ALTROPANE, SPECT OR PET IMAGING PROBE FOR DOPAMINE NEURONS I & IN PRIMATE BRAIN

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Increasing evidence suggests that the dopamine transporter is an important marker for pathological changes in dopamine neurons, including Parkinson's disease, aging and substance abuse. Potent dopamine transport inhibitors of the phenyltropane series (e.g. WIN 35,428 or CFT) are among the most effective candidates for PET (positron emission tomography) or SPECT (single photon emission computed tomography) imaging of the dopamine transporter in living brain. The goals of this project were to investigate whether altropane, an N-iodoallyl derivative of WIN 35,428 (IACFT:E-N-iodoallyl-2 -carbomethoxy-3 -(4-fluorophenyl)tropane), displays in vitro properties suitable for evaluation as a SPECT imaging agent. In cynomolgus monkey (Macaca fascicularis) striatum, the region containing the highest levels of dopamine in brain, the unlabeled E- isomer (IC50 6.62 q 0.78 nM) was more potent than the Z-isomer (IC50 52.6 q 0.3 nM) and displayed a relatively high dopamine:serotonin transporter selectivity (28-fold). In radiolabeled form, [125I]altropane bound to sites in the striatum with a single high affinity (KD 5.33 q 0.55 nM) and with a site density (BMAX 301 pmol/g original wet tissue weight) that was within the density range reported previously for the dopamine transporter in striatum. Saturation experiments revealed that [125I]altropane recognized a single affinity binding site, in contrast to the two binding components characteristically detected with [3H]WIN 35,428 or with other brain imaging agents, (e.g. [125I]RTI-55 ( -CIT) or [125I]RTI-121). This unanticipated property of altropane is advantageous because detection of a single affinity site allows for relative ease in quantifying the density of the transporter in vitro or in vivo. Drugs inhibited [125I]altropane binding with a rank order of potency that corresponded closely to their rank order for inhibiting [3H]WIN 35,428 binding (r2 0.99; p < 0.0001) and for blocking dopamine transport. These results indicate that the binding domain on the dopamine transporter can accommodate large groups in the region of the amine nitrogen of phenyltropanes. The selectivity of altropane for the dopamine over the serotonin transporter is also a favorable property of altropane because of the presence of the serotonin transporter in primate striatum, the possibility of serotonin fiber sprouting in the striatum, hyperinnervation of the host striatum by serotonin neurons from ventral mesencephalon grafts, and increased striatal contrast. Based on the high affinity and selectivity of altropane for the dopamine transporter, altropane is a candidate marker for imaging and monitoring the status of the dopamine transporter, and associated dopamine neurons in brain. Madras BK, Meltzer PC, Liang AY, Hanson R, Elmaleh DE, Babich J, Fischman AJ. [125I]Altropane, a SPECT Imaging Probe for