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    Enantiomers of 2'-Fluoralky1-6-nitroquipazine as serotonin transporter positron emission tomography imaging agents and antidepressant therapeutics
    1.
    发明授权
    Enantiomers of 2'-Fluoralky1-6-nitroquipazine as serotonin transporter positron emission tomography imaging agents and antidepressant therapeutics 有权
    2'-氟烷基-6-硝基喹嗪作为血清素转运蛋白正电子发射断层成像剂和抗抑郁药物的对映异构体

    公开(公告)号：US07998962B2

    公开(公告)日：2011-08-16

    申请号：US12887782

    申请日：2010-09-22

    申请人： John M. Gerdes ,  David B. Bolstad ,  Brian R. Kusche

    发明人： John M. Gerdes ,  David B. Bolstad ,  Brian R. Kusche

    IPC分类号： A61K31/496 ,  C07D401/04

    CPC分类号： C07D401/04

    摘要： Racemic mixtures and individual enantiomers of fluorine-18 or carbon-11 radiolabelled 2′-alkyl-6-nitroquipazine ligands are serotonin transporter (SERT) tracers for positron emission tomography (PET) imaging. The non-radioactive ligand forms possess therapeutic antidepressant in vitro and in vivo pharmacological binding profiles in rodent brain and cells expressing human serotonin transporter (hSERT). Twelve 2′-alkyl-6-nitroquipazine ligands potently bind in sub-nanomolar concentrations to the pre-synaptic SERT binding site where established antidepressant drugs bind and inhibit the re-uptake of the neurotransmitter serotonin (5-HT). In vivo tracer studies in rats as well as monkey PET scan trial have demonstrated the fluorine-18 and carbon-11 positron radionuclide labeled tracers perform as quantitative tracers of specific binding the SERT protein in live brain.

    摘要翻译： 氟-18或碳-11放射性标记的2'-烷基-6-硝基奎匹嗪配体的外消旋混合物和单独的对映异构体是用于正​​电子发射断层摄影（PET）成像的血清素转运蛋白（SERT）示踪剂。 非放射性配体形式在啮齿动物脑和表达人血清素转运蛋白（hSERT）的细胞中的体外和体内药理学结合图谱中具有治疗性抗抑郁药。 十二个2'-烷基-6-硝基奎匹嗪配体以亚纳摩尔浓度有力地结合到突触前SERT结合位点，其中建立的抗抑郁药物结合并抑制神经递质5-羟色胺（5-HT）的再摄取。 大鼠的体内示踪剂研究以及猴PET扫描试验已经证明，氟-18和碳-11正电子放射性核素标记的示踪剂作为活体脑中SERT蛋白特异性结合的定量示踪剂。

    1-[(2′-substituted)-piperazin-1′ -yl]-isoquinolines as norepinephrine transporter inhibitor therapeutics and positron emission tomography imaging agents
    3.
    发明授权
    1-[(2′-substituted)-piperazin-1′ -yl]-isoquinolines as norepinephrine transporter inhibitor therapeutics and positron emission tomography imaging agents 有权
    1 - [（2'-取代的） - 哌嗪-1' - 基] - 异喹啉作为去甲肾上腺素转运蛋白抑制剂治疗剂和正电子发射断层扫描成像剂

    公开(公告)号：US07887784B2

    公开(公告)日：2011-02-15

    申请号：US12077898

    申请日：2008-03-21

    申请人： John M. Gerdes ,  David B. Bolstad ,  Michael R. Braden ,  August W. Barany

    发明人： John M. Gerdes ,  David B. Bolstad ,  Michael R. Braden ,  August W. Barany

    IPC分类号： A61K51/04 ,  A61K31/497 ,  C07D401/04

    CPC分类号： C07D401/04

    摘要： Racemic mixtures and enantiomerically pure forms of novel 1-[(2′-substituted)-piperazin-1′-yl]-isoquinolines are norepinephrine (NE) transporter (NET) inhibitor compounds. Compounds of the invention are considered therapeutic agents for central nervous system (CNS) diseases and disorders, without limitation, including neurodegeneration, anxiety, depression, attention deficit disorders, drug dependency, and post traumatic stress disorder. Examples of the chemical syntheses of the compounds of the invention are provided. The isoquinoline compounds of the invention competitively bind at NET at nanomolar concentrations. The isoquinoline agents of the invention bind selectively to NET over other competitive transporter targets and receptor binding sites, including those of serotonin and dopamine, amongst others. The chemical syntheses of the invention are suitable for labeling with radionuclide atoms. Radiolabeled forms of the novel 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline compounds are positron emission tomography and single photon emission tomography imaging tracers. Methods of in vivo imaging with the tracers within various subjects and tissues therein, including regions of the brain, are provided. Imaging methods with the tracers in combination other NET inhibitor agents are provided. The imaging methods within subjects allow quantitative detection of NET, determinations of NET distributions, and measures of tracer interactions at NET in the presence or absence of non-radioactive NET agents. The tracer imaging methods are suitable to locate, diagnose, identify, evaluate, detect or quantitate NET, or abnormalities of NET, or NE abnormalities; that are associated with various CNS diseases and disorders.

