- Novel fluoroalkyl derivatives of selective kappa opioid receptor antagonist JDTic: Design, synthesis, pharmacology and molecular modeling studies
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Novel N- and O-fluoroalkyl derivatives of the highly potent KOR antagonist JDTic were designed and synthesized. Their opioid receptor properties were compared in both in vitro binding assays and modeling approach. All compounds displayed nanomolar affinit
- Schmitt, Sbastien,Colloc'h, Nathalie,Perrio, Ccile
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- Convenient Entry to 18F-Labeled Amines through the Staudinger Reduction
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Fluorine-18 possesses outstanding decay characteristics for positron emission tomography (PET) imaging. Therefore, it is ideally suited for clinical applications. As such, improved strategies to incorporate fluorine-18 into bioactive molecules are of utmo
- Stéen, E. Johanna L.,Shalgunov, Vladimir,Denk, Christoph,Mikula, Hannes,Kj?r, Andreas,Kristensen, Jesper L.,Herth, Matthias M.
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supporting information
p. 1722 - 1725
(2019/01/30)
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- Structure-Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors
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δ-Selective compounds 1 and 2 (DS1, compound 22; DS2, compound 16) were introduced as functionally selective modulators of δ-containing GABA type A receptors (GABAAR). In our hands, [3H]EBOB-binding experiments with recombinant GABAAR and compound 22 showed no proof of δ-selectivity, although there was a minimally higher preference for the α4β3δ and α6β2/3δ receptors with respect to potency. In order to delineate the structural determinants of δ preferences, we synthesized 25 derivatives of DS1 and DS2, and investigated their structure-activity relationships (SAR). Four of our derivatives showed selectivity for α6β3δ receptors (29, 38, 39, and 41). For all of them, the major factors that distinguished them from compound 22 were variations at the para-positions of their benzamide groups. However, two compounds (29 and 39), when tested in the presence of GABA, revealed effects at several additional GABAAR. The newly synthesized compounds will still serve as useful tools to investigate α6β3δ receptors.
- Yakoub, Kirsten,Jung, Sascha,Sattler, Christian,Damerow, Helen,Weber, Judith,Kretzschmann, Annika,Cankaya, Aylin S.,Piel, Markus,R?sch, Frank,Haugaard, Anne S.,Fr?lund, Bente,Schirmeister, Tanja,Lüddens, Hartmut
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p. 1951 - 1968
(2018/03/21)
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- Fast and reliable generation of [18F]triflyl fluoride, a gaseous [18F]fluoride source
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A novel strategy for the production of reactive [18F]fluoride has been developed, omitting time consuming azeotropic drying procedures. Gaseous [18F]triflyl fluoride is formed instantaneously at room temperature from hydrated [18F]fluoride, followed by distillation in less than 5 minutes into a dry aprotic solvent, in which dry [18F]fluoride is released in presence of base with >90% radiochemical yield. The reactivity of the [18F]fluoride has been confirmed by reaction with several model compounds and by the synthesis of the PET tracers [18F]fluoroestradiol ([18F]FES) and O-2-[18F]fluoroethyl-l-tyrosine ([18F]FET), providing good isolated radiochemical yields and molar activities of up to 123 GBq μmol?1.
