Radiolabeled inhibitors of the amino acid transporters ASCT1 and ASCT2

Inventors

Esslinger, Christopher SeanKavanaugh, Michael P.Lyda, BrentNatale, Nicholas R.

Assignees

University of Montana Missoula

Publication Number

US-9512074-B2

Publication Date

2016-12-06

Expiration Date

2032-07-16

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Abstract

The present invention relates to a compound of Formula (I) or (II) or a salt thereof, wherein R is described herein. The compounds are novel hydroxy-proline analog inhibitors of the ASCT1 and ASCT2 neutral amino acid transporters.

Core Innovation

The invention features novel hydroxy-proline analog compounds represented by Formula (I) or (II), or a salt thereof, wherein R is selected from alkyl, alkyl-ether, aryl, and aryl-ether groups. These compounds are selective and potent inhibitors of the neutral amino acid transporters ASCT1 (SLC1A4) and ASCT2 (SLC1A5). The compounds have been screened using electrophysiological and radioligand uptake assays to confirm their inhibition of these transporters.

The compounds, including their radiolabeled analogs (such as those incorporating fluorine-18), can be used both in research to study cell growth, proliferation, and glutamatergic neurotransmission and clinically to treat diseases associated with ASCT1 or ASCT2 dysfunction. These diseases include cancer, microbial infections, and ischemia-related central nervous system (CNS) injuries. The radiolabeled versions are particularly useful for diagnostic imaging via positron emission tomography (PET) and related modalities to visualize ASCT1/ASCT2 expression and activity in vivo and ex vivo.

The background highlights that existing ASCT2 inhibitors have been used as pharmacological tools or chemotherapeutic agents but that there remains a need for additional inhibitors to evaluate the physiological significance of ASCT1 and ASCT2 transporters. The invention addresses this need by providing novel compounds with defined selectivity and utility as research tools and therapeutic or diagnostic agents.

Claims Coverage

The independent claim in the patent covers the invention of a compound represented by Formula I or II, or a salt thereof, with specific features related to the R group and radiolabeling.

Compound represented by Formula I or II with variable R group

A compound is provided, represented by Formula I or II, or a salt thereof, wherein the R substituent can be alkyl, alkyl-ether, aryl, or aryl-ether, as described in the specification. This core structure encompasses a variety of hydroxy-proline analogs designed to inhibit ASCT1 and ASCT2 amino acid transporters.

The primary inventive feature is the set of new hydroxy-proline analogs with defined variable functional groups at the R position, encompassing chemical diversity for inhibition of ASCT1/ASCT2. Dependent claims further specify halogen and radionuclide substitutions, but the core inventive concept is the compound design and its functional intent.

Stated Advantages

The compounds selectively and potently inhibit the ASCT1 and ASCT2 neutral amino acid transporters.

Radiolabeled versions allow in vivo and ex vivo imaging by PET and other radiographic techniques.

The compounds are effective both as research tools for studying ASCT transporter function and as therapeutic agents for diseases related to ASCT1/ASCT2 dysfunction.

Radiolabeled compounds provide a diagnostic advance with improved synthetic accessibility for fluorine-18 complexes.

Documented Applications

Pharmacological inhibition of ASCT1 and ASCT2 in research settings to study cell growth, proliferation, and neurotransmission.

Treatment of human and animal diseases caused or influenced by abnormal ASCT1 or ASCT2 transporter function, such as cancer, microbial infections, and ischemia-related central nervous system injuries.

Diagnostic imaging in vivo or in ex vivo tissue samples for assessment of ASCT1/ASCT2 activity or expression using radiolabeled compounds and modalities like positron emission tomography (PET).

Veterinary medical imaging and treatment of animals with ASCT1/ASCT2-related functional abnormalities, including domesticated, companion, exotic, and farm animals, as well as research animals.

Use of radiolabeled compounds as research tools for in vitro and in vivo mechanistic studies in cell lines and animal models.

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