receptors
  • Dopamine receptors
  • Radioligand binding

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