Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
2001-11-16
2004-03-02
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C424S001110, C424S001650, C534S014000
Reexamination Certificate
active
06699458
ABSTRACT:
BACKGROUND OF INVENTION
Many of the procedures presently conducted in the field of nuclear medicine involve radiopharmaceuticals which provide diagnostic images of blood flow (perfusion) in the major organs and in tumors. The regional uptake of these radiopharmaceuticals within the organ of interest is proportional to flow; high flow regions will display the highest concentration of radiopharmaceutical, while regions of little or no flow have relatively low concentrations. Diagnostic images showing these regional differences are useful in identifying areas of poor perfusion, but do not provide metabolic information of the state of the tissue within the region of apparently low perfusion.
There is a need for new radiopharmaceuticals which specifically localize in hypoxic tissue, i.e., tissue which is deficient in oxygen, but still viable. These compounds should be retained in regions which are hypoxic, but should not be retained in regions which are normoxic. A radiopharmaceutical with these properties will display relatively high concentrations in such hypoxic regions, with low concentrations, in normoxic and infarcted regions. Diagnostic images with this radiopharmaceutical should readily allow the identification of tissue which is at risk of progressing to infarction, but still salvagable in, for example, the heart and brain.
It is well known that tumors often have regions within their mass which are hypoxic. These result when the rapid growth of the tumor is not matched by the extension of tumor vasculature. A radiopharmaceutical which localizes preferentially within regions of hypoxia could also be used to provide images which are useful in the diagnosis and management of therapy of tumors as suggested by Chapman, “Measurement of Tumor Hypoxia by Invasive and Non-Invasive Procedures—A Review of Recent Clinical Studies”,
Radiother. Oncol.
20(S1), 13-19 (1991). Additionally, a compound which localizes within the hypoxic region of tumors, but is labeled with a radionuclide with suitable &agr;- or &bgr;-emissions could be used for the internal radiotherapy of tumors.
As reported by Martin et al. (“Enhanced Binding of the Hypoxic Cell Marker [
3
E] Fluoro-misonidazole”,
J. Nucl. Med
., Vol. 30, No. 2, 194-201 (1989)) and, Hoffman et al. (“Binding of the Hypoxic Tracer [H-3] Misonidazole in Cerebral Ischemia”,
Stroke
, Vol. 18, 168 (1987) hypoxia-localizing moieties, for example, hypoxia-mediated nitroheterocyclic compounds (e.g., nitroimidazoles and derivatives thereof) are known to be retained in hypoxic tissue. In the brain or heart, hypoxia typically follows ischemic episodes produced by, for example, arterial occlusions or by a combination of increased demand and insufficient flow. Additionally, Koh et al., (“Hypoxia Imaging of Tumors Using [F-18]Fluoronitroimidazole”,
J. Nucl. Med
., Vol. 30, 789 (1989)) have attempted diagnostic imaging of tumors using a nitroimidazole radiolabeled with
18
F. A nitroimidazole labeled with
123
I has been proposed by Biskupiak et al. (“Synthesis of an (iodovinyl)misonidazole derivative for hypoxia imaging”,
J. Med. Chem
., Vol. 34, No. 7, 2165-2168 (1991)) as a radiopharmaceutical suitable for use with single-photon imaging equipment.
While the precise mechanism for retention of hypoxia-localizing compounds is not known, it is believed that nitroheteroaromatic compounds, such as misonidazole, undergo intracellular enzymatic reduction (for example, J. D. Chapman, “The Detection and Measurement of Hypoxic Cells in Tumors”,
Cancer
, Vol. 54, 2441-2449 (1984)). This process is believed to be reversible in cells with a normal oxygen partial pressure, but in cells which are deficient in oxygen, further reduction can take place. This leads to the formation of reactive species which bind to or are trapped as intracellular components, providing for preferential entrapment in hypoxic cells. It is necessary, therefore, for hypoxia imaging compounds to possess certain specific properties; they must be able to traverse cell membranes, and they must be capable of being reduced, for example, by reductases such as xanthine oxidase.
The hypoxia imaging agents mentioned above are less than ideal for routine clinical use. For example, the positron-emitting isotopes (such as
18
F) are cyclotron-produced and short-lived, thus requiring that isotope production, radiochemical synthesis and diagnostic imaging be performed at a single site or region. The costs of procedures based on positron-emitting isotopes are very high, and there are very few of these centers worldwide. While
123
I-radiopharmaceuticals may be used with widely-available gamma camera imaging systems,
123
I has a 13 hour half-life (which restricts the distribution of radiopharmaceuticals based on this isotope) and is expensive to produce. Nitroimidazoles labeled with
3
H are not suitable for in vivo clinical imaging and can be used for basic research studies only.
The preferred radioisotope for medical imaging is
99m
Tc. Its 140 keV &ggr;-photon is ideal for use with widely-available gamma cameras. It has a short (6 hour) half life, which is desirable when considering patient dosimetry.
99m
Tc is readily available at relatively low cost through commercially-produced
99
Mo/
99m
Tc generator systems. As a result, over 80% of all radionuclide imaging studies conducted worldwide utilize this radioisotope. To permit widespread use of a radio-pharmaceutical for hypoxia imaging, it is necessary that the compound be labeled with
99m
Tc. For radiotherapy, the rhenium radioisotopes, particularly
186
Re and
188
Re, have demonstrated utility.
EP 411,491 discloses boronic acid adducts of rhenium dioxime and technetium-99m dioxime complexes linked to various nitroimidazoles. Although these complexes are believed to be useful for diagnostic and therapeutic purposes, it would be desirable to obtain higher levels of the rhenium or technetium radionuclide in the targeted area, than are achieved with this class of capped-dioxime nitroimidazole complexes. It was demonstrated that the compounds disclosed in EP 411,491 possess reduction potentials similar to 2-nitroimidazole derivatives known to localize in hypoxic regions. In addition, the reduction of these compounds is catalyzed by xanthine oxidase. However, these compounds have poor membrane permeability. Thus, while these compounds might be retained by hypoxic cells, delivery of these compounds to the intracellular domain of these cells may be less than ideal. In addition, the complexes described in EP 411,491 require a heating step to form the hypoxia-localizing radiolabeled compounds. It would be more convenient for the routine use of such hypoxia-localizing radiolabeled compounds to be able to prepare such complexes at ambient temperatures.
Radiolabeled complexes of hypoxia-localizing moieties which retain the biochemical behavior and affinity of such moieties, which are labeled at room temperature with a suitable, easy-to-use radionuclide, and which are capable of providing increased amounts of the desired radionuclide to the targeted area, would be a useful addition to the art.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, novel ligands, metal complexes of such ligands, processes for their preparation, and diagnostic and therapeutic methods for their use, are disclosed. In particular, metal complexes, e.g., technetium and rhenium complexes, which are linked toga hypoxia localizing moiety, and wherein the complex has a permeability through cell membranes greater than that of
14
C-sucrose, are disclosed. Exemplary complexes are useful as diagnostic imaging agents in the case of technetium radionuclides and improved agents for radiotherapy in the case of rhenium radionuclides. Suitable novel ligands to form these complexes may include, but are not limited to di-, tri- or tetradentate ligands forming neutral complexes of technetium or rhenium with the metal preferably in the +5 oxidation state. Examples of such ligands are represented by the formulae
where at least one R is —(
DiRocco Richard J.
Linder Karen
Nowotnik David P.
Nunn Adrian D.
Pirro John P.
Bracco International B.V.
Jones Dameron L.
Kramer Levin Naftalis & Frankel LLP
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