No abstract

Chiral column liquid chromatography and enantiospecific enzymatic hydrolysis were utilized to separate the enantiomers of α‐ and β‐dihydrotetrabenazine and α‐9‐O‐desmethyldihydrotetrabenazine, three benzo[a]quinolizines derived from the amine‐depleting drug tetrabenazine. An X‐ray crystal structure analysis of (−)‐α‐9‐O‐desmethyldihydrotetrabenazine gave an absolute structure of that compound as the 2S, 3S, 11bS isomer. Therefore, (−)‐α‐dihydrotetrabenazine also has the 2S, 3S, 11bS absolute configuration. (+)‐α‐Dihydrotetrabenazine, the single biologically active isomer from the metabolic reduction of tetrabenazine, thus has the absolute configuration of 2R, 3R, 11bR. For further in vitro and in vivo studies of the vesicular monoamine transporter, it is now possible to use the single enantiomer of radiolabeled α‐dihydrotetrabenazine. Chirality 9:59–62, 1997. © 1997 Wiley‐Liss, Inc.

We used ["Cldihydrotetrabenazine, a new ligand for the type 2 vesicular monoamine transporter (vMAT2), with posi-tron emission tomography to study striatal monoaminergic presynaptic terminals in 4 patients with multiple system atrophy, 8 with sporadic olivopontocerebellar atrophy, and 9 normal control subjects. Specific binding in the striatum was significantly reduced in the multiple system atrophy patients as compared with the normal control group, with average reductions of 61% in the caudate nucleus (p = 0.002) and 58% in the putamen (p = 0.009). Smaller reductions were found in the sporadic olivopontocerebellar atrophy group, averaging 26% in the caudate nucleus (p = 0.05) and 24% in the putamen (p = 0.1 1). Mean blood-to-brain ["Cldihydrotetrabenazine transport (K,) was significantly different between groups only in the cerebellum, with values for the sporadic olivopontocerebellar atrophy group diminished compared with the normal control group. Cerebellar K, was not significantly decreased in the multiple system atrophy group. The finding of reduced striatal W T 2 in sporadic olivopontocerebellar atrophy patients suggests nigrostriatal pathology, indicating that some may later develop symptomatic extrapyramidal disease. Cilman, S, Frey KA, Koeppe RA, Juiick L, Little R, Vander Borght TM, Lohnian M, Martorello S, Lee LC, Jewett DM, Kilbourn MR. Decreased striatal monoaminergic terminals in olivopontocerebellar atrophy and multiple system atiophy demonstrated with positron emission tomography. Ann Neurol 1996;40:885-892 Multiple system atrophy (MSA) is a progressive neuro-logical disorder consisting of combinations of extra-pyramidal, pyramidal, cerebellar, and autonomic symptoms and signs [l-71. The term "possible MSA" is used for patients with only extrapyramidal symptoms that are poorly responsive or unresponsive to levodopa (striatonigral degeneration [SND]) and patients with a combination of cerebellar ataxia and extrapyramidal symptoms [2]. The term "probable MSA' pertains to patients with extrapyramidal symptoms poorly responsive or unresponsive to levodopa accompanied by auto-nomic symptoms with or without pyramidal and cere-bellar symptoms (Shy-Drager syndrome [SDS]) [2]. Similarly, the term "probable MSA' is applied to patients with cerebellar and autonomic symptoms with or without extrapyramidal and pyramidal symptoms [2]. The diagnosis of "definite MSA' requires a typical history and physical findings with subsequent postmor-tem verification [2]. In most patients with definite MSA, neuropathological examination demonstrates degenera-tivechanges in the cerebellum and brainstem as well as the basal ganglia and spinal cord [8]. The neuropathological changes in MSA include those seen with SND [9-121, SDS [3, 13-16], and olivopontocerebellar atrophy (OPCA) 13, 6-81. Neuronal loss and gliosis occur in the basal ganglia (putamen and globus pallidus), brainstem and cerebellum (substantial nigra, locus ceruleus, dorsal vagal nuclei, vestibular nuclei, inferior olives, pontine nu-clei, and cerebellar Purki...

Tetrabenazine is a high-affinity inhibitor of the vesicular monoamine transporter in mammalian brain. As part of a program to develop in vivo imaging agents for these transporters in human brain, a series of 2-alkylated dihydrotetrabenazine ligands was synthesized and evaluated in vitro and in vivo for binding to the brain vesicular monoamine transporter. Additions of organometallic reagents to tetrabenazine produced 2-methyl, 2-ethyl, 2-n-propyl, 2-isopropyl, and 2-isobutyl derivatives of dihydrotetrabenazine. The stereochemistry and conformation of the addition products were thoroughly verified by two-dimensional NMR techniques. All of these alkyl derivatives displayed in vitro affinity for the vesicular monoamine transporter binding site in rat brain using competitive assays with the radioligand [3H]methoxytetrabenazine. Except for the isopropyl derivative, all compounds when tested at 10 mg/kg iv showed an ability to inhibit in vivo accumulation of the radioligand [11C]methoxytetrabenazine in the mouse brain striatum. Derivatives with small alkyl groups (methyl, ethyl) were more effective than those with large groups (propyl, isobutyl). These studies suggest that large groups in the 2-position of the benzisoquinoline structure will significantly diminish both in vitro and in vivo binding of these compounds to the vesicular monoamine transporter.

Chiral column liquid chromatography and enantiospecific enzymatic hydrolysis were utilized to separate the enantiomers of α‐ and β‐dihydrotetrabenazine and α‐9‐O‐desmethyldihydrotetrabenazine, three benzo[a]quinolizines derived from the amine‐depleting drug tetrabenazine. An X‐ray crystal structure analysis of (−)‐α‐9‐O‐desmethyldihydrotetrabenazine gave an absolute structure of that compound as the 2S, 3S, 11bS isomer. Therefore, (−)‐α‐dihydrotetrabenazine also has the 2S, 3S, 11bS absolute configuration. (+)‐α‐Dihydrotetrabenazine, the single biologically active isomer from the metabolic reduction of tetrabenazine, thus has the absolute configuration of 2R, 3R, 11bR. For further in vitro and in vivo studies of the vesicular monoamine transporter, it is now possible to use the single enantiomer of radiolabeled α‐dihydrotetrabenazine. Chirality 9:59–62, 1997. © 1997 Wiley‐Liss, Inc.