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

Citation
Rr. Luedtke et al., Characterization of I-125-IABN, a novel azabicyclononane benzamide selective for D2-like dopamine receptors, SYNAPSE, 38(4), 2000, pp. 438-449
Citations number
63
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurosciences & Behavoir
Journal title
SYNAPSE
ISSN journal
0887-4476 → ACNP
Volume
38
Issue
4
Year of publication
2000
Pages
438 - 449
Database
ISI
SICI code
0887-4476(200012)38:4<438:COIANA>2.0.ZU;2-T
Abstract
The properties of an I-125-labeled structural analog of 2,3-dimethoxy-N-[9- (4-fluorobenzyl)-9-azabicyclo [3.3.1]nonan-3 beta -yl] benzamide (MABN), I- 125-IABN, are described. I-125-IABN was developed as a high-affinity radiol igand selective for the D2-like (D2, D3, and D4) dopamine receptor subtypes . I-125-IABN binds with picomolar affinity and nonselectively to rat D2 and D3 dopamine receptors expressed in Sig and HEK 293 cells. I-125-IABN binds with 7- to 25-fold lower affinity to human D4.4 dopamine receptors express ed in HEK 293 cells. Dissociation constants (Rd) calculated from kinetic ex periments were in agreement with equilibrium Kd values obtained from satura tion binding studies. Saturation plots of the binding of I-125-IABN With ra t caudate membrane preparations were monophasic and exhibited low nonspecif ic binding. The pharmacologic profile of the binding of I-125-IABN to rat c audate was consistent with a D2-like receptor, suggesting that the ligand b inds primarily to D2 dopamine receptors. In addition, IABN was found to bin d with low affinity to D1 dopamine receptors, as well as to the ol and sigm a2 receptor subtypes. Quantitative autoradiographic studies using rat brain slices indicate that I-125-IABN selectively labels the striatum and the ol factory tubercle area, which is consistent with the labeling of D2-like rec eptors. IABN blocks dopamine-dependent inhibition of adenylyl cyclase activ ity at D2 or D4.4 receptors expressed in HEK cells. Therefore, I-125-IABN a ppears to be a high-affinity, selective antagonist at D2-like dopamine rece ptors. Finally, a unique property of the azabicyclononane benzamide I-125-I ABN compared to previously studied substituted benzamides is that the bindi ng of this radioligand is not effected by variations in Na+ concentration. (C) 2000 Wiley-Liss, Inc.