Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1998-11-19
2001-10-09
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001770, C424S001650, C424S001110, C424S009100
Reexamination Certificate
active
06299857
ABSTRACT:
The present invention is in the field of nuclear medicine. More specifically, the invention relates to diagnostic imaging of cardiovascular tissue and thrombi.
BACKGROUND OF THE INVENTION
Clinical imaging technology plays a significant role in diagnosis of injuries and disease processes. Many parts of the human body can now be examined for diagnostic purposes using a variety of imaging techniques. Radiography has long been used to image body parts through which externally generated x-rays are transmitted. Computerized axial tomography (CAT) provides cross-sectional x-ray images of a plane of the body. Specific tissues or organs may be targeted in positron emission tomography (PET), single photon emission computed tomography (SPECT), and gamma scintigraphy. In PET, SPECT, and gamma scintigraphy, radiopharmaceutical agents capable of being sequestered (concentrated) to some degree in the target tissue or organ are internally administered to the patient, and images are generated by detecting the radioactive emissions from the concentrated radiopharmaceutical agent. Some of the radiopharmaceutical agents currently used for cardiovascular imaging include nuclides such as
201
Tl,
99m
Tc,
133
Xe, and the like; chelates of nuclides; radiolabeled metabolic agents such as
11
C-deoxy-D-glucose,
18
F-2-fluorodeoxy-D-glucose, [1-
11
C]- and [
123
I]-&bgr;-methyl fatty acid analogs,
13
N-ammonia, and the like; infarct avid agents such as
99m
Tc-tetracycline,
99m
Tc-pyrophosphate,
203
Hg-mercurials,
67
Ga-citrate, and the like; and radiolabeled ligands, proteins, peptides, and monoclonal antibodies. Whole cells such as erythrocytes, platelets, leukocytes, and other cells may also be labeled with a radionuclide and function as radiopharmaceutical agents.
The amount and type of clinical information that can be derived from PET, SPECT, and gamma scintigraphic images is related in part to the ability to concentrate the radiopharmaceutical agent in the target tissue or organ. Although many radiopharmaceuticals are available for clinical use, the resolution of the image generated may be limited depending on various factors. The resolution of a particular imaging agent for imaging diseased or injured tissue depends in part on the affinity of the radiopharmaceutical for the site of injury or disease as compared to its affinity for surrounding healthy tissue.
Radiopharmaceuticals are used in a variety of types of cardiovascular studies to obtain different kinds of information. For example, radiopharmaceutical agents used in cardiac blood flow and blood pool studies provide information on murmurs, cyanotic heart disease, and ischemic heart disease. Perfusion scintigraphy agents provide measurements of blood flow useful in detection of coronary artery disease, assessment of pathology after coronary arteriography, pre- and postoperative assessment of coronary artery disease, and detection of acute myocardial infarction. Infarct avid agents are used for “hot spot” infarct imaging. Radionuclide-containing antibodies directed against the heavy chain of cardiac myosin have been proposed to identify zones of acute myocardial necrosis, and
99m
Tc-labeled low density lipoprotein were proposed for detecting atheromatous lesions in their early stages after onset of endothelial damage.
Radiopharmaceutical ligands specific for &bgr;-adrenergic receptors demonstrate uptake in lungs and do not show sufficient specificity for heart tissue, as reviewed in Elmaleh, D. R., et al., in
Noninvasive Imaging of Cardiac Metabolism,
E. E. van der Wall, ed. (Martinus Nijhoff, Boston, 1987) pp. 1-37. The same reference describes preliminary studies of labeled muscarinic receptor ligands for cardiac imaging which showed some specificity for heart. Studies using
111
In-labeled insulin to image heart insulin receptors demonstrated less specificity for cardiovascular tissue.
