The serotonin transporter in rhesus monkey brain: comparison of DASB and citalopram binding sites.
We have characterized the interaction of the serotonin transporter ligand [3H]-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)-benzylamine (DASB) with rhesus monkey brain in vitro using tissue homogenate binding and autoradiographic mapping. [3H]-DASB, a tritiated version of the widely used [11C] positron emission tomography tracer, was found to selectively bind to a single population of sites with high affinity (K(d)=0.20+/-0.04 nM). The serotonin transporter density (B(max)) obtained for rhesus frontal cortex was found to be 66+/-8 fmol/mg protein using [3H]-DASB, similar to the B(max) value obtained using the reference radioligand [3H]-citalopram, a well-characterized and highly selective serotonin reuptake inhibitor (83+/-22 fmol/mg protein). Specific binding sites of both [3H]-DASB and [3H]-citalopram were similarly and nonuniformly distributed throughout the rhesus central nervous system, in a pattern consistent with serotonin transporter localization reported for human brain. Regional serotonin transporter densities, estimated from optical densities of the autoradiographic images, were well correlated between the two radioligands. Finally, DASB and fluoxetine showed dose-dependent full inhibition of [3H]-citalopram binding in a competition autoradiographic study, with K(i) values in close agreement with those obtained from rhesus brain homogenates. This side-by-side comparison of [3H]-DASB and [3H]-citalopram binding sites in rhesus tissue homogenates and in adjacent rhesus brain slices provides additional support for the use of [11C]-DASB to assess the availability and distribution of serotonin transporters in nonhuman primates.
Zeng
Zhizhen
Z
Imaging Department, Merck Research Laboratories, West Point, PA 19486, USA. zhizhen_zeng@merck.com
Chen
Tsing-Bau
TB
Miller
Patricia J
PJ
Dean
Dennis
D
Tang
Yui Sing
YS
Sur
Cyrille
C
Williams
David L
DL
D000818:Animals; D001345:Autoradiography; D001596:Benzylamines / Q000493:pharmacokinetics*; D001665:Binding Sites; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D015283:Citalopram / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008657:Metabolic Clearance Rate; D011485:Protein Binding; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D014018:Tissue Distribution; D014316:Tritium / Q000493:pharmacokinetics
D001596:Benzylamines; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins; D015283:Citalopram; D014316:Tritium