Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
2001-09-20
2003-09-30
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C534S010000
Reexamination Certificate
active
06627176
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to radioactive metal complexes which comprise a radioactive metal chelated by a ligand, inter alia, a substituted 1,4,8,1 1-tetraazabicyclo[6.6.2] hexadecane, a substituted 1,4,8,11-tetraazabicyclo[6.6.4] octadec-16-ene. The compounds of the present invention are suitable for use in radiodiagnostic compositions, radiotherapy, neutron capture therapy, and for chemotherapy. The diagnostic and therapeutic compositions of the present invention can further comprise one or more adjunct ingredients.
BACKGROUND OF THE INVENTION
Nuclear medicine procedures and treatments are based on internally distributed radioactive materials, such as radiopharmaceuticals or radionuclides, which emit electromagnetic radiations as gamma rays or photons. Following adequate administration, inter alia, intravenous injection, orally, inhalation, the gamma rays are readily detected and quantified within the body using instrumentation such as scintillation and gamma cameras. The gamma-emitting agents localize themselves into particular targeted tissue depending upon the characteristics of the radiopharmaceutical or radionuclide complex. Once localized, these agents yield either high signal intensity or a high radiation dose, as in the case of radiotherapeutics.
The use of neutron capture therapy for the treatment of cancer is accomplished by administering a target substance which emits short-range radiation when irradiated by neutrons.
10
B (boron-10) and
157
Gd (gadolinium-157) are commonly used radionuclides, the latter having a very high cross section for neutrons and is capable of emitting short range Auger-electrons. In the past neutron capture therapy has suffered from insufficient concentration of target substance in the desired cells and in the case of gadolinium, has suffered from the exclusion of the gadolinium from the inside of the cell.
There is a long felt need in the art for a ligand which is modifiable, forms a very stable complex, and which can suitably transport radioactive metals to target tissues. There is a need for a ligand/metal complex which can deliver sufficient gamma emitting material to tumor cells and other selected tissue to enhance radiotherapy techniques. There is also a need for a strongly binding ligand to concentrate radionuclides to target tissues.
SUMMARY OF THE INVENTION
The present invention meets the aforementioned needs in that it has been surprisingly discovered that certain radioactive transition metal complexes, inter alia, substituted 1,4,8,11-tetraazabicyclo[6.6.2] hexadecane transition metal complexes, are suitable for use as radiopharmaceuticals and radionuclides in medical radiotherapy. The ligands of the present invention can be varied to provide the proper affinity for different cell types, inter alia, tumor cells, organ tissue. The ligands of the present invention provide a very stable radionuclide complex thereby preventing the loss of radioactive metal through pre-mature release due to hydrolysis or metal oxide formation. The surprising stability of the complexes of the present invention in vivo insures delivery of the desired nuclide to the desired tissue in the desired amount thereby overcoming decreased efficacy and loss of targeting discrimination.
The first aspect of the present invention relates to transition metal complexes having the formula:
wherein M is a radioactive metal having a valence +2, +3, +4, or +5, m
+
designates the charge of the metal complex, each R is independently C
1
-C
8
linear or branched alkyl, a fifth ligand, and mixtures thereof; B is a bridging unit which comprises at least 2 carbon atoms; L is a pharmaceutically acceptable ligand; X is a pharmaceutically compatible anion in sufficient amount to provide electronic neutrality.
The present invention further relates to a diagnostic, therapeutic or radiotherapeutic or chemotherapeutic composition for visualization, therapy, chemotherapy or radiotherapy of tissues or organs comprising:
a) an effective amount, preferably from about 0.05 mmol, more preferably from about 0.1 mmol, most preferably from about 1 mmol to about 100 mmole, preferably to about 50.0 mmol, more preferably to about 25.0 mmol, most preferably to about 10 mmol per liter, or alternatively from about 0.01 micro Currie (&mgr;Ci), preferably from about 0.1 &mgr;Ci, more preferably from about 1 &mgr;Ci, most preferably from about 10 &mgr;Ci to about 200 &mgr;Ci, preferably to about 100 &mgr;Ci, more preferably to about 50 &mgr;Ci, most preferably to about 25 &mgr;Ci, of a transition metal radionuclide complex having the formula:
wherein M is a radioactive metal having a valence of +2, +3, +4, or +5; each R is independently C
1
-C
8
linear or branched alkyl, a fifth ligand, and mixtures thereof; B is a bridging unit which comprises at least 2 carbon atoms; L is a pharmaceutically acceptable ligand; X is a pharmaceutically compatible anion in sufficient amount to provide electronic neutrality; and
b) the balance a pharmaceutically acceptable carrier and other adjunct ingredients.
The present invention also relates to methods for providing radiochemical therapy. One aspect of these methods is a method which comprises the steps of:
a) administering to tissue either in vitro or in vivo an effective amount of a transition metal complex according to the present invention which is capable of emitting short-range radiation when irradiated by neutrons; and
b) irradiating said tissue with a source of neutrons.
A further aspect of the methods of the present invention relates to a method comprising the step of: contacting tissue with an effective amount of a transition metal complex according to the present invention which is capable of emitting radiation.
These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to transition metal complexes comprising a transition metal and ligand wherein said transition metal is a radioactive element having a valence of +2, +3, +4, or +5. The radioactive metal is chelated by a suitable ligand, non-limiting examples of which include substituted 1,4,8,11-tetraazabicyclo[6.6.2] hexadecane, substituted 1,4,8,11-tetraazabicyclo[6.6.4] octadec-16-ene, and the like described herein below. The complexes of the present invention are suitable for use as a radiopharmaceutical and as a radionuclide. The complexes of the present invention are suitable for use in the treatment of tissue, inter alia, for enhancing the contrast image of tissue, for use in killing targeted tissue.
One aspect of the present invention relates to the complexes of the present invention as radiotherapeutic agents and in this sense the complex functions as a radionuclide. For example, the complexes of the present invention can be used as neutron capture agents wherein the complex is delivered to a desired tissue, organ, or type or tissue, inter alia, tumor cells, and said site of delivery is subsequently irradiated with a source of neutrons to achieve emission of tissue damaging particles, inter alia, Auger electrons. The complexes of the present invention can be re-radiated until sufficient tissue therapy is achieved.
Another aspect of the present invention relates to delivery of radioactive metals which emit alpha or beta particles and in this sense the complex functions as a radiopharmaceutical. The ligand portion of the complex can be modified to target (be specifically delivered to) a particular type of tissue or organ such that the organ or tissue will have enhanced affinity for the complex. In addition to imbuing s
Hartley Michael G.
McBride James F.
Miller Steve W.
Procter & Gamble Company
Zerby Kim W.
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