- Synthesis of novel halo and tosyloxy nortropane derivatives as efficient precursors for the one-step synthesis of the dopamine transporter PET ligand [18F]FECNT
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The fluorine-18 labeled nortropane derivative 2β-carbomethoxy-3β- (4-chlorophenyl)-8-(2-fluoroethyl)-nortropane (FECNT) is a dopamine transporter (DAT) ligand. Currently, it is considered as reference for positron emission tomography imaging. Herein, the synthesis of novel precursors (N-tosyloxy-, chloro-, and bromo- analogues) for one-step radiosynthesis of [ 18F]FECNT is reported. Using the N-mesyloxy- precursor in a one-step radiosynthesis, the crude [18F]FECNT was obtained with the radiolabeling yield of 45 ± 10%, confirming the practical efficiency of this approach in the design of novel precursors for labeling. Copyright
- Pijarowska-Kruszyna,Jaron,Kachniarz,Kasprzak,Kowalska,Malkowski,Demphel,Dolle,Mikolajczak
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p. 148 - 157
(2014/04/03)
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- Synthesis and evaluation of novel tropane derivatives as potential PET imaging agents for the dopamine transporter
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A novel series of tropane derivatives containing a fluorinated tertiary amino or amide at the 2β position was synthesized, labeled with the positron-emitter fluorine-18 (t1/2 = 109.8 min), and tested as potential in vivo dopamine transporter (D
- Qiao, Hongwen,Zhu, Lin,Lieberman, Brian P.,Zha, Zhihao,Pl?ssl, Karl,Kung, Hank F.
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scheme or table
p. 4303 - 4306
(2012/08/07)
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- Synthesis and monoamine uptake inhibition of conformationally constrained 2β-carbomethoxy-3β-phenyl tropanes
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A series of 2β-carbomethoxy-3β-phenyl tropanes with conformationally constrained nitrogen substituents were synthesized as potential selective dopamine transporter ligands. These novel compounds were examined for their monoamine uptake inhibition potency at the human dopamine transporter (hDAT), the human serotonin transporter (hSERT) and the human noradrenalin transporter (hNET), stably expressed in human embryonic kidney cells (HEK). A SAR-study was conducted to determine the contribution of extended, 4-fluorinated, conformationally constrained C4 chains at the tropane nitrogen to human monoamine transporter affinity and selectivity. The Royal Society of Chemistry 2009.
- Riss, Patrick Johannes,Hummerich, Rene,Schloss, Patrick
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experimental part
p. 2688 - 2698
(2009/09/07)
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- Synthesis and monoamine transporter affinity of front bridged tricyclic 3β-(4′-halo or 4′-methyl)phenyltropanes bearing methylene or carbomethoxymethylene on the bridge to the 2β-position
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A series of front bridged tricyclic 3β-(4′-halo or 4′-methyl)phenyltropanes bearing methylene or carbomethoxymethylene on the bridge to the 2β-position was synthesized, and their binding affinities were determined in cells transfected to express human nor
- Zeng, Fanxing,Jarkas, Nachwa,Owens, Michael J.,Kilts, Clinton D.,Nemeroff, Charles B.,Goodman, Mark M.
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p. 4661 - 4663
(2007/10/03)
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- Novel tropane-based irreversible ligands for the dopamine transporter
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3α-(Diphenylmethoxy)tropane (benztropine) and its analogues are tropane ring-containing dopamine uptake inhibitors that display binding and behavioral profiles that are distinct from cocaine. We previously prepared a benztropine-based photoaffinity label [125I]-(N-[4-(4′-azido-3′-iodophenyl)butyl]- 3α-[bis(4′-fluorophenyl)methoxy]tropane, [125I]1, that covalently attached to the 1-2 transmembrane spanning region of the dopamine transporter (DAT). This was in contrast to the 4-7 transmembrane spanning region labeled by a cocaine-based photoaffinity label, [125I] 2 (RTI 82). To characterize further these different binding domains, photoaffinity ligands that had the 4′-azido-3′-iodophenyl substituent extended from the same position on the tropane ring were desirable. Thus, identification of the optimal alkyl linker between this substituent and the tropane nitrogen in the benztropine series was investigated to ultimately prepare the identical N-substituted analogue of 2. In this pursuit, the N-[4-(4′-azido-3′-iodophenyl)propyl] analogue of 3α-[bis(4′-fluorophenyl)methoxy]tropane (9a) was synthesized as well as two isothiocyanate analogues that do not require photoactivation (10a,b) for irreversible binding. The synthesis of these target compounds was achieved using a modification of the strategy developed for 1. Evaluation of these compounds for displacing [3H]WIN 35 428 binding at DAT in rat caudate putamen revealed that the 4′-azido-3′-iodophenylbutyl substituent, found in 1, provided optimal binding affinity and was chosen to replace the N-CH3 group on 2. Both the 4′-azido-3′-iodophenyl- and the 4′-isothiocyanatophenylbutyl analogues of 2 (25 and 26, respectively) were synthesized. Both products bound to DAT with comparable potency (IC50 = 30 nM) to RTI 82 (2). In addition, compound 26 demonstrated wash-resistant displacement of [3H]WIN 35 428 in HEK 293 cells stably transfected with hDAT. These ligands will provide important tools for further characterizing the binding domains for tropane-based dopamine uptake inhibitors at the DAT.