Diadenosine 5′, 5′″, P
1
,P
4
-tetraphosphate (Ap
4
A) is an adenine analog which is ubiquitously present in living cells, appearing to play an important role in extracellular signaling events in a variety of tissues. In particular, Ap
4
A is a competitive inhibitor of adenosine diphosphate (ADP)-induced platelet aggregation, which occurs through the binding ADP to a specific class of purine receptors found on platelets and megakaryocytes. U.S. Pat. No. 5,049,550 discloses antithrombotic analogs of Ap
4
A, the therapeutic efficacy of which is premised on the observation that thrombus (blood clot) formation includes an initial platelet aggregation step and on the hypothesis that inhibition of platelet aggregation will result in inhibition of clot formation. U.S. Pat. No. 5,219,841 discloses a pharmaceutical composition containing Ap
4
A as its active ingredient, for treatment of heart disease. U.S. Pat. No. 5,380,715 discloses use of Ap
4
A as a hypotensive agent, particularly in connection with surgical procedures which employ hypotensive anesthesia.
D. R. Elmaleh, et al. (1984)
Proc. Natl. Acad. Sci. USA
81, 918-921 discloses
99m
Tc-labeled Ap
4
A (
99m
Tc-Ap
4
A) used to image tumors implanted into rats. The method used to chelate the
99m
Tc to the Ap
4
A in this study yielded a mixture, in which
99m
Tc was attached to the Ap
4
A-dinucleotide and which also may have contained unchelated
99m
Tc. This study was based on the premise that some human tumor cells are permeable to exogenous ATP and ADP, and that these cells incorporate the intact nucleotides in intracellular pools, in contrast to normal cells. Ap
4
A was shown to permeate into hepatoma cells but not into a number of untransformed mammalian cell lines. In addition to accumulating in implanted tumors, the
99m
Tc-Ap
4
A in the 1984 study also accumulated in kidney, liver, bone, muscle, and lung. No accumulation of
99m
Tc-Ap
4
A in heart was observed in this study.
SUMMARY OF THE INVENTION
Radionuclide-labeled nucleotide polyphosphates accumulate with high specificity in atherosclerotic lesions and in heart tissue, and one embodiment of the invention generally features cardiovascular (which can include thrombi) imaging agents which include a radionuclide associated with a nucleotide polyphosphates, the latter being a targeting moiety.
In another embodiment, the invention provides a cardiovascular imaging agent that includes a radionuclide associated with a nucleotide polyphosphate targenting moiety. Typically, the targeting moiety is a residue of a targeting precursor; for example, a targeting precursor is reacted with a labeling entity which includes the radionuclide and a chelator for the radionuclide. The imaging agent is the reaction product which includes a residue of the targeting precursor and the chelator, in association with the radionuclide. The association may involve one or more of: chelation, co-valent bonding or electrostatic bonding, or it may involve other forces or combination of forces which maintains the nucleoside in spatial proximity to a targeting molecule. The imaging agent may be the reaction product of the above defined targeting precursor with a radionuclide-containing moiety, and such reaction may involve the formation of a chelate or a co-valent reaction product, or a product in which both chelation and co-valent bonds are involved. Typically, the targeting precursor is a molecule of the formula A), B), C), or D):
wherein,
(1) each of Nu
1
-Nu
4
is an independently selected nucleoside;
(2) p is selected from the group consisting of a phosphate moiety, a phosphorothioate moiety, an alkylphosphonate moiety, a phosphorodithioate moiety, a phosphoramidate moiety, an aminoalkylphosphoramidate moiety, an aminoalkylphophotriester moiety, an aminoalkylphosphorothioamidate moiety, and a thiophosphate moiety;
(3) each of X, X
1
, X
2
, and X
3
is selected from the group consisting of an alkyl group, a halogenated alkyl group, a nitrogen-containing alkyl group, a sulfur-containing alkyl group, an alkylene group, a halogenated alkylene group, a nitrogen-containing alkylene group, and a sulfur-containing alkylene group;
(4) (n
Babich John W.
Elmaleh David R.
Rapaport Eliezer
Zamecnik Paul C.
Foley, Hoag and Eliot, LLP
Jones Dameron L.
The General Hospital Corporation
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