- Synthesis and Pharmacological Evaluation of [11C]Granisetron and [18F]Fluoropalonosetron as PET Probes for 5-HT3 Receptor Imaging
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Serotonin-gated ionotropic 5-HT3 receptors are the major pharmacological targets for antiemetic compounds. Furthermore, they have become a focus for the treatment of irritable bowel syndrome (IBS) and there is some evidence that pharmacological modulation of 5-HT3 receptors might alleviate symptoms of other neurological disorders. Highly selective, high-affinity antagonists, such as granisetron (Kytril) and palonosetron (Aloxi), belong to a family of drugs (the "setrons") that are well established for clinical use. To enable us to better understand the actions of these drugs in vivo, we report the synthesis of 8-fluoropalonosetron (15) that has a binding affinity (Ki = 0.26 ± 0.05 nM) similar to the parent drug (Ki = 0.21 ± 0.03 nM). We radiolabeled 15 by nucleophilic 18F-fluorination of an unsymmetrical diaryliodonium palonosetron precursor and achieved the radiosynthesis of 1-(methyl-11C)-N-granisetron ([11C]2) through N-alkylation with [11C]CH3I, respectively. Both compounds [18F]15 (chemical and radiochemical purity >95%, specific activity 41 GBq/μmol) and [11C]2 (chemical and radiochemical purity ≥99%, specific activity 170 GBq/μmol) were evaluated for their utility as positron emission tomography (PET) probes. Using mouse and rat brain slices, in vitro autoradiography with both [18F]15 and [11C]2 revealed a heterogeneous and displaceable binding in cortical and hippocampal regions that are known to express 5-HT3 receptors at significant levels. Subsequent PET experiments suggested that [18F]15 and [11C]2 are of limited utility for the PET imaging of brain 5-HT3 receptors in vivo.
- Mu, Linjing,Müller Herde, Adrienne,Rüefli, Pascal M.,Sladojevich, Filippo,Milicevic Sephton, Selena,Kr?mer, Stefanie D.,Thompson, Andrew J.,Schibli, Roger,Ametamey, Simon M.,Lochner, Martin
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p. 1552 - 1564
(2016/11/29)
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- PROCESSES FOR THE PREPARATION OF PALONOSETRON
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The present invention relates to novel processes for the preparation of N-[(3S)-1- azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide of Formula I. The present invention further relates to processes for the preparation of palonosetron or its salts thereof using N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8- tetrahydronaphthalene-1-carboxamide of Formula I as an intermediate.
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Page/Page column 14-15
(2011/02/24)
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- PREPARATION OF CRYSTALLINE PALONOSETRON HYDROCHLORIDE
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Processes for the preparation of palonosetron hydrochloride and its crystalline forms.
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Page/Page column 22
(2010/06/15)
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- Processes for preparing palonosetron salts
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The present invention provides processes for preparing Palonosetron salts, especially, the hydrochloride salt and intermediates used to prepare Palonosetron salts.
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Page/Page column 11
(2008/12/08)
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- Tricyclic 5-HT3 receptor antagonists
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The present invention is directed to 5-HT 3 receptor antagonist compounds of formula I: STR1 in which the dashed line denotes an optional double bond;n is 1, 2 or 3;p is 0, 1, 2 or 3;q is 0, 1 or 2;each R 1 is independently selected from halogen, hydroxy, lower alkoxy, lower alkyl, nitro, amino, amino carbonyl, (lower alkyl)amino, di(lower alkyl)amino, and (lower alkanoyl)amino;each R 2 is lower alkyl; andR 3 is a group selected from Formulae (a), (b), (c) and (d): STR2 in which u is 0 or 1;z is 1, 2 or 3; andR 4 is C 1-7 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl, or a group (CH 2) t R 5 where t is 1 or 2 and R 5 is thienyl, pyrrolyl, or furyl, each optionally further substituted by one or two substituents selected from C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C 1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C 1-4 alkyl optionally substituted by hydroxy, C 1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy; and the pharmaceutically acceptable salts, individual isomers, mixtures of isomers, processes for preparation, compositions, and methods of use thereof.
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- 2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists
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Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series,2-(quinuclidin-3-yl)tetrahydropyrido[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridge
- Clark,Miller,Berger,Repke,Weinhardt,Kowalczyk,Eglen,Bonhaus,Lee,Michel,Smith,Wong
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p. 2645 - 2657
(2007/10/02)
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