ALTROPANE, A SPECT OR PET IMAGING PROBE FOR DOPAMINE NEURONS - II - DISTRIBUTION TO DOPAMINE-RICH REGIONS OF PRIMATE BRAIN

The dopamine transporter in brain, localized almost exclusively on dop amine neurons, is an effective window on dopamine neurons. SPECT or PE T imaging of the transporter in brain requires selective imaging agent s that display appropriate pharmacokinetic properties. We previously r eported that [I-125]altropane ([I-125]IACFT,2 beta-carbomethoxy-3 -flu oraphenyl)-n-(1-iodoprop-1-en-3-yl)nortropane) bound with high affinit y (Kd: 5.33 nM) to a single site on the dopamine transporter and was s elective for dopamine over the serotonin transporter in homogenates of monkey striatum. To determine whether the selective binding of [I-125 ]altropane is reflected in its brain distribution, the in vitro and ex vivo distribution of [I-125]altropane in squirrel monkey (Saimiri sci ureus) brain was determined by quantitative autoradiography of coronal . brain sections. In vitro, [I-125]altropane (2 nM) distribution was d iscrete and was detectable primarily in the dopamine-rich putamen, cau date nucleus, and nucleus accumbens. The resulting putamen:cerebellum ratio exceeded 120:1 (n = 3). The selective in vitro binding of [I-125 ]altropane to the dopamine transporter, at concentrations approaching its Kd value (Kd: 5.33 nM, a single high affinity site), highlight its suitability for investigating the density of the dopamine transporter in various brain regions in vitro. Ex vivo autoradiography was conduc ted in monkeys to determine whether the brain distribution of [I-125]a ltropane in vitro was predictive of its brain distribution pattern aft er intravenous administration. Thirty minutes after intravenous inject ion, highest levels of [I-125]altropane (0.3 nmol/kg) were detected in the caudate-putamen and nucleus accumbens and lowest levels in the ce rebellum and cortex. The putamen or caudate:cerebellum ratio was ?. SP ECT imaging of the brain within 30 min of i.v. injection confirmed the rapid and selective accumulation of [I-123]altropane to the striatum. The selective binding of altropane to the dopamine-rich striatum with in 30 min of i.v. administration indicates that it is uniquely suited for SPECT or PET imaging of the dopamine transporter and associated do pamine neurons. (C) 1998 Wiley-Liss, Inc.