Increasing evidence suggests that the dopamine transporter is situated almost exclusively on dopamine neurons. Accordingly, it is an excellent marker for Parkinson's disease, a neurodegenerative disease characterized by a severe loss of dopamine neurons. We previously demonstrated that the potent dopamine transport inhibitor [125I]altropane (IACFT:E-N-iodoallyl-2 -carbomethoxy-3 -(4-fluorophenyl)tropane) is a high affinity selective probe for the dopamine transporter in monkey brain and an effective SPECT imaging agent in nonhuman primate brain. This project had two objectives, to determine whether the favorable binding properties of altropane in nonhuman primates extends to human brain and to assess the suitability of altropane as a marker for Parkinson's diseased brain. In homogenates of human brain putamen, [125I]altropane bound to a single high affinity site (KD 4.96 q 0.38 nM, n = 4) and a site density (BMAX 212 q 41.1 pmol/g original wet tissue weight). The affinity was within the range of affinities reported for effective brain imaging agents and, equally significant, binding to a single affinity site increases the level of accuracy for density measurements. The density was within the density range reported previously for the dopamine transporter in this brain region. Drugs inhibited [125I]altropane binding with a rank order of potency that corresponded closely to their rank order for blocking dopamine transport (r 0.98, p <0.001). In post-mortem Parkinson's diseased brain, bound [125I]altropane (1 nM) was markedly reduced (89%, 99% in putamen, depending on measures of non-specific binding) compared with normal aged-matched controls (normal putamen 49.2 q 8.1 pmol/g ; Parkinson's diseased putamen 0.48q0.33 pmol/g; n = 4). In vitro autoradiography, conducted in tissue sections at a single plane of the basal ganglia, revealed high levels of [125I]altropane binding the caudate nucleus and putamen, but lower levels (73% of the caudate-putamen) in the nucleus accumbens (n = 7). In Parkinson's diseased brains (n = 4), [125I]altropane binding was 13% of the levels detected in normal putamen, 17% of normal values in the caudate nucleus and 25% of normal levels in nucleus accumbens. Accordingly, [125I]altropane detected losses of the dopamine transporter that are consistent with dopamine depletion reported previously. The association of [125I]altropane to the dopamine transporter in human post-mortem tissue, the marked reduction of [125I]altropane binding in Parkinson's diseased brains, its rapid entry into brain and highly localized distribution in dopamine-rich brain regions, support its use as a probe for monitoring the dopamine transporter and associated dopamine neurons in vitro and in vivo by SPECT or PET imaging technologies. As an in vivo imaging agent, altropane displays favorable pharmacokinetic properties, achieving equilibrium with the primate brain dopamine transporter within 30 - 60 minutes. These properties are well suited to both PET and SPECT imaging. In concert with this advantage is the feasibility of converting altropane into a chemically identical PET ([11C] or SPECT (123I]) imaging agent. A detailed assessment and comparison of PET vs SPECT imaging conducted under identical conditions with altropane is ongoing. Imaging of the dopamine transporter with WIN 35,428 and its congeners has been applied to the aging brain, Parkinson's disease, other neuropsychiatric disorders (e.g. Tourette's disorder, Lesch-Nyhan syndrome, and alcohol abuse. Investigation of the dopamine transporter as a target of psychostimulant drugs (e.g. cocaine, amphetamine) is another significant application of this class of probes. Cocaine induces neuroadaptive changes in the dopamine transporter and amphetamines are neurotoxic to dopamine neurons. Consequently, PET and SPECT imaging of the transporter can provide needed information on psychostimulant- induced addiction and toxicity in living brain and a useful strategy for investigating candidate cocaine medications. Notwithstanding these important applications, Parkinson's disease continues to be the dominant focus of dopamine transporter imaging research. Accurate imaging of dopamine nerve terminals will be useful in identifying subjects in the preclinical or early stages of the disease. This population may be candidates for emerging technologies designed to treat the disease by promoting regeneration of dopamine neurons. The effectiveness of agents that "rescue" and/or promote growth of dopamine neurons may be gauged by monitoring dopamine nerve terminals with altropane. Based on these and previous data from our laboratory a Phase I clinical trial is ongoing. Madras BK, Babich JW, Elmaleh DR, Meltzer PC, Fischman AJ. The SPECT ligand altropane effectively detects Parkinson's disease in human putamen. Soc Nucl. Med. 38 220, 1997. Madras BK, Gracz LM, Meltzer, PC, Babich J, Fischman AJ. [125I]Altropane, a SPECT imaging probe for dopamine neurons III. Human
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