- Optimization of 18F-syntheses using 19F-reagents at tracer-level concentrations and liquid chromatography/tandem mass spectrometry analysis: Improved synthesis of [18F]MDL100907
-
Traditional radiosynthetic optimization faces the challenges of high radiation exposure, cost, and inability to perform serial reactions due to tracer decay. To accelerate tracer development, we have developed a strategy to simulate radioactive 18F-syntheses by using tracer-level (nanomolar) non-radioactive 19F-reagents and LC-MS/MS analysis. The methodology was validated with fallypride synthesis under tracer-level 19F-conditions, which showed reproducible and comparable results with radiosynthesis, and proved the feasibility of this process. Using this approach, the synthesis of [18F]MDL100907 was optimized under 19F-conditions with greatly improved yield. The best conditions were successfully transferred to radiosynthesis. A radiochemical yield of 19% to 22% was achieved with the radiochemical purity >99% and the molar activity 38.8 to 53.6?GBq/ μmol (n?=?3). The tracer-level 19F-approach provides a high-throughput and cost-effective process to optimize radiosynthesis with reduced radiation exposure. This new method allows medicinal and synthetic chemists to optimize radiolabeling conditions without the need to use radioactivity.
- Zhang, Xiang,Dunlow, Ryan,Blackman, Burchelle N.,Swenson, Rolf E.
-
-
Read Online
- Immobilization of Substrates in Enzyme-Catalyzed Hydrolysis
-
A new technique - immobilization of substrates on solid supports - was applied to the synthesis of a new potent optically pure serotonin receptor antagonist.
- King, Chi-Hsin R.,Margolin, Alexey L.
-
-
Read Online
- Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET
-
Radiolabelled piperidine derivatives such as [11C]MDL 100907 and [18F]altanserin have played an important role in diagnosing malfunction in the serotonergic neurotransmission. A variety of novel piperidine MDL 100907 derivatives, possible to label with 18F-fluorine, were synthesized to improve molecular imaging properties of [11C]MDL 100907. Their in vitro affinities to a broad spectrum of neuroreceptors and their lipophilicities were determined and compared to the clinically used reference compounds MDL 100907 and altanserin. The novel compounds MA-1 (53) and (R)-MH.MZ (56) show Ki-values in the nanomolar range towards the 5-HT2A receptor and insignificant binding to other 5-HT receptor subtypes or receptors. Interestingly, compounds MA-1 (53), MH.MZ (55) and (R)-MH.MZ (56) provide a receptor selectivity profile similar to MDL 100907. These compounds could possibly be preferable antagonistic 18F-tracers for visualization of the 5-HT2A receptor status. Medium affine compounds (VK-1 (32), (51), (52), (54)) were synthesized and have Ki values between 30 and 120 nM. All promising compounds show log P values between 2 and 3, that is, within the range of those for the established radiotracers altanserin and MDL 100907. The novel compounds MA-1 (53) and (R)-MH.MZ (56) thus appear to be promising high affine and selective tracers of 18F-labelled analogues for 5-HT2A imaging with PET.
- Herth, Matthias M.,Kramer, Vasko,Piel, Markus,Palner, Mikael,Riss, Patrick J.,Knudsen, Gitte M.,Roesch, Frank
-
experimental part
p. 2989 - 3002
(2009/09/05)
-
- Processes for the preparation of (R)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol"
-
The present invention provides various processes for the preparation of (R)-±-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol. These processes may be characterized by the following scheme:
- -
-
Page/Page column 12; 47
(2010/11/25)
-
- Use of MDL-100,907 for treatment of allergic and eosinophil mediated diseases
-
Methods of modulating eosinophil migration, chemotaxis or generation, in vitro, ex vivo, and in vivo are provided. Methods include contacting eosinophils with an amount of 5-HT2A receptor agonist or antagonist sufficient to modulate eosinophil migration, chemotaxis or generation.
- -
-
Page/Page column 10; 11
(2010/10/20)
-
- The "reverse-tethered" ruthenium (II) catalyst for asymmetric transfer hydrogenation: Further applications
-
The attachment of a tethering group from the basic nitrogen atom to the arene ligand of a ruthenium(II) catalyst greatly improves its ability to catalyze asymmetric transfer hydrogenation (ATH) reactions. In this paper, we describe further applications of this versatile system to an extended substrate range.
- Morris, David J.,Hayes, Aidan M.,Wills, Martin
-
p. 7035 - 7044
(2007/10/03)
-
- Novel processes for the preparation of (R)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
-
The present invention provides various processes for the preparation of (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol. These processes may be characterized by the following scheme:
- -
-
-
- Novel processes for the preparation or (R)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
-
The present invention provides various processes for the preparation of (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol. These processes may be characterized by the following scheme:
- -
-
-
- A practical synthesis of the serotonin 5-HT(2a) receptor antagonist MDL 100907, its enantiomer and their 3-phenolic derivatives as precursors for [11C ]labeled PET ligands
-
A practical synthesis of the 3-phenolic precursor of MDL 100907, a selective 5-HT(2A) receptor antagonist, is described. The route was also applied to the enantiomeric series, thus affording the direct precursors of both 3-[11C]MDL 100907 and its enantiomer as ligands for positron emission tomography. Similar methodology was developed for the direct synthesis of MDL 100907 and its enantiomer, MDL 100009. The routes utilized classical optical resolution of the N-nor intermediates in at least 98% enantiomeric excess and easily afforded multigram amounts of the chiral precursors of a variety of N- and 3-O-substituted enantiomers. Copyright (C) 2000 Elsevier Science Ltd.
- Ullrich, Thomas,Rice, Kenner C.
-
p. 2427 - 2432
(2007/10/03)
-
- An efficient synthesis of the precursors of [11C]MDL 100907 labeled in two specific positions
-
An efficient, integrated route for the synthesis of two precursors of [11C]MDL 100907 labeled in the 2'- or 3'-methoxy position is reported. The synthesis involved a one-pot, two-step process to transform the intermediate esters to ketones and subsequent resolution of the racemic alcohols to their respective enantiomers. The resolved, enantiomerically pure phenol precursors were reacted with high specific activity [11C]methyl iodide to produce [11C]MDL 100907 labeled in two specific positions.
- Huang, Yiyun,Mahmood, Khalid,Mathis, Chester A.
-
p. 949 - 957
(2007/10/03)
-
- Synthesis and preliminary in vivo evaluation of [11C]MDL 100907: A potent and selective radioligand for the 5-HT2A receptor system
-
11C-Labeled MDL 100907 and MDL 100009 were prepared by the reaction of [11C]CH3I with the corresponding phenol precursors. In vivo studies conducted in rats and a baboon demonstrated that intravenously injected [2-O[11C]CH3]MDL 100907 was regionally distributed in the brain in a manner consistent with the known distribution of 5-HT2A receptors. Injection of [2-O[11C]CH3]MDL 100009 resulted in a uniform brain distribution of radioactivity without regional localization consistent with the lower affinity of MDL 100009 for 5-HT2A receptors.
- Mathis,Mahmood,Huang,Simpson,Gerdes,Price
-
-