IPT - A NOVEL IODINATED LIGAND FOR THE CNS DOPAMINE TRANSPORTER

An iodinated cocaine derivative, N-(3'-iodopropen-2'-yl)-2 beta-carbom ethoxy-3 beta-(4-chlorophenyl) tropane (IPT), was evaluated as a probe for in vitro and in vivo labeling of dopamine (DA) and serotonin (5-H T) transporters in Sprague-Dawley rat brain. Saturation analysis of[I- 125]IPT in rat striatal homogenates, in two different buffer solutions , Tris-HCl and phosphate, demonstrated a one-site binding with affinit ies (K-d) of 0.25 +/- 0.02 and 0.16 +/- 0.02 nM and densities (B-max) of 939 +/- 161 and 1,982 +/- 137 fmol/mg protein, respectively. Compet ition by known DA transporter ligands showed a rank order of RTI-55 > IPT > GBR12909 > mazindol > (-)cocaine. Binding to 5-HT transporter si tes was evaluated in rat cortical homogenates. Saturation experiment r esults showed a single site with a K-d value of 1.2 +/- 0.2 nM and a B -max value of 100 +/- 20 fmol/mg protein. The rank order of potency of several monoamine uptake inhibitors (paroxetine > fluoxetine > mazind ol > R-nisoxetine > GBR12909) suggests that [I-125] IPT labels 5-HT tr ansporters in rat cortical homogenates. Both ex vivo and in vitro auto radiographic studies revealed high densities of [I-125]IPT binding sit es in the caudate nucleus, putamen, olfactory tubercle and nucleus acc umbens, areas known to be rich in dopaminergic innervation. Moderate a ccumulation of activity was also observed in the substantia nigra. The dorsal raphe, a region with a high density of 5-HT innervation, was l abeled using in vitro autoradiography with [I-125]IPT, but the labelin g using ex vivo autoradiography was less prominent at 30 min postinjec tion and not noticeable at 60 min postinjection. Furthermore, systemic administration of IPT to rats increased the locomotor activity, a beh avioral effect consistent with the in vitro and in vivo characteristic s of compounds acting at dopaminergic sites. These results demonstrate that [I-125]IPT is a useful ligand for in vitro labeling of DA and 5- HT transporters and a ligand selective for labeling of DA transport si tes in vivo. When labeled with I-123, [I-123]IPT holds promise as a SP ECT imaging agent for studies of neuropsychiatric disorders that invol ve DA transporters. (C) 1995 Wiley-Liss, Inc.