- Zou,Kopajtic,Katz,Wirtz,Justice Jr.,Newman
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p. 4453 - 4461
(2007/10/03)
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- 3alpha-(4-Substituted phenyl)nortropane-2beta-carboxylic acid methyl esters show selective binding at the norepinephrine transporter.
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A series of 3alpha-(4-substituted)nortropane-2beta-carboxylic acid methyl esters was synthesized and evaluated for the ability to inhibit radioligand binding at the dopamine, serotonin, and norepinephrine transporters. 3alpha-(4-Methylphenyl)nortropane-2beta-carboxylic acid methyl ester (4c) was found to be selective and highly potent for the norepinephrine transporter (NET) relative to the dopamine and serotonin transporters.
- Blough,Holmquist,Abraham,Kuhar,Carroll
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p. 2445 - 2447
(2007/10/03)
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- Synthesis and characterization of radioiodinated N-(3-iodopropen-1-yl)- 2β-carbomethoxy-3β-(4-chlorophenyl)tropanes: Potential dopamine reuptake site imaging agents
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Methods have been developed for the preparation of radioiodinated N- substituted 2β-carbomethoxy-3β-(4-chlorophenyl)tropanes. The syntheses, physical properties, radiolabeling, and characterization of the pharmacological properties of N-(3(Z)-iodopropen-1-yl)-2β-carbomethoxy-3β- (4-chlorophenyl)tropane (12) and N-(3(E)-iodopropen-1-yl)-2β-carbomethoxy- 3β-(4-chlorophenyl)tropane (13) are described. 2β-Carbomethoxy-3β-(p- substituted-phenyl)tropanes are potent ligands for the dopamine transporter. The radioiodinated derivatives are of interest because of the high uptake and prolonged striatal retention that may result from specific binding to low- capacity, high-affinity, dopamine reuptake sites. Radioiodine was introduced into the 3Z and 3E-position of N-(3-iodopropen-1-yl)-2β-carbomethoxy-3β- (4-chlorophenyl)tropane by iododemetalation of the corresponding 3-(tri-n- butylstannyl) derivatives. Competition binding data of various dopamine reuptake ligands with rat striatal tissue preparation for either [125I]- 12 or [125I]-13 exhibited the following order of potency: E-13 > Z-12 > GBR 12909 >> mazindol >>> (-)-cocaine. Tissue distribution studies in rats showed that the E-13 was the best analogue. E-13 showed high striatal uptake (60 min, 1.23% dose/g; 120 min, 0.61% dose/g) and high striatal to cerebellum ratios (60 min, 15.9/1; 120 min, 16.5/1). These studies indicate that iodine- 123-labeled E-13 is a potentially useful agent for imaging the dopamine reuptake sites by single-photon-emission computerized tomography.
- Goodman,Kung,Kabalka,Kung,Switzer
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p. 1535 - 1542
(2007/10/02)
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- Secondary amine analogues of 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid esters and N-norcocaine exhibit enhanced affinity for serotonin and norepinephrine transporters.
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N-Norcocaine (2) and six N-nor-3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid esters (4a-f) were synthesized by N-demethylation of cocaine (1) and the appropriate 3 beta-(substituted phenyl)-tropane analogues (3a-f) with alpha-chloroethyl chloroformate. Radioligand binding affinities of 2 and 4a-f at the DA, 5-HT, and NE transporter were measured and compared to those of 1 and 3a-f. N-Demethylation produced relatively small effects at the DA transporter. In contrast, 4-19-fold and 2-44-fold enhanced affinity at the serotonin and norepinephrine transporter resulted from demethylation. N-Nor-3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid methyl ester (4d) with an IC50 = 0.36 nM showed the greatest affinity for the serotonin transporter. However, N-nor-3 beta-(4'-ethylphenyl)tropane-2 beta-carboxylic acid methyl ester (4e) showed the greatest selectivity for the serotonin transporter.
- Boja,Kuhar,Kopajtic,Yang,Abraham,Lewin,Carroll
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p. 1220 - 1223
(2007/10/02)
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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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