Synthesis and in vivo studies of a selective ligand for the dopamine transporter: 3β-(4-[125I]iodophenyl) tropan-2β-carboxylic acid isopropyl ester ([125I]RTM-21)

Abstract A selective ligand for the dopamine transporter 3β-(4-iodophenyl)tropan-2β-carboxylic acid isopropyl ester (RTI-121) has been labeled with iodine-125 by electrophilic radioiododestannylation. The [ 125 I]RTI-121 was obtained in good yield (86 ± 7%, n = 3) with high radiochemical purity (>99%) and specific radioactivity (1210–1950 mCi/μmol). After i.v. administration of [ 125 I]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 [ 125 I]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, [ 125 I]RTI-121 is readily prepared, and is a useful tracer for dopamine transporter studies in vivo .