    摘要翻译： 新颖的1 - [（2'-取代的） - 哌嗪-1'-基] - 异喹啉的外消旋混合物和对映体纯形式是去甲肾上腺素（NE）转运蛋白（NET）抑制剂化合物。 本发明的化合物被认为是中枢神经系统（CNS）疾病和病症的治疗剂，但不限于，包括神经变性，焦虑，抑郁，注意力缺陷障碍，药物依赖性和创伤后应激障碍。 提供了本发明化合物的化学合成的实例。 本发明的异喹啉化合物在NET下以纳摩尔浓度竞争结合。 本发明的异喹啉试剂与其它竞争性转运靶标和受体结合位点选择性结合，包括血清素和多巴胺等。 本发明的化学合成适用于用放射性核素原子标记。 新型1 - [（2'-取代） - 哌嗪-1'-基] - 异喹啉化合物的放射性标记形式为正电子发射断层扫描和单光子发射断层成像示踪剂。 提供了使用包括脑区域在内的各种受试者和组织内的示踪剂进行体内成像的方法。 提供与其他NET抑制剂组合的示踪剂的成像方法。 受试者中的成像方法允许NET的定量检测，NET分布的确定，以及在存在或不存在非放射性NET剂的情况下NET的示踪剂相互作用的测量。 示踪成像方法适用于定位，诊断，识别，评估，检测或定量NET，或NET异常或NE异常; 这与各种CNS疾病和疾病有关。

    Enantiomers of 2′-fluoralkyl-6-nitroquipazine as serotonin transporter positron emission tomography imaging agents and antidepressant therapeutics
    4.
    发明授权
    Enantiomers of 2′-fluoralkyl-6-nitroquipazine as serotonin transporter positron emission tomography imaging agents and antidepressant therapeutics 有权
    2'-氟烷基-6-硝基喹嗪作为血清素转运体正电子发射断层扫描成像剂和抗抑郁治疗剂的对映异构体

    公开(公告)号：US07812162B2

    公开(公告)日：2010-10-12

    申请号：US11796227

    申请日：2007-04-26

    申请人： John M. Gerdes ,  David B. Bolstad ,  Brian R. Kusche

    发明人： John M. Gerdes ,  David B. Bolstad ,  Brian R. Kusche

    IPC分类号： C07D401/04 ,  A61K31/496 ,  G01N33/53

    CPC分类号： C07D401/04

    摘要： Racemic mixtures and individual enantiomers of fluorine-18 or carbon-11 radio-labelled 2′-alkyl-6-nitroquipazine ligands are serotonin transporter (SERT) tracers for positron emission tomography (PET) imaging. The non-radioactive ligand forms possess therapeutic antidepressant in vitro and in vivo pharmacological binding profiles in rodent brain and cells expressing human serotonin transporter (hSERT). Twelve 2′-alkyl-6-nitroquipazine ligands potently bind in sub-nanomolar concentrations to the pre-synaptic SERT binding site where established antidepressant drugs bind and inhibit the re-uptake of the neurotransmitter serotonin (5-HT). In vivo tracer studies in rats as well as monkey PET scan trial have demonstrated the fluorine-18 and carbon-11 positron radionuclide labeled tracers perform as quantitative tracers of specific binding the SERT protein in live brain.

