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Publication Number
US-9446157-B2
Publication Date
2016-09-20
Expiration Date
Abstract
Compounds as defined herein are provided which are useful in (1) diagnostic methods for detecting and/or identifying cells presenting PSMA; (2) compositions comprising a compound of the invention together with a pharmaceutically acceptable diluent; and (3) methods for imaging prostate cancer cells.
Core Innovation
The disclosure relates to chelated compounds or pharmaceutically acceptable salts thereof in which a divalent linking group is bonded to a chelating agent, with n being 1 or greater, and the chelating agent optionally associated with a PET-active or therapeutic radioisotope. The chelated construct includes terminal "*-end" attachment and variable linker architectures while maintaining the chelator linkage context.
The divalent linking group is described through multiple structural classes and subtypes, including alkyl, aryl, heteroaryl, and cycloalkyl frameworks, with optional heteroatom substitutions such as oxygen, sulfur, nitrogen, carbonyl, ester, amides, sulfonamide, and phosphate-type variants. Additional embodiments include (OCH2CH2)n motifs, amino-acid derived amide linkers, phenyl-containing amide linkers, and covalent bond attachment as an alternative.
The disclosure further presents chelator-linked radiolabeled embodiments using named chelators such as DOTA, NOTA, PCTA, DO3A, desferrioxamine, Bn-NOTA, Bn-PCTA, Bn-Oxo-DO3A, DTPA, and TETA, together with radioisotopes including 68Ga and other PET-active or therapeutic radionuclides. Example contexts include chelator-labeled PSMA inhibitors, peptidomimetic PSMA-binding cores, and radiolabeled constructs such as 99mTc-DTPA-SCN-CTT-54.
Claims Coverage
The consolidated claim coverage centers on chelated compounds defined by a divalent linking group bonded to a chelating agent with n ≥ 1 and optional association with a PET-active or therapeutic radioisotope. Dependent features refine the coverage by specifying named chelating agents, enumerated radionuclides, detailed divalent linker structures terminating at the terminal "*-end," and additional PET imaging and pharmaceutical composition contexts. Across the provided claim sets, there is 1 independent claim family with multiple dependent claim refinements.
Chelated compound with divalent linking group bonded to a chelating agent
A compound, or pharmaceutically acceptable salt thereof, wherein n is 1 or greater and R comprises a divalent linking group bonded to a chelating agent, wherein the chelating agent is optionally a PET-active or therapeutic radioisotope.
Radioisotope association for the chelating agent
The chelating agent is associated with one of 89Zr, 64Cu, 68Ga, 186/188Re, 90Y, 177Lu, 153Sm, 213Bi, 225Ac, or 223Ra.
Named chelating-agent selection
The chelating agent comprises DOTA, NOTA, PCTA, DO3A, desferrioxamine, Bn-NOTA, Bn-PCTA, Bn-Oxo-DO3A, DTPA, or TETA.
Detailed divalent linker structures terminating at the terminal *-end
The divalent linking group attached between the chelating agent and the compound terminates at the *-end and is selected from specified divalent linker structures including alkylene/ether chains, (OCH2CH2)n motifs, amino-acid-containing amide linkers, phenyl-containing amide linkers, alkyl, aryl, heteroaryl, and cycloalkyl frameworks, with variable parameters and alternative covalent bond attachment.
Pharmaceutical composition including a pharmaceutically acceptable carrier
A pharmaceutical composition comprising the compound together with a pharmaceutically acceptable carrier.
PET imaging of cancer cells in a patient
A method of imaging one or more cancer cells in a patient by administering a PET-active radioisotope compound and performing PET imaging.
Overall, the claims are directed to chelated compounds defined by a divalent linking group bonded to a chelating agent with n ≥ 1 and optional PET-active or therapeutic radioisotope association. The dependent coverage further specifies named chelators, enumerated radionuclides, and terminal "*-end" linker architectures, and includes pharmaceutical composition and PET imaging claim coverage.
Stated Advantages
The disclosed chelate characteristics include labeling efficiency, yield, specific activity, stability, and PSMA inhibitory potency with irreversible inhibition and cell binding selectivity, including saline and blood stability.
Documented Applications
Imaging one or more cancer cells in a patient by administering a PET-active radioisotope compound and performing PET imaging.
PET/CT evaluation and biodistribution in tumor-bearing mice are described in the example chemistry context [procedural detail omitted for safety].
Compounds configured for PET imaging and compounds configured as therapeutic radioisotope chelates.
PSMA targeting and imaging of prostate cancer cells and/or tumor-associated vasculature.
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