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Are Celeste - One of the best experts on this subject based on the ideXlab platform.

  • Una estrategia unificada para la síntesis enantioselectiva de los alcaloides del grupo de las madangaminas
    'Edicions de la Universitat de Barcelona', 2018
    Co-Authors: Are Celeste
    Abstract:

    El presente trabajo se centra en los alcaloides del grupo de las madangaminas, un pequeño grupo de alcaloides diaminopentacíclicos, aislados de esponjas marinas pertenecientes al orden Haplosclerida y derivados biogenéticamente de precursores con estructura de 3-alquilpiperidina. Estructuralmente, las madangaminas se caracterizan por la presencia de un núcleo diazatricílico (anillos ABC), sin precedentes entre los productos naturales, y dos puentes de carbono lineales que conectan el nitrógeno N-7 al carbono de la posición C-9 (anillo D) y el nitrógeno N-1 al carbono de la posición C-3 (anillo E). El anillo macrocíclico D varía en cada madangamina, tanto en tamaño (de 13 a 15 miembros) como en posición y grado de insaturación, mientras que el anillo E es idéntico en las madangaminas A-E (dos insaturaciones y 11 miembros) pero es diferente en la madangamina F (cuatro insaturaciones; 13 miembros). Además, la madangamina F incorpora una función hidroxilo en la posición C-4. Tras alcanzar la primera síntesis total de un alcaloide del grupo de las madangaminas, llevada a cabo por nuestro grupo en el 2014,1 en la presente Tesis Doctoral nos propusimos abordar la síntesis de otros alcaloides de esta familia. Para ello, centramos nuestra atención en las madangaminas A, B, C y E, para las que, al inicio de la presente Tesis Doctoral, no se había descrito ninguna síntesis total. Nuestra estrategia sintética se basa en la construcción enantioselectiva de un núcleo diazatricíclico altamente funcionalizado a partir de una lactama quiral derivada del R- fenilglicinol y en la posterior formación de los macrociclos D y E. La síntesis del sistema tricíclico 16 se ha logrado de forma satisfactoria y a gran escala (multigramos) mediante una secuencia sintética de 13 etapas con un rendimiento global del 15% a partir de la lactama derivada del feniglicinol 1a. A partir de este intermedio se ha estudiado la construcción del sistema ABCE común a las madangaminas A-E. En concreto, la estrategia basada en una reacción de Wittig con el iluro derivado de la sal de fosfonio 47 con posterior macrolactamización ha mostrado ser la más eficiente para la construcción del anillo macrocíclico E común a todas las madangaminas. De esta manera se ha sintetizado el tetraciclo ABCE de forma satisfactoria. Por otro lado, también a partir del compuesto tricíclico 16 se ha explorado la construcción de los macrociclos D de las madangaminas A, B, C y E. Un proceso de ring closing metathesis altamente eficiente (90% de rendimiento) ha permitido la construcción del anillo D de la madangamina C de trece miembros, aunque como mezcla inseparable de isómeros. Por hidrogenación del anterior se ha podido acceder al sistema tetracíclico ABCD de la madangamina E. Por otra parte, una estrategia basada en una reacción de coupling entre un alquino terminal y un ioduro diinico y posterior reducción del triple enlace resultante a trans- alqueno ha permitido por primera vez alcanzar la construcción del complejo macrociclo D de la madangamina B en una piperidina modelo. Finalmente, se ha descrito una nueva aproximación enantioselectiva a la síntesis de la madangamina A. La síntesis del sistema pentacíclico 111 representa la síntesis formal del alcaloide.Madangamines alkaloids constitute a small group of complex pentacyclic alkaloids isolated from marine sponges of the order Haposclerida. Structurally, these alkaloids have an unprecedented skeletal type, characterized by a diazatricyclic core (ABC rings) and two linear carbon bridges. The peripheral macrocyclic ring D is different in each madangamine, in size as well as in degree and position of unsaturation, whereas ring E is identical in madangamines A-E. In the context of our studies on the enantioselective synthesis of complex Piperidine-containing natural products from phenylglycinol- derived bicyclic lactams, we have developed a unified strategy to access the variety of alkaloids of this group. Appling this strategy, that involves the formation of the macrocyclic rings after the construction of the highly functionalized central core, recently in our group was carried out the enantioselective synthesis of madangamine D, which represents the first total synthesis of an alkaloid of the madangamine group.1 In this Doctoral Thesis we focused our attention in the total synthesis of other members of the family: madangamines A, B, C and E. Starting from tricyclic intermediate 16, which was prepared by 13 steps, we performed the construction of the complex E ring, common to madangamines A-E. The construction of the different D rings was explored in model compounds as well in the tricyclic and tetracyclic intermediates; these studies allowed to accomplish the synthesis of the ring of madangamine B in a Piperidine Derivative, the ABCD system of madangamines C and E and the pentacyclic system of madangamine A, which represent the formal synthesis of this alkaloid

  • Una estrategia unificada para la síntesis enantioselectiva de los alcaloides del grupo de las madangaminas
    'Edicions de la Universitat de Barcelona', 2018
    Co-Authors: Are Celeste
    Abstract:

    [spa] El presente trabajo se centra en los alcaloides del grupo de las madangaminas, un pequeño grupo de alcaloides diaminopentacíclicos, aislados de esponjas marinas pertenecientes al orden Haplosclerida y derivados biogenéticamente de precursores con estructura de 3-alquilpiperidina. Estructuralmente, las madangaminas se caracterizan por la presencia de un núcleo diazatricílico (anillos ABC), sin precedentes entre los productos naturales, y dos puentes de carbono lineales que conectan el nitrógeno N-7 al carbono de la posición C-9 (anillo D) y el nitrógeno N-1 al carbono de la posición C-3 (anillo E). El anillo macrocíclico D varía en cada madangamina, tanto en tamaño (de 13 a 15 miembros) como en posición y grado de insaturación, mientras que el anillo E es idéntico en las madangaminas A-E (dos insaturaciones y 11 miembros) pero es diferente en la madangamina F (cuatro insaturaciones; 13 miembros). Además, la madangamina F incorpora una función hidroxilo en la posición C-4. Tras alcanzar la primera síntesis total de un alcaloide del grupo de las madangaminas, llevada a cabo por nuestro grupo en el 2014,1 en la presente Tesis Doctoral nos propusimos abordar la síntesis de otros alcaloides de esta familia. Para ello, centramos nuestra atención en las madangaminas A, B, C y E, para las que, al inicio de la presente Tesis Doctoral, no se había descrito ninguna síntesis total. Nuestra estrategia sintética se basa en la construcción enantioselectiva de un núcleo diazatricíclico altamente funcionalizado a partir de una lactama quiral derivada del R- fenilglicinol y en la posterior formación de los macrociclos D y E. La síntesis del sistema tricíclico 16 se ha logrado de forma satisfactoria y a gran escala (multigramos) mediante una secuencia sintética de 13 etapas con un rendimiento global del 15% a partir de la lactama derivada del feniglicinol 1a. A partir de este intermedio se ha estudiado la construcción del sistema ABCE común a las madangaminas A-E. En concreto, la estrategia basada en una reacción de Wittig con el iluro derivado de la sal de fosfonio 47 con posterior macrolactamización ha mostrado ser la más eficiente para la construcción del anillo macrocíclico E común a todas las madangaminas. De esta manera se ha sintetizado el tetraciclo ABCE de forma satisfactoria. Por otro lado, también a partir del compuesto tricíclico 16 se ha explorado la construcción de los macrociclos D de las madangaminas A, B, C y E. Un proceso de ring closing metathesis altamente eficiente (90% de rendimiento) ha permitido la construcción del anillo D de la madangamina C de trece miembros, aunque como mezcla inseparable de isómeros. Por hidrogenación del anterior se ha podido acceder al sistema tetracíclico ABCD de la madangamina E. Por otra parte, una estrategia basada en una reacción de coupling entre un alquino terminal y un ioduro diinico y posterior reducción del triple enlace resultante a trans- alqueno ha permitido por primera vez alcanzar la construcción del complejo macrociclo D de la madangamina B en una piperidina modelo. Finalmente, se ha descrito una nueva aproximación enantioselectiva a la síntesis de la madangamina A. La síntesis del sistema pentacíclico 111 representa la síntesis formal del alcaloide.[eng] Madangamines alkaloids constitute a small group of complex pentacyclic alkaloids isolated from marine sponges of the order Haposclerida. Structurally, these alkaloids have an unprecedented skeletal type, characterized by a diazatricyclic core (ABC rings) and two linear carbon bridges. The peripheral macrocyclic ring D is different in each madangamine, in size as well as in degree and position of unsaturation, whereas ring E is identical in madangamines A-E. In the context of our studies on the enantioselective synthesis of complex Piperidine-containing natural products from phenylglycinol- derived bicyclic lactams, we have developed a unified strategy to access the variety of alkaloids of this group. Appling this strategy, that involves the formation of the macrocyclic rings after the construction of the highly functionalized central core, recently in our group was carried out the enantioselective synthesis of madangamine D, which represents the first total synthesis of an alkaloid of the madangamine group.1 In this Doctoral Thesis we focused our attention in the total synthesis of other members of the family: madangamines A, B, C and E. Starting from tricyclic intermediate 16, which was prepared by 13 steps, we performed the construction of the complex E ring, common to madangamines A-E. The construction of the different D rings was explored in model compounds as well in the tricyclic and tetracyclic intermediates; these studies allowed to accomplish the synthesis of the ring of madangamine B in a Piperidine Derivative, the ABCD system of madangamines C and E and the pentacyclic system of madangamine A, which represent the formal synthesis of this alkaloid

Conceicao De Fatima Alves - One of the best experts on this subject based on the ideXlab platform.

  • Adição diastereosseletiva de nucleofilos de carbono a ions N-aciliminios ciclicos: Aplicação na síntese de sistemas pirrolizidínico e indolizidínico monosubstituidos
    2017
    Co-Authors: Conceicao De Fatima Alves
    Abstract:

    Resumo: Na adição de nucleófilos de carbono derivados dos tioesteres tiopropionato de terc-butila 84 e tiopropionato de fenila 96 e do ester propionato de terc-butila 95 aos íons acilimínios cíclicos provenientes dos a-etoxicarbamatos 79 (5 membros) e 80 (6 membros), observou-se boa diastereosseletividade na formação dos produtos provenientes da piperidina. Neste caso, a estereoquímica relativa 2RS, 1'SR do isômero majoritário derivado do tiopropionato de terc-butila, foi determinada após a conversão dos compostos 86syn e 86anti nas respectivas uretanas 89 e 90. As reações envolvendo a adição de sililenoleteres derivados das cetonas aromáticas 103a-f aos a-etoxicarbamatos 79 e 80, mostrou-se altamente diastereosseletiva. A análise cristalográfica de raio-x do composto 106f (derivado da piperidina) permitiu determinar a mesma esteroquímica relativa 2RS, 1'SR observada para o composto 86syn. Para explicar os resultados observados nestes estudos foi proposto um modelo de aproximação aberto (Esquema 32) onde, no caso do íon acilimínio derivado da piperidina, o carbono nucleófilico aproxima-se do centro eletrofílico colocando seu menor grupo sobre o anel minimizando desta forma, as possíveis interações estéricas entre nucleófilo e eletrófilo. Na série da pirrolidina, a estereoquímica relativa 2RS, 1'RS sugerida para os isômeros majoritários provenientes da adição dos sililcetenotioacetais 85 e 98c e sililcetenoacetal 98b, foi possível através de correlações química entre eles. Entretanto, para os isômeros majoritários derivados das cetonas aromáticas 103a-f foi determinado a configuração relativa 2RS, 1'SR mediante a correlação de RMNC e RMNH destes compostos. A adição de enolatos de boro da propionil oxazolidinona aquiral 111 e quiral 116 ao íon acilimínio de 5 membros, mostrou-se altamente diastereosseletiva, sendo observado a formação exclusiva do diastereoisômero 117 de configuração absoluta 2R, 1'R (determinado por raio-x). A formação de 117 pode ser entendida através de um modelo de aproximação (Esquema 46) análogo ao proposto no Esquema 32, entretanto a topologia de aproximação é diferente (a aproximação ocorre entre a face si do acilimínio e face si do enolato ). O mesmo não foi observado para o íon acilimínio derivado da piperidina, onde o grande impedimento estérico entre o enolato de boro da propionil oxazolidina e o íon acilimínio não possibilitou a formação do produto de acoplamento. Entretanto, a utilização de um nucleófilo menos volumoso, no caso, o N,O-sililcetenoacetal da propionil oxazolidinona aquiral 111 em reação com o íon acilimínio de 6 membros permitiu isolar o produto de acoplamento,mas em baixa diastereosseletividade. O emprego desta metodologia permitiu preparar os sistemas pirrolizidínico 196 e indolizidínico 205 nas formas enantiomericamente puras e em elevado rendimento, que se constituem em potenciais precursores dos alcalóides (-)-isoretronecanol e (+)-epi- tashiromina.Abstract: Good diastereoeselection was observed in the addition of the carbon nucleophiles derived from S-tert-butyl thiopropionate 84, S-phenyl thiopropionate 96 and tert-butyl propionate 95 to the 6-membered N-acyliminium ion derived from 2-ethoxy carbamate 80. The 2RS, 1'SR relative stereochemistry of the major isomer formed in the addition of O-silylketeneacetal derived from tert-butyl S-thiopropionate 84 to the 6-membered N-acyliminium ion was determined after conversion of 86syn and 86anti to the corresponding urethanes 89 and 90, respectively. The addition of the silylenolethers derived from aromatic ketones 103a-f to the 6-membered N-acyliminium ion (derived from 80) was highly stereoselective. X-ray diffraction analysis of 106f (Piperidine Derivative) revealed the 2RS,1'SR relative stereochernistry, as determined for 86syn. The 2RS,1'SR relative configuration of the major isomer for the remaining 2-Piperidines emerged from correlation of their H- and C-NMR data. An open transition state model (Scheme 32) was proposed to account for the relative configuration of the major product formed in the Piperidine series: the nucleophilic carbon approaches the N-acyliminium ion with its less bulky substituent over the 6-membered ring so as to minimize steric interactions. In the pyrrolidine series, the 2RS,1'RS relative configuration was suggested for the major isomer formed from silylketenethioacetals 85 an 98c and from silyl keteneacetal 98b. However, the 2RS, 1'SR relative configuration was suggested for the major isomer formed from silylenolethers derived from aromatic ketones 103a-f. The additon of the boron enolate from N-propionyl-2-oxazolidinones 116 to the 5-membered N-acyliminium ion (derived from 79) afforded exclusively 117 which had its 2R, 1'R absolute configuration at the newly formed stereogenic centers determined by X- ray diffraction analysis. However, under the same reaction conditions boron enolates (derived from 111) did not react with the 6-membered N-acyliminium ion (derived from 80). The lack of reactivity was ascribed to severe steric interactions which develop during the approach of the boron enolate of N-propionyl-2-oxazolidinones and the 6-membered N-acyliminium ion which are in part relieved in the case of the flattened 5- membered N-acyliminium ion (Scheme 46). The N,O-silylketeneacetal derived from N-propionyl-2-oxazolidinone 111 afforded the corresponding 2-Piperidine Derivative, albeit in low diastereoselectivity . The methodology described above allowed the stereoselective preparation of chiral non-racemic pyrrolizidine 197 and indolizidine 206 which are potential precursors for the total synthesis of the alkaloids (-)-isoretronecanol and (+)-epi-tashiromine

  • Adição diastereosseletiva de nucleofilos de carbono a ions N-aciliminios ciclicos: Aplicação na síntese de sistemas pirrolizidínico e indolizidínico monosubstituidos
    Universidade Estadual de Campinas. Instituto de Quimica, 1998
    Co-Authors: Conceicao De Fatima Alves
    Abstract:

    Na adição de nucleófilos de carbono derivados dos tioesteres tiopropionato de terc-butila 84 e tiopropionato de fenila 96 e do ester propionato de terc-butila 95 aos íons acilimínios cíclicos provenientes dos a-etoxicarbamatos 79 (5 membros) e 80 (6 membros), observou-se boa diastereosseletividade na formação dos produtos provenientes da piperidina. Neste caso, a estereoquímica relativa 2RS, 1'SR do isômero majoritário derivado do tiopropionato de terc-butila, foi determinada após a conversão dos compostos 86syn e 86anti nas respectivas uretanas 89 e 90. As reações envolvendo a adição de sililenoleteres derivados das cetonas aromáticas 103a-f aos a-etoxicarbamatos 79 e 80, mostrou-se altamente diastereosseletiva. A análise cristalográfica de raio-x do composto 106f (derivado da piperidina) permitiu determinar a mesma esteroquímica relativa 2RS, 1'SR observada para o composto 86syn. Para explicar os resultados observados nestes estudos foi proposto um modelo de aproximação aberto (Esquema 32) onde, no caso do íon acilimínio derivado da piperidina, o carbono nucleófilico aproxima-se do centro eletrofílico colocando seu menor grupo sobre o anel minimizando desta forma, as possíveis interações estéricas entre nucleófilo e eletrófilo. Na série da pirrolidina, a estereoquímica relativa 2RS, 1'RS sugerida para os isômeros majoritários provenientes da adição dos sililcetenotioacetais 85 e 98c e sililcetenoacetal 98b, foi possível através de correlações química entre eles. Entretanto, para os isômeros majoritários derivados das cetonas aromáticas 103a-f foi determinado a configuração relativa 2RS, 1'SR mediante a correlação de RMNC e RMNH destes compostos. A adição de enolatos de boro da propionil oxazolidinona aquiral 111 e quiral 116 ao íon acilimínio de 5 membros, mostrou-se altamente diastereosseletiva, sendo observado a formação exclusiva do diastereoisômero 117 de configuração absoluta 2R, 1'R (determinado por raio-x). A formação de 117 pode ser entendida através de um modelo de aproximação (Esquema 46) análogo ao proposto no Esquema 32, entretanto a topologia de aproximação é diferente (a aproximação ocorre entre a face si do acilimínio e face si do enolato ). O mesmo não foi observado para o íon acilimínio derivado da piperidina, onde o grande impedimento estérico entre o enolato de boro da propionil oxazolidina e o íon acilimínio não possibilitou a formação do produto de acoplamento. Entretanto, a utilização de um nucleófilo menos volumoso, no caso, o N,O-sililcetenoacetal da propionil oxazolidinona aquiral 111 em reação com o íon acilimínio de 6 membros permitiu isolar o produto de acoplamento,mas em baixa diastereosseletividade. O emprego desta metodologia permitiu preparar os sistemas pirrolizidínico 196 e indolizidínico 205 nas formas enantiomericamente puras e em elevado rendimento, que se constituem em potenciais precursores dos alcalóides (-)-isoretronecanol e (+)-epi- tashiromina.Good diastereoeselection was observed in the addition of the carbon nucleophiles derived from S-tert-butyl thiopropionate 84, S-phenyl thiopropionate 96 and tert-butyl propionate 95 to the 6-membered N-acyliminium ion derived from 2-ethoxy carbamate 80. The 2RS, 1'SR relative stereochemistry of the major isomer formed in the addition of O-silylketeneacetal derived from tert-butyl S-thiopropionate 84 to the 6-membered N-acyliminium ion was determined after conversion of 86syn and 86anti to the corresponding urethanes 89 and 90, respectively. The addition of the silylenolethers derived from aromatic ketones 103a-f to the 6-membered N-acyliminium ion (derived from 80) was highly stereoselective. X-ray diffraction analysis of 106f (Piperidine Derivative) revealed the 2RS,1'SR relative stereochernistry, as determined for 86syn. The 2RS,1'SR relative configuration of the major isomer for the remaining 2-Piperidines emerged from correlation of their H- and C-NMR data. An open transition state model (Scheme 32) was proposed to account for the relative configuration of the major product formed in the Piperidine series: the nucleophilic carbon approaches the N-acyliminium ion with its less bulky substituent over the 6-membered ring so as to minimize steric interactions. In the pyrrolidine series, the 2RS,1'RS relative configuration was suggested for the major isomer formed from silylketenethioacetals 85 an 98c and from silyl keteneacetal 98b. However, the 2RS, 1'SR relative configuration was suggested for the major isomer formed from silylenolethers derived from aromatic ketones 103a-f. The additon of the boron enolate from N-propionyl-2-oxazolidinones 116 to the 5-membered N-acyliminium ion (derived from 79) afforded exclusively 117 which had its 2R, 1'R absolute configuration at the newly formed stereogenic centers determined by X- ray diffraction analysis. However, under the same reaction conditions boron enolates (derived from 111) did not react with the 6-membered N-acyliminium ion (derived from 80). The lack of reactivity was ascribed to severe steric interactions which develop during the approach of the boron enolate of N-propionyl-2-oxazolidinones and the 6-membered N-acyliminium ion which are in part relieved in the case of the flattened 5- membered N-acyliminium ion (Scheme 46). The N,O-silylketeneacetal derived from N-propionyl-2-oxazolidinone 111 afforded the corresponding 2-Piperidine Derivative, albeit in low diastereoselectivity . The methodology described above allowed the stereoselective preparation of chiral non-racemic pyrrolizidine 197 and indolizidine 206 which are potential precursors for the total synthesis of the alkaloids (-)-isoretronecanol and (+)-epi-tashiromine

Prabal Banerjee - One of the best experts on this subject based on the ideXlab platform.

Jorg Steinbach - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and evaluation of a 18f labeled spirocyclic Piperidine Derivative as promising σ1 receptor imaging agent
    Bioorganic & Medicinal Chemistry, 2014
    Co-Authors: Yuanyuan Chen, Jorg Steinbach, Winnie Deutherconrad, Xia Wang, Jinming Zhang, Xiaojun Zhang, Yiyun Huang, Mengchao Cui, Peter Brust, Boli Liu
    Abstract:

    Abstract Several spirocyclic Piperidine Derivatives were designed and synthesized as σ 1 receptor ligands. In vitro competition binding assays showed that the fluoroalkoxy analogues with small substituents possessed high affinity towards σ 1 receptors and subtype selectivity. Particularly for ligand 1′-((6-(2-fluoroethoxy)pyridin-3-yl)methyl)-3 H -spiro[2-benzofuran-1,4′-Piperidine] ( 2 ), high σ 1 receptor affinity ( K i  = 2.30 nM) and high σ 1 /σ 2 subtype selectivity (142-fold) as well as high σ 1 /VAChT selectivity (234-fold) were observed. [ 18 F] 2 was synthesized using an efficient one-pot, two-step reaction method in a home-made automated synthesis module, with an overall isolated radiochemical yield of 8–10%, a radiochemical purity of higher than 99%, and specific activity of 56–78 GBq/μmol. Biodistribution studies of [ 18 F] 2 in ICR mice indicated high initial brain uptake and a relatively fast washout. Administration of haloperidol, compound 1 and different concentrations of SA4503 (3, 5, or 10 μmol/kg) 5 min prior to injection of [ 18 F] 2 significantly decreased the accumulation of radiotracer in organs known to contain σ 1 receptors. Ex vivo autoradiography in Sprague–Dawley rats demonstrated high accumulation of radiotracer in brain areas with high expression of σ 1 receptors. These encouraging results prove that [ 18 F] 2 is a suitable candidate for σ 1 receptor imaging with PET in humans.

  • a 18f labeled fluorobutyl substituted spirocyclic Piperidine Derivative as a selective radioligand for pet imaging of sigma1 receptors
    ChemMedChem, 2011
    Co-Authors: Aurelie Maisonial, Eva Grosse Maestrup, Steffen Fischer, Achim Hiller, Matthias Scheunemann, Christian Wiese, Dirk Schepmann, Jorg Steinbach, Winnie Deutherconrad, Bernhard Wunsch
    Abstract:

    In this study, we synthesized and evaluated a new spirocyclic Piperidine Derivative 3, containing a 4-fluorobutyl side chain, as a PET radioligand for neuroimaging of σ₁ receptors. In vitro, compound 3 displayed high affinity for σ₁ receptors (K(i) =1.2 nM) as well as high selectivity. [¹⁸F]3 radiosynthesis was performed from the corresponding tosylate precursor, with high radiochemical yield (45-51 %), purity (>98 %), and specific activity (>201 GBq μmol⁻¹). Metabolic stability of [¹⁸F]3 in the brain of CD-1 mice was verified, and no penetration of peripheral radiometabolites into the cerebral tissue was observed. Results of ex vivo autoradiography revealed that the distribution of [¹⁸F]3 in the brain corresponded to regions with high σ₁ receptor density. The highest region-specific total-to-nonspecific ratio was determined in the facial nucleus (4.00). Biodistribution studies indicated rapid and high levels in brain uptake of [¹⁸F]3 (2.2 % ID per gram at 5 min p.i.). Pre-administration of haloperidol significantly inhibited [¹⁸F]3 uptake into the brain and σ₁ receptor-expressing organs, further confirming in vivo target specificity.

