公开(公告)号：WO2008115593A1

公开(公告)日：2008-09-25

申请号：PCT/US2008/003792

申请日：2008-03-21

申请人： THE UNIVERSITY OF MONTANA ,  GERDES, John, M. ,  BOLSTAD, David, B. ,  BRADEN, Michael, R. ,  BARANY, August, W.

发明人： GERDES, John, M. ,  BOLSTAD, David, B. ,  BRADEN, Michael, R. ,  BARANY, August, W.

IPC分类号： A61K31/496 ,  C07D401/04 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P25/30

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 comoundss 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： 外消旋混合物和对映体纯形式的新的1 - [（2'-取代的） - 哌嗪-1'-基] - 异喹啉是去甲肾上腺素（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。 新颖的1 - [（2'-取代的） - 哌嗪-1'-基] - 异喹啉的放射标记形式是正电子发射断层扫描和单光子发射层析成像示踪剂。 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。