- Pees,Sewing,Vosjan,Tadino,Herscheid,Windhorst,Vugts
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supporting information
p. 10179 - 10182
(2018/09/13)
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- Novel fluoroalkyl derivatives of selective kappa opioid receptor antagonist JDTic: Design, synthesis, pharmacology and molecular modeling studies
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Novel N-and O-fluoroalkyl derivatives of the highly potent KOR antagonist JDTic were designed and synthesized. Their opioid receptor properties were compared in both in vitro binding assays and modeling approach. All compounds displayed nanomolar affiniti
- Schmitt, Sébastien,Colloc'H, Nathalie,Perrio, Cécile
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p. 742 - 750
(2015/04/14)
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- Synthesis and evaluation of a 18F-labeled spirocyclic piperidine derivative as promising σ1receptor imaging agent
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Several spirocyclic piperidine derivatives were designed and synthesized as σ1receptor ligands. In vitro competition binding assays showed that the fluoroalkoxy analogues with small substituents possessed high affinity towards σ1rece
- Chen, Yuan-Yuan,Wang, Xia,Zhang, Jin-Ming,Deuther-Conrad, Winnie,Zhang, Xiao-Jun,Huang, Yiyun,Li, Yan,Ye, Jia-Jun,Cui, Meng-Chao,Steinbach, J?rg,Brust, Peter,Liu, Bo-Li,Jia, Hong-Mei
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p. 5270 - 5278
(2014/12/11)
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- MONOCYCLIC PYRIDINE DERIVATIVE
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The present invention provides a novel compound having FGFR inhibitory activity or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same. Specifically, the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: wherein n represents 0 to 2; A represents an arylene group or a heteroarylene group; G represents a single bond, an oxygen atom or —CH2—; E represents a nitrogen-containing non-aromatic heterocycle; R1 represents an alkoxy group or the like; R2 represents a hydrogen atom or the like; and R3 represents a hydrogen atom, an alkyl group, an alkoxy group or the like, with the proviso that when E represents an azetidine ring and R2 or R3 is present on a nitrogen atom on the azetidine ring, the R2 or R3 does not represent a hydrogen atom.
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Paragraph 0304; 0305; 0306
(2014/09/03)
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- Synthesis and evaluation of new 18F-labelled acetamidobenzoxazolone-based radioligands for imaging of the translocator protein (18 kDa, TSPO) in the brain
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The visualization of the activated microglia/TSPO is one of the main aspects of neuroimaging. Here we describe two new 18F-labelled molecules, 2-[5-(4-[18F]fluoroethoxyphenyl)- ([18F]2) and 2-[5-(4-[18F]fluoropr
- Tiwari, Anjani K.,Fujinaga, Masayuki,Yui, Joji,Yamasaki, Tomoteru,Xie, Lin,Kumata, Katsushi,Mishra, Anil K.,Shimoda, Yoko,Hatori, Akiko,Ji, Bin,Ogawa, Masanao,Kawamura, Kazunori,Wang, Feng,Zhang, Ming-Rong
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p. 9621 - 9630
(2015/02/19)
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- Development of [18F]-labeled pyrazolo[4,3-e ]-1,2,4-triazolo[1, 5-c ]pyrimidine (SCH442416) analogs for the imaging of cerebral adenosine A 2A receptors with positron emission tomography
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Cerebral adenosine A2A receptors (A2ARs) are attractive therapeutic targets for the treatment of neurodegenerative and psychiatric disorders. We developed high affinity and selective compound 8 (SCH442416) analogs as in vivo probes for A2ARs using PET. We observed the A2AR-mediated accumulation of [18F] fluoropropyl ([18F]-10b) and [18F]fluoroethyl ([ 18F]-10a) derivatives of 8 in the brain. The striatum was clearly visualized in PET and in vitro autoradiography images of control animals and was no longer visible after pretreatment with the A2AR subtype-selective antagonist KW6002. In vitro and in vivo metabolite analyses indicated the presence of hydrophilic (radio)metabolite(s), which are not expected to cross the blood-brain-barrier. [18F]-10b and [18F]-10a showed comparable striatum-to-cerebellum ratios (4.6 at 25 and 37 min post injection, respectively) and reversible binding in rat brains. We concluded that these compounds performed equally well, but their kinetics were slightly different. These molecules are potential tools for mapping cerebral A2ARs with PET.
- Khanapur, Shivashankar,Paul, Soumen,Shah, Anup,Vatakuti, Suresh,Koole, Michel J. B.,Zijlma, Rolf,Dierckx, Rudi A. J. O.,Luurtsema, Gert,Garg, Prabha,Van Waarde, Aren,Elsinga, Philip H.
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p. 6765 - 6780
(2014/09/29)
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- Synthesis and evaluation of novel radioligands for positron emission tomography imaging of metabotropic glutamate receptor subtype 1 (mGluR1) in rodent brain
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We designed three novel positron emission tomography ligands, N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-[ 11C]methoxy-N-methylbenzamide ([11C]6), 4-[ 18F]fluoroethoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1, 3-thiazol-2-yl]-N-methylbenzamide ([18F]7), and 4-[ 18F]fluoropropoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1, 3-thiazol-2-yl]-N-methylbenzamide ([18F]8), for imaging metabotropic glutamate receptor type 1 (mGluR1) in rodent brain. Unlabeled compound 6 was synthesized by benzoylation of 4-pyrimidinyl-2-methylaminothiazole 10, followed by reaction with isopropylamine. Removal of the methyl group in 6 gave phenol precursor 12 for radiosynthesis. Two fluoroalkoxy analogues 7 and 8 were prepared by reacting 12 with tosylates 13 and 14. Radioligands [ 11C]6, [18F]7, and [18F]8 were synthesized by O-[11C]methylation or [18F]fluoroalkylation of 12. Compound 6 showed high in vitro binding affinity for mGluR1, whereas 7 and 8 had weak affinity. Autoradiography using rat brain sections showed that [ 11C]6 binding is aligned with the reported distribution of mGluR1 with high specific binding in the cerebellum and thalamus. PET study with [ 11C]6 in rats showed high brain uptake and a similar distribution pattern to that in autoradiography, indicating the usefulness of [ 11C]6 for imaging brain mGluR1.
- Fujinaga, Masayuki,Yamasaki, Tomoteru,Yui, Joji,Hatori, Akiko,Xie, Lin,Kawamura, Kazunori,Asagawa, Chiharu,Kumata, Katsushi,Yoshida, Yuichiro,Ogawa, Masanao,Nengaki, Nobuki,Fukumura, Toshimitsu,Zhang, Ming-Rong
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experimental part
p. 2342 - 2352
(2012/05/31)
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- Synthesis and cardiac imaging of 18F-ligands selective for β1-adrenoreceptors
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A series of potent and selective β1-adrenoreceptor ligands were identified (IC50 range, 0.04-0.25 nM; β1/ β2 selectivity range, 65-450-fold), labeled with the PET radioisotope fluorine-18 and evaluated in normal Sprague-Dawley rats. Tissue distribution studies demonstrated uptake of each radiotracers from the blood pool into the myocardium (0.48-0.62% ID/g), lung (0.63-0.97% ID/g), and liver (1.03-1.14% ID/g). Dynamic μPET imaging confirmed the in vivo dissection studies.
- Radeke, Heike S.,Purohit, Ajay,Harris, Thomas D.,Hanson, Kelley,Jones, Reinaldo,Hu, Carol,Yalamanchili, Padmaja,Hayes, Megan,Yu, Ming,Guaraldi, Mary,Kagan, Mikhail,Azure, Michael,Cdebaca, Michael,Robinson, Simon,Casebier, David
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supporting information; experimental part
p. 650 - 655
(2011/11/05)
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- Design, synthesis, and structure-affinity relationships of regioisomeric N-benzyl alkyl ether piperazine derivatives as σ-1 receptor ligands
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A series of N-(benzofuran-2-ylmethyl)-N′-benzylpiperazines bearing alkyl or fluoroalkyl aryl ethers were synthesized and evaluated at various central nervous system receptors. Examination of in vitro σ1 {[3H](+)-pentazocine} and σ2 ([3H]DTG) receptor binding profiles of piperazines 11-13 and 25-36 revealed several highly potent and σ1 selective ligands, notably, N-(benzofuran-2- ylmethyl)-N′-(4′-methoxybenzyl)piperazine (13, Ki = 2.7 nM, σ2/σ1 = 38) and N-(benzofuran-2-ylmethyl)- N′-(4′-(2″-fluoroethoxy)benzyl)piperazine (30, Ki = 2.6 nM, σ2/σ1 = 187). Structural features for optimal σ1 receptor affinity and selectivity over the σ2 receptor were identified. On the basis of its favorable log D value, 13 was selected as a candidate for the development of a σ1 receptor positron emission tomography radiotracer. [ 11C]13 showed high uptake in the brain and other σ receptor-rich organs of a Papio hamadryas baboon. The in vivo evaluation of [11C]13 indicates that this radiotracer is a suitable candidate for imaging the σ1 receptor in neurodegenerative processes.