Winnie Deutherconrad - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and evaluation of a 18f labeled spirocyclic Piperidine Derivative as promising σ1 receptor imaging agent
    Bioorganic & Medicinal Chemistry, 2014
    Co-Authors: Yuanyuan Chen, Jorg Steinbach, Winnie Deutherconrad, Xia Wang, Jinming Zhang, Xiaojun Zhang, Yiyun Huang, Mengchao Cui, Peter Brust, Boli Liu
    Abstract:

    Abstract Several spirocyclic Piperidine Derivatives were designed and synthesized as σ 1 receptor ligands. In vitro competition binding assays showed that the fluoroalkoxy analogues with small substituents possessed high affinity towards σ 1 receptors and subtype selectivity. Particularly for ligand 1′-((6-(2-fluoroethoxy)pyridin-3-yl)methyl)-3 H -spiro[2-benzofuran-1,4′-Piperidine] ( 2 ), high σ 1 receptor affinity ( K i  = 2.30 nM) and high σ 1 /σ 2 subtype selectivity (142-fold) as well as high σ 1 /VAChT selectivity (234-fold) were observed. [ 18 F] 2 was synthesized using an efficient one-pot, two-step reaction method in a home-made automated synthesis module, with an overall isolated radiochemical yield of 8–10%, a radiochemical purity of higher than 99%, and specific activity of 56–78 GBq/μmol. Biodistribution studies of [ 18 F] 2 in ICR mice indicated high initial brain uptake and a relatively fast washout. Administration of haloperidol, compound 1 and different concentrations of SA4503 (3, 5, or 10 μmol/kg) 5 min prior to injection of [ 18 F] 2 significantly decreased the accumulation of radiotracer in organs known to contain σ 1 receptors. Ex vivo autoradiography in Sprague–Dawley rats demonstrated high accumulation of radiotracer in brain areas with high expression of σ 1 receptors. These encouraging results prove that [ 18 F] 2 is a suitable candidate for σ 1 receptor imaging with PET in humans.

  • a 18f labeled fluorobutyl substituted spirocyclic Piperidine Derivative as a selective radioligand for pet imaging of sigma1 receptors
    ChemMedChem, 2011
    Co-Authors: Aurelie Maisonial, Eva Grosse Maestrup, Steffen Fischer, Achim Hiller, Matthias Scheunemann, Christian Wiese, Dirk Schepmann, Jorg Steinbach, Winnie Deutherconrad, Bernhard Wunsch
    Abstract:

    In this study, we synthesized and evaluated a new spirocyclic Piperidine Derivative 3, containing a 4-fluorobutyl side chain, as a PET radioligand for neuroimaging of σ₁ receptors. In vitro, compound 3 displayed high affinity for σ₁ receptors (K(i) =1.2 nM) as well as high selectivity. [¹⁸F]3 radiosynthesis was performed from the corresponding tosylate precursor, with high radiochemical yield (45-51 %), purity (>98 %), and specific activity (>201 GBq μmol⁻¹). Metabolic stability of [¹⁸F]3 in the brain of CD-1 mice was verified, and no penetration of peripheral radiometabolites into the cerebral tissue was observed. Results of ex vivo autoradiography revealed that the distribution of [¹⁸F]3 in the brain corresponded to regions with high σ₁ receptor density. The highest region-specific total-to-nonspecific ratio was determined in the facial nucleus (4.00). Biodistribution studies indicated rapid and high levels in brain uptake of [¹⁸F]3 (2.2 % ID per gram at 5 min p.i.). Pre-administration of haloperidol significantly inhibited [¹⁸F]3 uptake into the brain and σ₁ receptor-expressing organs, further confirming in vivo target specificity.