Synthesis and biological activity of iodinated and photosensitive derivatives of tetrabenazine

Aranda, G.; Beaucourt, JP; Ponchant, M.; Isambert, M.F.; Henry, JP

doi:10.1016/0223-5234(90)90121-i

Cited by 5 publications

(3 citation statements)

References 26 publications

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“…["C]TBZOH, and the presence of potential radiolabeled metabolites may complicate quantitative phannacokinetic modeling. As large substituents can be attached at the hydroxyl function of a-TBZOH and such derivatives retain high binding aSlnity for the monoamine vesicular transporter (Scherman er al., 1988;Aranda et al, 1990), we have investigated derivatives of TBZQH as possible improved, less metabolixed in viuo imaging agents. We report here the synthesis of the *Current address: PET Centre, Clarke Institute of Psychiatry, University of Toronto, Toronto, Ontario.…”

Section: Iilbodrctiodmentioning

confidence: 99%

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Synthesis of a [11C]Methoxy derivative of α-Dihydrotetrabenazine: a radioligand for studying the vesicular monoamine transporter

DaSilva

Kilbourn

Mangner

1993

Applied Radiation and Isotopes

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The synthesis of [11C]TBZOMe, a [11C]methoxy derivative at the 2-hydroxy position of alpha-dihydrotetrabenazine, was carried out by an O-[11C]methylation reaction. The product [11C]TBZOMe (100-200 mCi) was obtained in 15-40% radiochemical yield (corrected for decay) within 37 min, and in high specific activity (2000-2500 Ci/mmol) and radiochemical purity (> 97%). [11C]TBZOMe is a potential new radioligand for studying the vesicular monoamine transporter using positron emission tomography.

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Section: Iilbodrctiodmentioning

confidence: 99%

“…The synthesis of ["CjTBZOMe first required synthesis of a-TBZOH, which was prepared by modification of reported methods (Shwartz et al, 1966, Aranda et al, 1990, Scherman et al, 1981. Sodium borohydride reduction (3.5 equiv.)…”

Section: Discwsiollmentioning

confidence: 99%

Synthesis of a [11C]Methoxy derivative of α-Dihydrotetrabenazine: a radioligand for studying the vesicular monoamine transporter

DaSilva

Kilbourn

Mangner

1993

Applied Radiation and Isotopes

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“…Development of new imaging agents for the vesicular monoamine transporter will require a better knowledge of the structural requirements and limitations for high-affinity binding to the VMAT2. A number of benzisoquinolines have been prepared over the years, including (a) analogs of 2 with different 3-alkyl substituents, (b) derivatives of 1a with alkyl substituents at the 2-position, , and (c) benzisoquinoline analogs with amino, amido, and ester functional groups at the 2-position. , There has, however, never been a systematic study of the in vitro or in vivo structure−activity relationship of benzisoquinoline binding to the VMAT2 site (or, for that matter, any systematic study of the binding site requirement for VMAT2). Alterations of the structure of 2 do have profound effects on its biological activity; some modifications increase pharmacologic activity, while others produce differential depletions of certain monoamines .…”

Section: Introductionmentioning

confidence: 99%

In Vitro and in Vivo Studies of Benzisoquinoline Ligands for the Brain Synaptic Vesicle Monoamine Transporter

et al. 1996

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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.

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Photoaffinity Labeling in Activity-Based Protein Profiling

Geurink

Prely

Marel

et al. 2011

Topics in Current Chemistry

111

105

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Activity-based protein profiling has come to the fore in recent years as a powerful strategy for studying enzyme activities in their natural surroundings. Substrate analogs that bind covalently and irreversibly to an enzyme active site and that are equipped with an identification or affinity tag can be used to unearth new enzyme activities, to establish whether and at what subcellular location the enzymes are active, and to study the inhibitory effects of small compounds. A specific class of activity-based protein probes includes those that employ a photo-activatable group to create the covalent bond. Such probes are targeted to those enzymes that do not employ a catalytic nucleophile that is part of the polypeptide backbone. An overview of the various photo-activatable groups that are available to chemical biology researchers is presented, with a focus on their (photo)chemistry and their application in various research fields. A number of comparative studies are described in which the efficiency of various photo-activatable groups are compared.

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Synthesis and biological activity of iodinated and photosensitive derivatives of tetrabenazine

Cited by 5 publications

References 26 publications

Synthesis of a [11C]Methoxy derivative of α-Dihydrotetrabenazine: a radioligand for studying the vesicular monoamine transporter

Synthesis of a [11C]Methoxy derivative of α-Dihydrotetrabenazine: a radioligand for studying the vesicular monoamine transporter

In Vitro and in Vivo Studies of Benzisoquinoline Ligands for the Brain Synaptic Vesicle Monoamine Transporter

Photoaffinity Labeling in Activity-Based Protein Profiling

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