- Moussa, Iman A.,Banister, Samuel D.,Beinat, Corinne,Giboureau, Nicolas,Reynolds, Aaron J.,Kassiou, Michael
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experimental part
p. 6228 - 6239
(2010/11/02)
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- FLUORINATED DIHYDROTETRABENAZINE ETHER IMAGING AGENTS AND PROBES
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The present invention provides novel fluorinated ether compounds having structure I wherein R1 is a C2-C10 fluorinated aliphatic radical; R2 is a C1-C10 aliphatic radical, or a C3/sub
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Page/Page column 22
(2009/05/29)
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- INTERMEDIATES FOR FLUORINATED DIHYDROTETRABENAZINE ETHER IMAGING AGENTS AND PROBES
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The present invention provides novel fluorophilic compounds having structure VI wherein R1 is a C2-C20 aliphatic, a C3-C20 cycloaliphatic, or a C3-C20 aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent; R2 is a C1-C10 aliphatic radical, or a C3-C10 cycloaliphatic radical; R3 is hydrogen or a C1-C10 aliphatic radical; and R4 is hydrogen or a C1-C10 aliphatic radical. The fluorophilic compounds are provided in both racemic and enantiomerically enriched forms and are useful as intermediates in the preparation of novel PET imaging agents and probes useful in the discovery and performance assessment of PET imaging agents. The fluorophilic compounds are particularly useful in the preparation of PET imaging agents and probes having a high affinity for VMAT-2, a biomarker implicated in human diabetes and other illnesses such as Parkinson's disease.
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Page/Page column 21-22
(2009/05/28)
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- Synthesis and evaluation of two fluorine-18 labelled phenylbenzothiazoles as potential in vivo tracers for amyloid plaque imaging
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Uncharged derivatives of thioflavin-T have known in vitro and in vivo affinity for amyloid β. We synthesized and evaluated two derivatives with a fluorine-18 labelled fluoropropoxy substituent either at the 6-position or at the 2′-position of the 2-(4′-am
- Serdons,Vanderghinste,Van Eeckhoudt,Borghgraef,Kung,Van Leuven,De Groot,Bormans,Verbruggen
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experimental part
p. 473 - 481
(2010/08/06)
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- RADIOLABELED DIHYDROTETRABENAZINE DERIVATIVES AND THEIR USE AS IMAGING AGENTS
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This invention relates to a method of imaging vesicular monoamine transporters and to labeled compounds and pharmaceutical compositions thereof, and methods of making labeled compounds useful in imaging vesicular monoamine transporters. This invention als
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Page/Page column 49-50
(2008/06/13)
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- Radiosynthesis of 3-(3-[18F]fluoropropoxy)-4-(benzyloxy)-N-[(1- dimethylaminocyclopentyl)methyl]-5-methoxybenzamide, a potential PET radiotracer for the glycine transporter GlyT-2
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The recently described selective and potent GlyT2 antagonist, 4-benzyloxy-3, 5-dimethoxy-N-[(1-dimethylaminocyclopentyl) methyl]benzamide (IC50 = 16 nM) provided an important additional tool to further characterize GlyT2 pharmacology. In order to identify an effective PET radioligand for in vivo assessment of the GlyT-2 transporter, 3-(3-[ 18F]fluoropropoxy)-4-(benzyloxy)-N-((1-dimethylaminocyclopentyl) methyl)-5-methoxybenzamide ([18F]3), a novel analog of 4-benzyloxy-3,5-dimethoxy-N-[(1-dimethylaminocyclopentyl) methyl]benzamide was synthesized using a one-pot, two-step method. The NCA radiofluorination of 1,3-propanediol di-p-tosylate in the presence of K2CO3 and Kryptofix-222 in acetonitrile gave 81% 3-[18F]fluoropropyl tosylate, which was subsequently coupled with 4-benzyloxy-3-hydroxy-5-methoxy-N-[(1- dimethylaminocyclopentyl) methyl]-benzamide in the same reaction vessel. Solvent extraction and HPLC (Eclipse XDB-C8 column, 80/20/0.1 MeOH/H 2O/Et3N, 3.0 ml/min) gave [18F]3 in 98.5% radiochemical purity. The radiochemical yield was determined to be 14.0-16.2% at EOS, and the specific activity was 1462 ± 342 GBq/μmol. The time of synthesis and purification was 128 min. The final product was prepared as a sterile saline solution suitable for in vivo use. Copyright
- Tian, Haibin,Vogel, Rebecca,Amici, Louis,Tamagnan, Gilles,Baldwin, Ronald M.
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p. 1247 - 1258
(2007/10/03)
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- AZABICYCLOHEPTYL COMPOUNDS SUITABLE FOR TREATING DISORDERS THAT RESPOND TO MODULATION OF THE DOPAMINE D3 RECEPTOR
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The present invention relates to a compound of the formula (I) wherein R1 is H, C1-C6-alkyl which may be substituted by C3-C6-cycloalkyl, fluorinated C1-C6-alkyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C3-C6-alkenyl, fluorinated C3-C6-alkenyl, formyl, acetyl or propionyl; A is phenylene, pyridylene, pyrimidylene, pyrazinylene, pyridazinylene or thiophenylene, which can be substituted by one ore more substituents selected from halogen, methyl, methoxy and CF3; E is NR5 or CH2, wherein R5 is H or C1-C3-alkyl; Ar is a cyclic radical selected from the group consisting of phenyl, a 5- or 6-membered heteroaromatic radical comprising as ring members 1, 2 or 3 heteroatoms selected from N, O and S and a phenyl ring fused to a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic ring, where the heterocyclic ring comprises as ring members 1, 2 or 3 heteroatoms selected from N, O and S and/or 1, 2 or 3 heteroatom-containing groups each independently selected from NR8, where R8 is H, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkylcarbonyl or fluorinated C1-C4-alkylcarbonyl, and where the cyclic radical Ar may carry 1, 2 or 3 substituents Ra; wherein the variable Ra has the meanings given in the claims and in the description; and physiologically tolerated acid addition salts thereof. The invention also relates to the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the treatment of a medical disorder susceptible to treatment with a dopamine D3 receptor ligand.
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Page/Page column 96
(2008/06/13)
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- HETEROCYCLIC COMPOUNDS SUITABLE FOR TREATING DISORDERS THAT RESPOND TO MODULATION OF THE DOPAMINE D3 RECEPTOR
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The invention relates to compounds of the formula (I) wherein n is 0, 1 or 2; G is CH2 or CHR3; R1 is H, C,-C6-alkyl, C,-C6-alkyl substituted by C3-C6-cycloalkyl, Cl-C6-hydroxyalkyl, fluorinated C,-C6-alkyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C3-C6- alkenyl, fluorinated C3-C6-alkenyl, formyl, acetyl or propionyl; R2, R3 and R4 are, independently of each other, H, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl; A is phenylene, pyridylene, pyrimidylene, pyrazinylene, pyridazinylene or thiophenylene, which can be substituted by one ore more substituents selected from halogen, methyl, methoxy and CF3; E is NR5 or CH2, wherein R5 is H or C1 -C3-alkyl; Ar is a cyclic radical selected from the group consisting of phenyl, a 5- or 6- -membered heteroaromatic radical comprising as ring members 1, 2 or 3 heteroatoms selected from N, O and S and a phenyl ring fused to a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic ring, where the heterocyclic ring comprises as ring members 1, 2 or 3 heteroatoms selected from N, O and S and/or 1, 2 or 3 heteroatom-containing groups each independently selected from NR8, where R8 is H, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkylcarbonyl or fluorinated C1-C4-alkylcarbonyl, and where the cyclic radical Ar may carry 1, 2 or 3 substituents Ra, wherein the variable Ra has the meanings given in the claims and in the description; and physiologically tolerated acid addition salts thereof. The invention also relates to the use of a compound of the formula I or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the treatment of a medical disorder susceptible to treatment with a dopamine D3 receptor ligand.
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Page/Page column 107
(2010/11/08)
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- Synthesis and in vitro evaluation of new benzovesamicol analogues as potential imaging probes for the vesicular acetylcholine transporter
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Our goal was to synthesize new stereospecific benzovesamicol analogues, which could potentially be used as SPECT or PET radioligands for the vesicular acetylcholine transporter (VAChT). This paper describes the chemical synthesis, resolution and determination of binding affinity for four enantiomeric pairs of derivatives. Their intrinsic affinities were determined by competition against binding of [3H]vesamicol to human VAChT. Of the eight enantiomers, (E)-(R,R)-5-AOIBV [(R,R)-3], and (R,R)-5-FPOBV [(R,R)-4] displayed the highest binding affinities for VAChT (Kd = 0.45 and 0.77 nM, respectively), which indicated that an elongation of the chain from 5-idodo as in the case of 5-iodobenzovesamicol (5-IBVM), to a 5-(E)-3-iodoallyloxy or 5-fluoropropoxy substituent, as in 5-AOIBV and 5-FPOBV, respectively, was very well tolerated at the vesamicol binding site. The enantiomer (R,R)-4-MAIBV [(R,R)-16], which retains the basic structure of (-)-5-IBVM but possess an additional aminomethyl substituent in the 4-position of the piperidine ring, displayed lower binding affinity (Kd = 8.8 nM). Nevertheless, the result suggests that substitution at this position may be an interesting alternative to investigate for development of new benzovesamicol analogues. As expected, the corresponding (S,S) enantiomers displayed lower Kd values, they were approximately 10-fold lower in the case of (S,S)-5-FPOBV (Kd = 8.4 nM) and (E)-(S,S)-5-AOIBV (Kd = 4.3 nM). (R,R)-3, and (R,R)-4 showed the same high affinity for VAChT as (-)-5-IBVM and may be suitable as imaging agents of cholinergic nerve terminals.
- Zea-Ponce, Yolanda,Mavel, Sylvie,Assaad, Thaer,Kruse, Shane E.,Parsons, Stanley M.,Emond, Patrick,Chalon, Sylvie,Giboureau, Nicolas,Kassiou, Michael,Guilloteau, Denis
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p. 745 - 753
(2007/10/03)
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- Triazolopyrimidines
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Novel triazolopyrimidines of the formula in which R1, R2, R3 and X have the meanings given in the description, a process for preparing these novel substances and their use for controlling undesirable microorganisms and animal pests. Novel amines of the formula in which R4 has the meanings given in the description, and processes for their preparation.
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- Synthesis and Receptor Binding Properties of Fluoro- and Iodo-Substituted High Affinity ? Receptor Ligands: Identification of Potential PET and SPECT ? Receptor Imaging Agents
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Unlabeled fluoro- and iodo-substituted ligands exhibiting very high affinity and selectivity for ? receptors were synthesized based on three different structural classes of ? receptor ligands.These compounds were evaluated for ? receptor affinity and spec
- Costa, Brian de,Radesca, Lilian,Dominguez, Celia,Paolo, Lisa Di,Bowen, Wayne D.
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p. 2221 - 2230
(2007/10/02)
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