Altropane, a SPECT or PET imaging probe for dopamine neurons: II. distribution to dopamine-rich regions of primate brain

Abstract

The dopamine transporter in brain, localized almost exclusively on dopamine neurons, is an effective window on dopamine neurons. SPECT or PET imaging of the transporter in brain requires selective imaging agents that display appropriate pharmacokinetic properties. We previously reported that [125I]altropane ([125I]IACFT,2beta-carbomethoxy-3beta-(4-fluorophenyl)-n-(1- iodoprop-1-en-3-yl)nortropane) bound with high affinity (Kd: 5.33 nM) to a single site on the dopamine transporter and was selective for dopamine over the serotonin transporter in homogenates of monkey striatum. 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 (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 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 min of i.v. administration indicates that it is uniquely suited for SPECT or PET imaging of the dopamine transporter and associated dopamine neurons.

Altropane, a SPECT or PET imaging probe for dopamine neurons: III. Human dopamine transporter in postmortem normal and Parkinson's diseased brain

“…In Parkinson's diseased putamen, [ 125 I]altropane detected losses of the dopamine transporter that are consistent with dopamine depletion reported previously (Kish et al, 1988;Wilson et al, 1996). Based on the binding properties of altropane in human striatum and its pharmacokinetic properties Fischman et al, , 1998Madras et al, 1998b), it can be concluded that altropane has important advantages for imaging the dopamine transporter with either SPECT or PET technologies.…”

“…Wilson et al (1996) used high concentrations of [ 3 H]WIN 35,428 (100 nM) and mazindol (500 nM) to achieve saturation of the dopamine transporter. As WIN 35,428 is 12-fold selective for the dopamine over the serotonin transporter (Meltzer et al, 1993) and mazindol (the baseline drug) is about twofold selective for the dopamine over the serotonin transporter (D'Amato et al, 1987;Javitch et al, 1984) (Kaufman and Madras, 1992;Madras et al, 1998b). Finally, as an in vivo imaging agent altropane displays favorable pharmacokinetic properties, achieving equilibrium with the primate brain dopamine transporter within 30-60 min (Fischman et al, , 1997a.…”

Assessment of Striatal Dopamine Transporter Binding in Individuals With Major Depressive Disorder

“…Notably, the only PET study reported reduced DAT availability in the putamen in a small MDD group (n = 9). In addition to showing a 28-fold selectivity for DAT over the serotonin transporter (vs 1:1 for [ 123 I]β-CIT and 3:1 for TRODAT), altropane accumulates within 30 minutes almost exclusively to DA-rich striatal regions, and the putamen:cerebellum ratio is 120:1, highlighting an exceptional degree of binding selectivity . We speculate that using this highly selective PET tracer allowed us to more reliably probe DAT function in unmedicated MDD.…”

Performance of a novel collimator for high‐sensitivity brain SPECT

“…This substantial improvement in sensitivity, especially near the center of the FOV, can play a key role in neuroreceptor imaging, particularly dynamic receptor imaging. The reduction in noise near the center of the FOV is crucial for precise measurement of binding potential, which is affected in Parkinson's disease and other movement disorders, 4,[11][12][13] as well as in attention deficit hyperactivity disorder. 14 The improvement in neuroreceptor imaging is obvious in the 123 I-altropane dopamine transporter study reported in this work; the striata were clearly visible with the SensOgrade collimator but not with the standard parallelhole collimator under the same imaging conditions, despite the fact that the latter offers sensitivity two to three times greater than that of a conventional dual-head SPECT camera.…”