Synthesis and in vivo studies of a selective ligand for the dopamine transporter: 3 beta-(4-[125I]iodophenyl) tropan-2 beta-carboxylic acid isopropyl ester ([125I]RTI-121).
A selective ligand for the dopamine transporter 3 beta-(4-iodophenyl)tropan-2 beta-carboxylic acid isopropyl ester (RTI-121) has been labeled with iodine-125 by electrophilic radioiododestannylation. The [125I]RTI-121 was obtained in good yield (86 +/- 7%, n = 3) with high radiochemical purity (> 99%) and specific radioactivity (1210-1950 mCi/mumol). After i.v. administration of [125I]RTI-121 to mice, the rank order of regional brain tissue radioactivity (striatum > olfactory tubercles > > cortex, hippocampus, thalamus, hypothalamus, cerebellum) was consistent with dopamine transporter labeling. Specific in vivo binding in striatum and olfactory tubercles was saturable, and was blocked by the dopamine transporter ligands GBR 12,909 and (+/-)-nomifensine. By contrast, binding was not reduced by paroxetine, a serotonin transporter inhibitor, or desipramine, a norepinephrine transporter inhibitor. A variety of additional drugs having high affinities for recognition sites other than the neuronal dopamine transporter also had no effect. The [125I]RTI-121 binding in striatum and olfactory tubercles was inhibited by d-amphetamine in dose-dependent fashion. Nonmetabolized radioligand represents 85% of the signal observed in extracts of whole mouse brain. Thus, [125I]RTI-121 is readily prepared, and is a useful tracer for dopamine transporter studies in vivo.
Lever
J R
JR
Department of Environmental Health Sciences and Radiology, Johns Hopkins University, Baltimore, MD 21205, USA.
Scheffel
U
U
Stathis
M
M
Seltzman
H H
HH
Wyrick
C D
CD
Abraham
P
P
Parham
K
K
Thomas
B F
BF
Boja
J W
JW
Kuhar
M J
MJ
Carroll
F I
FI
D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D007457:Iodine Radioisotopes; D007553:Isotope Labeling / Q000379:methods; D007700:Kinetics; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D014018:Tissue Distribution
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D007457:Iodine Radioisotopes; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C079213:RTI 121; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine