Synthesis and in vivo studies of a selective ligand for the dopamine transporter: 3 beta-(4-[I-125]iodophenyl)tropan-2 beta-carboxylic acid isopropyl ester ([I-125]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 [I-125]RTI-121 was obtained in good yield (86 +/- 7%, n = 3) with high radiochemical purity(>99%) and specific radioactivity (1210-1950 mCi/mu mol). After i.v. administration of [I-125]Rn-121 to mice, the rank order of regional brain tissue radioactivity (striatum > olfactory tubercles much greater than cortex, hippocampus, thalamus, hypothalamus, cerebellum) was consistent with dopamine transporter labeling, Specific in pike 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 [I-125]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, [I-125]RTI-121 is readily prepared, and is a useful tracer for dopamine transporter studies in vivo