Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2001-12-27
2003-02-11
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S001110, C424S001650, C424S009100, C424S009300, C424S009362, C424S009400, C424S009361, C534S010000, C534S014000
Reexamination Certificate
active
06517814
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to new macrocyclic chelants and metal chelates thereof, methods of preparing the chelants and metal chelates, and pharmaceutical compositions comprising the macrocyclic chelants and metal chelates. This invention relates particularly to the use of the new metal chelates as contrast agents in X-ray or CT, MRI imaging, and radiopharmaceuticals for the diagnosis of cardiovascular disorders, infectious disease and cancer. This invention also relates to new bifunctional chelants (BFCs) for attaching diagnostic and therapeutic isotopes to target-specific biomolecules such as proteins, peptides, peptidomimetics, and non-peptide receptor ligands. In addition, the macrocyclic chelants are useful for heavy metal detoxification.
BACKGROUND OF THE INVENTION
Medical imaging modalities, such as MRI, X-ray, gamma scintigraphy, and CT scanning, have become extremely important tools in the diagnosis and treatment of various diseases and illness. The imaging of internal body parts relies on the contrast between the targeted organ and the surrounding tissues. The targeted organs or tissues are visible by the use of a particular metallopharmaceutical contast agent. In X-ray and CT diagnostics, increased contrast of internal organs, such as the kidney, the urinary tract, the digestive tract, the cardiovascular system, tumors, and so forth is obtained by administering a contrast agent which is substantially radiopaque. In conventional proton MRI diagnostics, increased contrast of internal organs and tissues may be obtained by administrating compositions containing paramagnetic metal species, which increase the relativity of surrounding water protons. In ultrasound diagnostics, improved contrast is obtained by administering compositions having acoustic inpedances different from that of blood and other tissues. In gamma scintigraphy, contrast of internal organ is obtained by the specific localization of a gamma ray emitting radiopharmaceutical.
Attachment of metal ions to biomolecules (BM) such as antibodies, antibody fragments, peptides, peptidomimetics, and non-peptide receptor ligands leads to useful target-specific diagnostic and therapeutic metallopharmaceuticals. These include fluorescent, radioactive and paramagnetic metal ions attached to proteins that can be used as probes in vivo in biological systems and in vitro in analytical systems as radioimmunoassays. For example, attachment of radionuclides to monoclonal antibodies that recognize tumor associated antigens provides radioimmunoconjugates useful for cancer diagnosis and therapy. The monoclonal antibodies are used as carriers of desired radioisotope to the tumor in vivo.
Radiopharmaceuticals can be classified into two primary classes: those whose biodistribution is determined exclusively by their chemical and physical properties; and those whose ultimate distribution is determined by receptor binding or other biological interactions. The latter class is often called target-specific radiopharmaceuticals. In general, a target specific radiopharmaceutical can be divided into four parts: a targeting molecule, a linker, a BFC, and a radionuclide.
The targeting molecule serves as a vehicle, which carries the radionuclide to the receptor site at the diseased tissue or organ. The targeting molecules can be macromolecules such as antibodies; they can also be small biomolecules: peptides, peptidomimetics, and non-peptide receptor ligands. The choice of biomolecule depends upon the targeted disease or disease state.
The radionuclide is the radiation source. The selection of radionuclide depends on the intended medical use (diagnostic or therapeutic) of the radiopharmaceutical. Radionuclides, such as
99m
Tc,
131
I,
123
I,
117m
SN,
111
IN,
97
Ru,
203
Pb,
67
Ga,
68
Ga,
89
Zr, and
64
Cu, are &ggr;-emitters useful for diagnostic imaging. Nearly 80% of radiopharmaceuticals used in nuclear medicine are
99m
Tc-labeled compounds. The reason for such a preeminent position of
99m
Tc in clinical use is its extremely favorable physical and nuclear characteristics. The 6 h half-life is long enough to allow a radiochemist to carry out radiopharmaceutical synthesis and for nuclear medicine practitioners to collect useful images. At the same time, it is short enough to permit the administration of millicurie amounts of
99m
Tc radioactivity without significant radiation dose to the patient. The monochromatic 140 KeV photons are readily collimated to give images of superior spatial resolution.
99m
Tc is readily available from commercial
99
Mo-
99m
Tc generators at low cost. Radionuclides, such as
90
Y,
177
Lu,
149
Pm,
153
Sm,
166
Ho,
131
I,
32
p,
211
At,
47
SC,
109
Pd,
105
Rh,
186/188
Re, and
67
CU, are potentially useful for radiotherapy. Among these therapeutic radionuclides, lanthanide radioisotopes are of particular interest. There are several lanthanide isotopes to choose, including low energy &bgr;-emitter
177
Lu, medium energy &bgr;-emitters,
149
Pm and
153
Sm, and high-energy &bgr;-emitters,
166
Ho and
90
Y. Yttrium and lanthanide metals share similar coordination chemistry. The chelator technology and their coordination chemistry are well developed and well understood.
Between the targeting molecule and the radionuclide is the BFC, which binds strongly to the metal ion and is covalently attached to the targeting molecule either directly or through a linker. Selection of a BFC is largely determined by the nature and oxidation state of the metallic radionuclide. The linker can be a simple hydrocarbon chain or a long poly(ethylene glycol) (PEG), which is often used for modification of pharmacokinetics. Sometimes, an anionic poly (amino acid) is used to increase the blood clearance and to reduce the background activity, thereby improving the target-to-background ratio.
The use of metallic radionuclides offers many opportunities for designing new radiopharmaceuticals by modifying the coordination environment around the metal with a variety of chelants. The coordination chemistry of the metallic radionuclide will determine the geometry and solution stability of the metal chelate. Different metallic radionuclides have different coodination chemistries, and require BFCs with different donor atoms and ligand frameworks. For “metal essential” radiopharmaceuticals, the biodistribution is exclusively determined by the chemical and physical properties of the metal chelate. For target-specific radiopharmaceuticals, however, the “metal label” is not totally innocent because the target uptake and biodistribution will be affected by not only the targeting biomolecule but also the metal chelate and the linker. This is especially true for radiopharmaceuticals based on small molecules such as peptides due to the fact that in many cases the metal chelate contributes greatly to the overall size and molecular weight. Therefore, the design and selection of the BFC is very important for the development of a new radiopharmaceutical.
The same principle used for target-specific metallo-radiopharmaceuticals also applies to target-specific MRI contrast and ultrasound agents. Unlike the target-specific metalloradiopharmaceutical, where the excess unlabeled biomolecule can compete with the radiolabeled BFC-BM conjugate and block the docking of the radiolabeled receptor ligand, MRI and ultrasound contrast agents contain no excess unlabeled BFC-BM conjugate. Saturation of the receptor sites will maximize the contrast between the diseased tissues and normal tissue provided that the use of a relatively large amount of metal-BFC-BM chelate does not cause unwanted side effects.
For a therapeutic radiopharmaceutical or an MRI contrast agent, it is especially important to keep the metal chelate intact under physiological conditions, particularly in the presence of native chelators, such as transferrin, which have very high affinity for trivalent lanthanide metal ions. This requires the chelant to form a metal chelate with high thermodynamic stability and kinetic inertness.
Several BFC systems such as ethylenediaminete
Bristol-Myers Squibb Pharma Company
Jones Dameron L.
Woodcock & Washburn LLP
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