- [3H]MFZ 2-12: A novel radioligand for the dopamine transporter
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In an effort to develop a tritiated dopamine transporter radioligand with higher affinity than the widely used [3H]WIN 35,428, we have synthesized [3H]2β-carbomethoxy-3β-(3′,4′- dichlorophenyl)tropane ([3H]MFZ 2-12). Unlabeled MFZ 2-12 and the N-demethylated intermediate (MFZ 2-13) inhibited dopamine uptake by the human dopamine transporter with IC50's of 1.1 and 1.4 nM, respectively. The N-nor-intermediate (MFZ 2-13) was treated with CT3I resulting in [3H]MFZ 2-12; S.A. = 80 Ci/mmol). [3H]MFZ 2-12 reversibly bound with a KD of 2.8 nM to human dopamine transporter expressed heterologously in EM4 cells.
- Newman, Amy Hauck,Zou, Mu-Fa,Ferrer, Jasmine V.,Javitch, Jonathan A.
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- Chemical Targeting of Voltage Sensitive Dyes to Specific Cells and Molecules in the Brain
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Voltage sensitive fluorescent dyes (VSDs) are important tools for probing signal transduction in neurons and other excitable cells. The impact of these highly lipophilic sensors has, however, been limited due to the lack of cell-specific targeting methods in brain tissue or living animals. We address this key challenge by introducing a nongenetic molecular platform for cell- and molecule-specific targeting of synthetic VSDs in the brain. We employ a dextran polymer particle to overcome the inherent lipophilicity of VSDs by dynamic encapsulation and high-affinity ligands to target the construct to specific neuronal cells utilizing only native components of the neurotransmission machinery at physiological expression levels. Dichloropane, a monoamine transporter ligand, enables targeting of dense dopaminergic axons in the mouse striatum and sparse noradrenergic axons in the mouse cortex in acute brain slices. PFQX in conjunction with ligand-directed acyl imidazole chemistry enables covalent labeling of AMPA-type glutamate receptors in the same brain regions. Probe variants bearing either a classical electrochromic ANEP dye or state-of-the-art VoltageFluor-type dye respond to membrane potential changes in a similar manner to the parent dyes, as shown by whole-cell patch recording. We demonstrate the feasibility of optical voltage recording with our probes in brain tissue with one-photon and two-photon fluorescence microscopy and define the signal limits of optical voltage imaging with synthetic sensors under a low photon budget determined by the native expression levels of the target proteins. This work demonstrates the feasibility of a chemical targeting approach and expands the possibilities of cell-specific imaging and pharmacology.
- Fiala, Tomas,Wang, Jihang,Dunn, Matthew,?ebej, Peter,Choi, Se Joon,Nwadibia, Ekeoma C.,Fialova, Eva,Martinez, Diana M.,Cheetham, Claire E.,Fogle, Keri J.,Palladino, Michael J.,Freyberg, Zachary,Sulzer, David,Sames, Dalibor
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p. 9285 - 9301
(2020/06/04)
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- Rhodamine-labeled 2β-carbomethoxy-3β-(3,4-dichlorophenyl)tropane analogues as high-affinity fluorescent probes for the dopamine transporter
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Novel fluorescent ligands were synthesized to identify a high-affinity probe that would enable visualization of the dopamine transporter (DAT) in living cells. Fluorescent tags were extended from the N- or 2-position of 2β-carbomethoxy-3β-(3,4-dichlorophenyl)tropane, using an ethylamino linker. The resulting 2-substituted (5) and N-substituted (9) rhodamine-labeled ligands provided the highest DAT binding affinities expressed in COS-7 cells (Ki = 27 and 18 nM, respectively) in the series. Visualization of the DAT with 5 and 9 was demonstrated by confocal fluorescence laser scanning microscopy in stably transfected HEK293 cells.
- Cha, Joo Hwan,Zou, Mu-Fa,Adkins, Erika M.,Rasmussen, S?ren G. F.,Loland, Claus Juul,Schoenenberger, Bernhard,Gether, Ulrik,Newman, Amy Hauck
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p. 7513 - 7516
(2007/10/03)
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- Synthesis of iodinated and radioiodinated (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(3',4'-dichlorophenyl) notropane (β-CDIT): A ligand for the dopamine transporter
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The synthesis of (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(3',4'-dichlorophenyl) nortropane (β-CDIT) and its radioiodinated analogues is described. Three different synthetic methods are reported for the preparation of (E)-N-[3-(tributylstannyl)-2-enyl]-2β-carbomethoxy-3β-(3', 4'-dichlorophenyl) nortropane, which was iododestannylated for the preparation of the corresponding iodinated derivative. We also report the radiolabelling of β-CDIT with 125I or 123I that could be used for in vitro and in vivo exploration of the dopamine transporter.
- Emond,Boazi,Duchene,Chalon,Besnard,Guilloteau,Frangin
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p. 757 - 772
(2007/10/03)
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- Substituted 3-Phenyltropane Analogs of Cocaine: Synthesis, Inhibition of Binding at Cocaine Recognition Sites, and Positron Emission Tomography Imaging
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It is now accepted that (-)-cocaine binds to specific recognition sites associated with monoamine transporters in the mammalian brain. In this study, several analogs of 3β-phenyltropane-2β-carboxylic acid methyl ester were prepared and their potency for inhibiting the binding of -3β-(4-fluorophenyl)tropane-2β-carboxylic acid methyl ester to primate caudate-putamen was evaluated. The synthesis and binding affinity of 3β-(3,4-dichlorophenyl)tropane-2β-carboxylic acid methyl ester, one of the most potent cocaine congeners yet reported, is presented. The feasibility of synthesizing high-affinity ligands for cocaine recognition sites and their suitability as PET imaging ligands for cocaine receptors in vivo is demonstrated.
- Meltzer, P. C.,Liang, A. Y.,Brownell, A.-L.,Elmaleh, D. R.,Madras, B. K.
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p. 855 - 862
(2007/10/02)
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