Tetrahydroxamate chelators of zirconium89 and niobium90 for use in diagnostic applications
Inventors
Brechbiel, Martin W. • Guerard, Francois • Lee, Yong-Sok
Assignees
US Department of Health and Human Services
Publication Number
US-10137212-B2
Publication Date
2018-11-27
Expiration Date
2034-03-12
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Abstract
Disclosed is a compound of formula (I) or (II) in which R1-R4, R1′-R5′, Z1+-Z4, and Z1′-Z4′ are as described herein. Also disclosed are a 89Zr- or 90Nb-containing complex of a compound of formula (I) or (II) and a method for obtaining a diagnostic image, such as a positron emission tomography (PET) image.
Core Innovation
Positron emission tomography (PET) is a significant nuclear imaging technique for detecting pathologies such as cancers. Although radionuclides like 18F, 64Cu, 86Y, and 124I are used in PET imaging, there remains a need for additional radionuclides with half-lives better matching human blood kinetics.
The invention provides tetrahydroxamate ligands capable of forming thermodynamically stable metal complexes, particularly with zirconium-89 (89Zr) or niobium-90 (90Nb). These chelating agents exhibit prearranged geometries superior to the tris-hydroxamate desferrioxamine B (DFB) in complex stability, facilitating safer and more efficient nuclear imaging.
Compounds of formula (I) or (II) incorporate specified substituents and can be conjugated to biomolecules for targeted delivery. Complexes comprising such compounds chelate 89Zr or 90Nb through four deprotonated hydroxy groups, forming octahedral complexes. These complexes are useful in diagnostic imaging methods such as PET, enabling visualization of tissues or tumors by administering the complex and exposing subjects to an energy source for imaging.
Claims Coverage
The patent includes sixteen independent claims covering novel compounds, complexes with radionuclides, compositions, and imaging methods. The main inventive features relate to the compound structures, their metal coordination, and diagnostic imaging uses.
Compounds of formula (I) or (II) with specific substituents
The invention claims compounds of formula (I) or (II) wherein substituents R1-R4, R1′-R5′, Z1-Z4, and Z1′-Z4′ have defined structures permitting stable metal chelation and optional biomolecule conjugation.
Complexes chelating 89Zr or 90Nb
Complexes comprising the compounds of formula (I) or (II) chelated to 89Zr or 90Nb through hydroxamate groups where the hydroxy hydrogens are absent, allowing both oxygens to coordinate the metal.
Pharmaceutical compositions including the complexes
Compositions containing the described metal complexes and pharmaceutically acceptable carriers suitable for parenteral or oral administration.
Methods for PET imaging using the metal complexes
Methods involving administering the complexes to subjects or tissues in amounts effective for PET imaging, followed by exposure to an energy source to obtain diagnostic images.
The claims collectively cover the novel tetrahydroxamate compounds, their stable complexation with 89Zr or 90Nb, pharmaceutical formulations thereof, and their diagnostic imaging applications through PET, demonstrating a comprehensive scope from molecular structures to clinical use.
Stated Advantages
The tetrahydroxamate chelators provide dramatically improved stability of 89Zr and 90Nb complexes compared to existing agents like desferrioxamine B (DFB).
The compounds have a prearranged geometry that favors the formation of thermodynamically stable and kinetically inert complexes suitable for in vivo applications.
The radionuclides 89Zr and 90Nb have half-lives that better match the blood kinetics of human patients, enhancing imaging efficacy over previous radionuclides.
Documented Applications
Use in positron emission tomography (PET) imaging for detecting various diseases including cancers.
Imaging of specific tissues and organs such as skin, heart, brain, digestive tract, respiratory system, lymphatic and hematopoietic tissues, and carcinomas of multiple types.
Visualization and quantification of tumor accumulation of antibodies and fragments using 89Zr and 90Nb complexes.
Targeted diagnosis or monitoring of inflammation and antigen detection, e.g., VEGF in tumors and neovasculature.
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