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

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If neuron-specific, molecular targets for PET or SPECT brain imaging agents may also serve as a window on the status of associated neurons. The dopamine transporter is a particularly attractive target for imaging, as it is expressed uniquely on dopamine neurons. As dopamine neurons degenerate markedly in Parkinson's disease in tandem with the dopamine transporter, imaging agents targeted to the transporter can expedite the diagnosis and treatment of Parkinson's disease. SPECT or PET imaging of the transporter in brain requires selective imaging agents that display appropriate pharmacokinetic properties. We discovered that [125I]altropane ([125I]IACFT,2 -carbomethoxy-3 -(4-fluorophenyl)-n-(1-iodoprop-1-en-3-yl)nortropane) bound with high affinity 5 nM) to a single site on the dopamine transporter and was selective for the dopamine over the serotonin transporter in homogenates of monkey striatum. The goals of this project were to determine whether the selective binding of [125I]altropane is reflected in its brain distribution, the in vitro and ex vivo distribution of [125I]altropane in squirrel monkey (Saimiri sciureus) brain was determined by quantitative autoradiography of coronal brain sections. In vitro, [125I]altropane (2 nM) distribution was discrete and was detectable primarily in the dopamine-rich putamen, caudate nucleus and nucleus accumbens. The resulting putamen:cerebellum ratio exceeded 120:1 (n=3). The selective in vitro binding of [125I]altropane to the dopamine transporter, at concentrations approaching its Kd value highlight its suitability for investigating the density of the dopamine transporter in various brain regions in vitro. Ex vivo autoradiography was conducted in monkeys to determine whether the brain distribution of [125I]altropane in vitro was predictive of its brain distribution pattern after intravenous administration. Thirty minutes after intravenous injection, highest levels of [125I]altropane (0.3 nmol/kg) were detected in the caudate-putamen and nucleus accumbens and lowest levels in the cerebellum and cortex. The putamen or caudate:cerebellum ratio was 7. SPECT imaging of the brain within 30 min of i.v. injection confirmed the rapid and selective accumulation of [123I]altropane to the striatum. The selective binding of altropane to the dopamine-rich striatum within 30 minutes of intravenous administration indicates that it is uniquely suited for SPECT or PET imaging of the dopamine transporter and associated dopamine neurons. [125I]Altropane, a dopamine transporter probe, is a promising imaging agent for the dopamine transporter and associated dopamine neurons in brain. In vitro, [125I]altropane distribution in vitro is strikingly similar to the distribution of the dopamine transporter or transporter mRNA in brain. The resulting putamen:cerebellum ratio 100:1, a ratio not achieved previously, suggests that it is among the most selective probes for the dopamine transporter. The favorable binding properties of altropane in vitro are not necessarily predictive of the rate at which it may enter the brain, distribute or clear the brain in vivo. Ex vivo autoradiography is an effective procedure for gauging the appropriateness of a probe for imaging. It provides information on brain penetrance of a ligand, rate of entry and a detailed anatomical map of the distribution of a ligand. Administered intravenously, the paramount properties of [125I]altropane were rapid entry into brain, selective accumulation in striatum within 30 minutes and a similar distribution in vitro and in vivo. The rapid entry into brain and high degree of localization to striatum within 30 minutes anticipated that altropane was a promising SPECT candidate. SPECT imaging with [123I]altropane in human subjects and in monkeys fully support this expectation. The unique pharmacokinetic properties of [123I]altropane allow SPECT imaging sessions to be conducted within a short time period after administration of the probe, a substantial convenience for clinical studies. Conversion of altropane from a SPECT to a PET ligand without changing its molecular structure is feasible, by insertion of [11C] as a methyl group on the 2 -carbomethoxy position. PET and SPECT imaging with [11C] and [123I]altropane, conducted under virtually the same conditions and time frame, will permit detailed assessment of the relative advantages and disadvantages associated with the two imaging techniques. With emerging technologies targeted to neuroprotective and neuroregenerative agents, the capacity to view the status of dopamine neurons will offer objective information on the efficacy of these novel approaches. Imaging of the dopamine transporter in living brain in a longitudinal study can clarify the neuroadaptive processes that occur consequent to cocaine. From the medications development perspective, imaging of the transporter can provide important information of level of occupancy of candidate cocaine medications. By virtue of its favorable pharmacokinetic properties and rapid, selective accumulation in the striatum, altropane is a promising SPECT and PET imaging probe. The production of an identical PET and SPECT imaging agent will allow for meaningful comparisons to be made between the two imaging techniques. Finally, the close correspondence between in vitro and in vivo distribution of altropane supports the feasibility of comparing measures of dopamine neurons in living brain tissue and in post-mortem tissue with an identical probe. Madras BK, Gracz LM. Meltzer PC, Liang AY, Elmaleh DR, Fischman AJ. Altropane, a SPECT imaging probe for dopamine neurons II. In vitro and ex vivo distribution in primate brain, Synapse, in press, 1998. Madras BK, Gracz LM, Kaufman MJ, Meltzer PC, Elmaleh D, Fischman AJ. Altropane, a novel SPECT imaging agent for cocaine binding sites on the dopamine transporter, NIDA Res. Monograph, 176 1996. Fischman AJ, Babich JW, Elmaleh DE, Barrow SA, Meltzer PC, Madras BK. SPECT imaging of dopamine transporter sites in normal