    摘要翻译： 氟-18或碳-11放射性标记的2'-烷基-6-硝基奎匹嗪配体的外消旋混合物和单独的对映异构体是用于正​​电子发射断层摄影（PET）成像的血清素转运蛋白（SERT）示踪剂。 非放射性配体形式在啮齿动物脑和表达人血清素转运蛋白（hSERT）的细胞中的体外和体内药理学结合图谱中具有治疗性抗抑郁药。 十二个2'-烷基-6-硝基奎匹嗪配体以亚纳摩尔浓度有力地结合到突触前SERT结合位点，其中建立的抗抑郁药物结合并抑制神经递质5-羟色胺（5-HT）的再摄取。 大鼠的体内示踪剂研究以及猴PET扫描试验已经证明，氟-18和碳-11正电子放射性核素标记的示踪剂作为活体脑中SERT蛋白特异性结合的定量示踪剂。

    1-[(2'-Substituted)-piperazin-1' -yl]-isoquinolines as norepinephrine transporter inhibitor therapeutics and positron emission tomography imaging agents
    5.
    发明申请
    1-[(2'-Substituted)-piperazin-1' -yl]-isoquinolines as norepinephrine transporter inhibitor therapeutics and positron emission tomography imaging agents 有权
    1 - [（2'-取代的） - 哌嗪-1' - 基] - 异喹啉作为去甲肾上腺素转运蛋白抑制剂治疗剂和正电子发射断层扫描成像剂

    公开(公告)号：US20080267870A1

    公开(公告)日：2008-10-30

    申请号：US12077898

    申请日：2008-03-21

    申请人： John M. Gerdes ,  David B. Bolstad ,  Michael R. Braden ,  August W. Barany

    发明人： John M. Gerdes ,  David B. Bolstad ,  Michael R. Braden ,  August W. Barany

    IPC分类号： C07D401/04 ,  A61K31/496 ,  A61P25/00 ,  A61K51/04 ,  G01T1/161

    CPC分类号： C07D401/04

    摘要： Racemic mixtures and enantiomerically pure forms of novel 1-[(2′-substituted)-piperazin-1′-yl]-isoquinolines are norepinephrine (NE) transporter (NET) inhibitor compounds. Compounds of the invention are considered therapeutic agents for central nervous system (CNS) diseases and disorders, without limitation, including neurodegeneration, anxiety, depression, attention deficit disorders, drug dependency, and post traumatic stress disorder. Examples of the chemical syntheses of the compounds of the invention are provided. The isoquinoline compounds of the invention competitively bind at NET at nanomolar concentrations. The isoquinoline agents of the invention bind selectively to NET over other competitive transporter targets and receptor binding sites, including those of serotonin and dopamine, amongst others. The chemical syntheses of the invention are suitable for labeling with radionuclide atoms. Radiolabeled forms of the novel 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline compounds are positron emission tomography and single photon emission tomography imaging tracers. Methods of in vivo imaging with the tracers within various subjects and tissues therein, including regions of the brain, are provided. Imaging methods with the tracers in combination other NET inhibitor agents are provided. The imaging methods within subjects allow quantitative detection of NET, determinations of NET distributions, and measures of tracer interactions at NET in the presence or absence of non-radioactive NET agents. The tracer imaging methods are suitable to locate, diagnose, identify, evaluate, detect or quantitate NET, or abnormalities of NET, or NE abnormalities; that are associated with various CNS diseases and disorders.

    摘要翻译： 新颖的1 - [（2'-取代的） - 哌嗪-1'-基] - 异喹啉的外消旋混合物和对映体纯形式是去甲肾上腺素（NE）转运蛋白（NET）抑制剂化合物。 本发明的化合物被认为是中枢神经系统（CNS）疾病和病症的治疗剂，但不限于，包括神经变性，焦虑，抑郁，注意力缺陷障碍，药物依赖性和创伤后应激障碍。 提供了本发明化合物的化学合成的实例。 本发明的异喹啉化合物在NET下以纳摩尔浓度竞争结合。 本发明的异喹啉试剂与其它竞争性转运靶标和受体结合位点选择性结合，包括血清素和多巴胺等。 本发明的化学合成适用于用放射性核素原子标记。 新型1 - [（2'-取代） - 哌嗪-1'-基] - 异喹啉化合物的放射性标记形式为正电子发射断层扫描和单光子发射断层成像示踪剂。 提供了使用包括脑区域在内的各种受试者和组织内的示踪剂进行体内成像的方法。 提供与其他NET抑制剂组合的示踪剂的成像方法。 受试者中的成像方法允许NET的定量检测，NET分布的确定，以及在存在或不存在非放射性NET剂的情况下NET的示踪剂相互作用的测量。 示踪成像方法适用于定位，诊断，识别，评估，检测或定量NET，或NET异常或NE异常; 这与各种CNS疾病和疾病有关。

    Cholinesterase Inhibitors
    8.
    发明申请
    Cholinesterase Inhibitors 审中-公开
    胆碱酯酶抑制剂

