Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
2002-02-22
2004-03-30
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001110, C424S009100, C548S400000, C548S401000, C549S200000, C549S201000
Reexamination Certificate
active
06713042
ABSTRACT:
FIELD OF THE INVENTION
This invention is related to the use of ascorbic acid analogs as buffering reagents and chelating agents for the preparation of metalloradiopharmaceuticals. This invention is particularly related to the use of ascorbic acid as a buffering reagent, a chelating agent, and a stabilizer for the preparation and stabilization of radiopharmaceuticals. This invention is also related to processes of making stable radiopharmaceutical compositions using ascorbic acid analogs as buffering agents, chelating agents, and stabilizers.
BACKGROUND
Radiopharmaceuticals are drugs containing a radionuclide. Radiopharmaceuticals are used routinely in nuclear medicine for the diagnosis or therapy of various diseases. They are typically small organic or inorganic compounds with a definite composition. They can also be macromolecules, such as antibodies or antibody fragments, that are not stoichiometrically labeled with a radionuclide. Radiopharmaceuticals form the chemical basis for the diagnosis and therapy of various diseases. The in vivo diagnostic information is obtained by intravenous injection of the radiopharmaceutical and determining its biodistribution using a gamma camera. The biodistribution of the radiopharmaceutical depends on the physical and chemical properties of the radiolabeled compound and can be used to obtain information about the presence, progression, and state of disease.
Radiopharmaceuticals can be divided into two primary classes: those whose biodistribution is determined exclusively by their chemical and physical properties; and those whose ultimate distribution is determined by their receptor binding or other biological interactions. The latter class is often called target-specific radiopharmaceuticals.
Metalloradiopharmaceuticals include a metallic radionuclide. A target-specific metalloradiopharmaceutical can be divided into four parts: a targeting molecule, a linker, a bifunctional Chelator (BFC), and a metallic radionuclide. The targeting molecule serves as a vehicle, which carries the radionuclide to the receptor site at the diseased tissue. The targeting molecules can be macromolecules such as antibodies or small biomolecules (BM), including peptides, peptidomimetics, and non-peptides. The choice of biomolecule depends upon the targeted disease or disease state. The radionuclide is the radiation source. The selection of metallic radionuclide depends on the intended medical use (e.g., diagnostic or therapeutic) of the target specific metalloradiopharmaceutical. The BFC is covalently attached to the targeting molecule either directly or through a linker and binds strongly to the metallic radionuclide via several coordination bonds. 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) or a “naive” poly anionic or cationic peptide sequence, which is often used for modification of pharmacokinetics. Sometimes, a metabolizeable linker 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 chelators. The coordination chemistry of the metallic radionuclide will determine the geometry of the metal chelate and the solution stability of the radiopharmaceutical. Different metallic radionuclides have different coordination chemistries, and require BFCs with different donor atoms and chelator frameworks. For “metal essential” radiopharmaceuticals, the biodistribution is exclusively determined by the physical properties of the metal chelate. For target-specific radiopharmaceuticals, the “metal tag” may have significant impact on the target uptake and biodistribution of the radiopharmaceutical. This is especially true for metalloradiopharmaceuticals based on small molecules since 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 diagnostic or therapeutic radiopharmaceutical.
Metallic radionuclides, such as
99m
Tc,
117m
Sn,
111
In,
67
Ga,
68
Ga,
89
Zr, and
64
Cu, have been proposed 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 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 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. Furthermore,
99m
Tc is readily available from commercial
99
Mo-
99m
Tc generators at low cost.
For
99m
Tc-labeling of biomolecules, bifunctional chelators include N
2
S
2
diaminedithiols, N
2
S
2
diaminedithiols, N
2
S
2
monoamidemonoamidedithiols, N
3
S aminediamidethiols, N
3
S triamidethiols, and HYNIC, which forms various ternary ligand systems when used in combination with tricine/water soluble phosphines, or tricine/pyridine analogs or tricine/substituted imime-N containing heterocycles. These ternary ligand systems have been disclosed in U.S. Pat. No. 5,744,120; U.S. Pat. No. 6,010,679; U.S. Pat. No. 5,879,659; and PCT Patent Application WO 98/53858. Various
99m
Tc-labeling techniques have been described in several reviews (Liu, S. and Edwards, D. S. Chem. Rev. 1999, 99, 2235-2268; Jurisson, S. and Lydon, J. D. Chem. Rev. 1999, 99, 2205-2218; Liu et al. Bioconjugate Chem. 1997, 8, 621-636). After radiolabeling, the resulting reaction mixture may optionally be purified using one or more chromatographic methods, such as Sep-Pack or high performance liquid chromatography (HPLC). The preferred radiolabeling procedures are those in which the chelation can be achieved without post-labeling purification.
Metallic radionuclides, including
90
Y,
177
Lu,
149
Pm,
153
Sm,
166
Ho,
211
At,
47
SC,
109
Pd,
105
Rh,
186/188
Re, and
67
Cu, are potentially useful for radiotherapy. Among these 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 90Y. Yttrium and lanthanide metals share similar coordination chemistry. The chelator technology and their coordination chemistry are well developed and well understood.
For radionuclides, such as
90
Y,
111
In,
67
Ga,
68
Ga,
89
Zr,
62
Cu,
64
Cu and
67
Cu, diethylenetriaminepentaacetic acid (DTPA), tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA) and their derivatives would be the candidates of choice as BFCs. The macrocyclic chelators such as DOTA are known to form highly stable metal chelates due to their highly preorganized macrocyclic ligand framework. Krejcarek and Tucker (Biochem. Biophys. Res. Commun. 1976, 77, 581-588) developed an activated DTPA analog via a mixed anhydride, which can be linked to proteins. Later, Hnatowich et al (Science 1983, 220, 613-616) used the cyclic anhydride of DTPA for the same purpose. These linear BFCs bond to various metal ions and form thermodynamically stable metal chelates. However, metal chelates of linear BFCs are kinetically labile, which contributes to the loss of radionuclide from the metal chelate and often leads to severe bone marrow toxicity. Gansow et al (Bioconjugate Chem. 1991, 2, 187-194; Inorg. Chem. 1986, 25, 2772-2781) prepared a series of substituted DTPA analogs, which form metal chelates with improved solution stability.
Meares and coworkers were the first to synthesize macrocyclic BFCs (Anal.
Bristol-Myers Squibb Pharma Company
Ferguson Blair Q.
Golian Paul D.
Jones Dameron L.
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