1-[(2′-substituted)-piperazin-1′ -yl]-isoquinolines as norepinephrine transporter inhibitor therapeutics and positron emission tomography imaging agents

Inventors

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

Assignees

University of Montana Missoula

Publication Number

US-7887784-B2

Publication Date

2011-02-15

Expiration Date

2028-03-21

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Abstract

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.

Core Innovation

The invention provides structurally novel 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline compounds that exhibit potent and selective binding affinity for the norepinephrine transporter (NET) protein in peripheral and central nervous system tissues. These compounds are distinguished by their unique chemical structures, which are different from other known NET inhibitor drugs and agents. The compounds possess high selectivity for NET over other CNS competitive binding sites and demonstrate potent pharmacological binding at NET, especially within brain tissues.

The core problem addressed by the invention is the lack of potent and highly selective NET inhibitor agents, especially those suitable for both therapeutic uses and imaging applications. Existing NET inhibitors often lack selectivity and cross-react with other transporter proteins such as the serotonin transporter (SERT) and the dopamine transporter (DAT), which undermines their utility for specific detection, diagnosis, and treatment of CNS conditions linked to norepinephrine (NE) or NET abnormalities.

The compounds of the invention may be formulated as racemic mixtures or as enantiomerically pure forms, including analogs, salts, derivatives, and pro-drugs. When labeled with suitable radionuclide atoms, such as carbon-11 or fluorine-18, these compounds serve as imaging tracers for quantitative, in vivo detection and distribution analysis of NET by positron emission tomography (PET), single photon emission computed tomography (SPECT), or autoradiography. Imaging methods employing the radiotracers enable quantitative detection, localization, diagnosis, evaluation, and quantitation of NET and its abnormalities in various tissues and subjects, with particular use in diseases and disorders associated with NET or NE dysfunction, such as neurodegeneration, anxiety, depression, attention deficit disorders, drug dependency, and post traumatic stress disorder.

Claims Coverage

The patent contains multiple independent claims covering six main inventive features.

Compound having a 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline structure

A compound comprising the structure of 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline, where substitutions are as defined in the claim. The structure incorporates specific R group substitutions, allowing for racemic mixtures or enantiomeric forms.

Pharmaceutical composition containing 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline

A pharmaceutical composition that includes a compound with the 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline structure, as defined, and a pharmaceutically acceptable carrier.

Method of treating depression by administering 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline

A method of treating depression by administering to a subject in need a therapeutically effective amount of the compound having the 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline structure.

Radiotracer having a 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline structure

A radiotracer comprising a 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline structure, where the compound is labeled with a radionuclide atom as specified.

Pharmaceutical composition comprising the radiotracer

A pharmaceutical composition comprising the radiotracer with a 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline structure, together with a pharmaceutically acceptable carrier.

Method for in vivo imaging using the radiotracer

A method for in vivo imaging comprising administering to a subject a radiotracer having the defined 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline structure, and detecting the resulting distribution of norepinephrine transporter protein via imaging.

Method for tissue imaging using the radiotracer

A method comprising contacting a tissue that contains norepinephrine transporter protein with a radiotracer having the defined structure and detecting the radiotracer in vitro or ex vivo. The method allows for detection in cultured or excised tissue samples.

The claims provide coverage for novel NET inhibitor compounds and radiotracers with 1-[(2′-substituted)-piperazin-1′-yl]-isoquinoline structures, their pharmaceutical and diagnostic compositions, and methods of therapeutic and imaging use in subjects or tissues.

Stated Advantages

The compounds possess potent and selective binding affinity for the norepinephrine transporter (NET) protein with high selectivity over other competitive transporter targets and receptor binding sites, including serotonin and dopamine transporters.

The radiolabeled forms of the compounds serve as suitable and effective imaging agents for quantitative, in vivo detection and distribution analysis of NET using PET, SPECT, and autoradiography methods.

The compounds can be used in the treatment or prophylaxis of diseases and disorders characterized by NET or norepinephrine abnormalities, including anxiety, depression, attention deficit disorder, drug dependency, post traumatic stress disorder, and neurodegenerative disorders.

The imaging methods allow quantitative detection, localization, diagnosis, identification, evaluation, and quantitation of NET and abnormalities thereof associated with various CNS diseases and disorders.

Documented Applications

Therapeutic use of the NET inhibitor compounds for the treatment or prophylaxis of diseases and disorders characterized by NET or norepinephrine abnormalities, including neurodegeneration, anxiety, depression, attention deficit disorders, drug dependency, and post traumatic stress disorder.

In vivo imaging of the norepinephrine transporter using PET and SPECT tracers for detection and quantification of NET in live tissues, including brain, to locate, diagnose, identify, evaluate, detect, and quantify NET, or abnormalities thereof.

In vitro and ex vivo tissue imaging using radiotracers to detect and quantify NET densities in tissue samples.

Assessment of NET protein occupancy by other non-radioactive NET inhibitor drugs via competitive binding analysis in imaging studies.

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