[3H]4-(dimethylamino)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl) butyl)benzamide: a selective radioligand for dopamine D(3) receptors. II. Quantitative analysis of dopamine D(3) and D(2) receptor density ratio in the caudate-putamen.
4-(Dimethylamino)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)benzamide (WC-10), a N-phenyl piperazine analog, displays high affinity and moderate selectivity for dopamine D(3) receptors versus dopamine D(2) receptors (Chu et al. [2005] Bioorg Med Chem 13:77-87). In this study, WC-10 was radiolabeled with tritium (specific activity = 80 Ci/mmol), and quantitative autoradiography studies were conducted using rhesus monkey and Sprague-Dawley rat brain sections. K(d) values for the binding of [3H]WC-10 to D(3) receptors obtained from quantitative autoradiography with rhesus monkey and rat brain sections are in agreement with K(d) values obtained from cloned human and rat receptors (Xu et al. [2009] Synapse 63:717-728). The D(2) selective antagonist [3H]raclopride binds with 11-fold higher affinity to human HEK D(2L) (K(d) = 1.6 nM) than HEK D(3) (K(d) = 18 nM) receptors; [3H]raclopride binds to rat Sf9 rD(2L) receptors with a K(d) of 6.79 nM, a value that is 4-fold lower than binding to human HEK D(2L) receptors and 2.5-fold higher than binding to rat Sf9 rD(3) receptors. In vitro quantitative autoradiography studies with [3H]WC-10 and [3H]raclopride were conducted on adult rat and rhesus monkey brain sections. A mathematical model for calculating the absolute densities of dopamine D(2) and D(3) receptors based on the in vitro receptor binding data of [3H]WC-10 and [3H]raclopride was developed.
Xu
Jinbin
J
Department of Radiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
Hassanzadeh
Babak
B
Chu
Wenhua
W
Tu
Zhude
Z
Jones
Lynne A
LA
Luedtke
Robert R
RR
Perlmutter
Joel S
JS
Mintun
Mark A
MA
Mach
Robert H
RH
D000818:Animals; D001345:Autoradiography / Q000379:methods; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology*; D002421:Caudate Nucleus / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D018492:Dopamine Antagonists / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D055641:Mathematical Concepts; D008962:Models, Theoretical; D010879:Piperazines / Q000378:metabolism*; D011699:Putamen / Q000378:metabolism*; D020891:Raclopride / Q000378:metabolism; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000187:drug effects / Q000378:metabolism*
D018492:Dopamine Antagonists; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C543148:WC10 compound; D020891:Raclopride