    公开(公告)号：US20130343994A1

    公开(公告)日：2013-12-26

    申请号：US13926661

    申请日：2013-06-25

    申请人： Charles M. Thompson ,  John M. Gerdes ,  Syed K. Ahmed ,  Yamina Belabassi

    发明人： Charles M. Thompson ,  John M. Gerdes ,  Syed K. Ahmed ,  Yamina Belabassi

    IPC分类号： A61K51/04 ,  C07F9/40 ,  C07F9/38

    CPC分类号： C07F9/4071 ,  A61K51/0489 ,  C07B59/004 ,  C07F9/38 ,  C07F9/4021

    摘要： The invention provides compounds that inhibit cholinesterases, such as acetylcholinesterase and butyrylcholinesterase. Such compounds are useful to prevent or treat exposure of a patient (e.g., a human) to an organophosphoric nerve agent (e.g., sarin and VX) or to treat a patient suffering from a neurodegenerative disorder such as Alzheimer's Disease or Lewy Body Dementia. The compounds are further useful as diagnostic tools for use in medical or research radiography (e.g., positron emission tomography) when synthesized with a radionuclide (e.g., [18F]. Synthetic schemes to produce such compounds are also provided.

    摘要翻译： 本发明提供抑制胆碱酯酶如乙酰胆碱酯酶和丁酰胆碱酯酶的化合物。 这样的化合物可用于预防或治疗患者（例如人）暴露于有机磷神经药物（例如沙林和VX）或治疗患有神经变性疾病如阿尔茨海默病或路易体痴呆的患者。 当用放射性核素（例如[18 F]）合成时，这些化合物可用作用于医学或研究放射照相术（例如正电子发射断层摄影）的诊断工具。还提供了合成方案来制备这些化合物。

    Enantiomers of 2'-Fluoralkyl-6-nitroquipazine as Serotonin Transporter Positron Emission Tomography Imaging Agents and Antidepressant Therapeutics
    10.
    发明申请
    Enantiomers of 2'-Fluoralkyl-6-nitroquipazine as Serotonin Transporter Positron Emission Tomography Imaging Agents and Antidepressant Therapeutics 有权
    2'-氟烷基-6-硝基喹嗪作为血清素转运体的对映异构体正电子发射断层成像剂和抗抑郁药治疗

    公开(公告)号：US20110009419A1

    公开(公告)日：2011-01-13

    申请号：US12887782

    申请日：2010-09-22

    申请人： John M. Gerdes ,  David B. Bolstad ,  Brian R. Kusche

    发明人： John M. Gerdes ,  David B. Bolstad ,  Brian R. Kusche

    IPC分类号： A61K31/496 ,  C07D401/04 ,  A61P25/24

    CPC分类号： C07D401/04

    摘要： Racemic mixtures and individual enantiomers of fluorine-18 or carbon-11 radiolabelled 2′-alkyl-6-nitroquipazine ligands are serotonin transporter (SERT) tracers for positron emission tomography (PET) imaging. The non-radioactive ligand forms possess therapeutic antidepressant in vitro and in vivo pharmacological binding profiles in rodent brain and cells expressing human serotonin transporter (hSERT). Twelve 2′-alkyl-6-nitroquipazine ligands potently bind in sub-nanomolar concentrations to the pre-synaptic SERT binding site where established antidepressant drugs bind and inhibit the re-uptake of the neurotransmitter serotonin (5-HT). In vivo tracer studies in rats as well as monkey PET scan trial have demonstrated the fluorine-18 and carbon-11 positron radionuclide labeled tracers perform as quantitative tracers of specific binding the SERT protein in live brain.

    摘要翻译： 氟-18或碳-11放射性标记的2'-烷基-6-硝基奎匹嗪配体的外消旋混合物和单独的对映异构体是用于正​​电子发射断层摄影（PET）成像的血清素转运蛋白（SERT）示踪剂。 非放射性配体形式在啮齿动物脑和表达人血清素转运蛋白（hSERT）的细胞中的体外和体内药理学结合图谱中具有治疗性抗抑郁药。 十二个2'-烷基-6-硝基奎匹嗪配体以亚纳摩尔浓度有力地结合到突触前SERT结合位点，其中建立的抗抑郁药物结合并抑制神经递质5-羟色胺（5-HT）的再摄取。 大鼠的体内示踪剂研究以及猴PET扫描试验已经证明，氟-18和碳-11正电子放射性核素标记的示踪剂作为活体脑中SERT蛋白特异性结合的定量示踪剂。