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
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.