Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Reexamination Certificate
2001-07-03
2002-07-09
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
C558S169000, C424S009370
Reexamination Certificate
active
06417384
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the field of radiopharmaceuticals and biological probes, and more specifically to radiolabelled analogs of phospholipid ethers useful in cancer diagnosis and treatment.
BACKGROUND OF THE INVENTION
The early detection of cancer has been one of the primary goals of modern imaging technology, since the identification of a suspected tumor in a localized stage significantly improves the chances for successful treatment and elimination of the cancerous tissue. A large number of imaging strategies have therefore been designed, using a variety of techniques and modalities, to aid the physician in making an accurate diagnosis as early as possible.
Unfortunately, conventional imaging techniques such as computerized tomography (CT) and MRI (magnetic resonance imaging) are limited m their ability to afford a conclusive diagnosis of a suspected lesion, since they are only capable of observing differences in the density or morphology of tissues. A more invasive and costly biopsy procedure is often necessary to provide a definitive diagnosis. In contrast, nuclear medicine techniques such as positron emission tomography (PET) and single photon emission tomography (SPECT) can provide functional or biochemical information about a particular organ or area of interest. However, the success of these nuclear imaging techniques depends in large part on the selective uptake and detection of appropriate radiopharmaceuticals. Selective uptake, in turn, depends upon the development of radiopharmaceuticals with a high degree of specificity for the target tissue. Unfortunately, the tumor-localizing agents developed thus far for oncological applications have had only limited application.
For example, one of these prior art compounds,
67
Ga gallium citrate, was originally identified for its ability to accumulate in tumor tissue. Unfortunately,
67
Ga gallium citrate is taken up by a variety of other non-tumorous lesions as well, including inflammatory lesions, and unacceptable amounts of radioactivity can also accumulate in liver and spleen tissue. The rapid buildup of a radiopharmaceutical in these organs can seriously interfere with the imaging of nearby lesions and also negatively impacts the dosage that can safely be given to a patient.
An alternative approach has been to develop radiolabelled monoclonal antibodies (Mabs) directed to tumor-specific antigens. However, these monoclonal antibodies are specific only to the particular tumor tissue for which they have been produced, and therefore will not localize generally in neoplastic tissue. Moreover, the use of Mabs for diagnostic imaging has lead to additional problems, including varying degrees of antigen expression, low tumor uptake, non-specific binding and adverse immunogenic reactions.
In an attempt to address these problems, the present inventors have recently identified and developed a series of novel compounds demonstrating useful tumor specificity. See, e.g., U.S. Pat. Nos. 4,925,649; 4,965,391; 5,087,721; and 5,347,030; all of which are herein incorporated by reference. It is believed that these radioiodinated phospholipid ether analogs take advantage of a unique biochemical characteristic of malignant tumor cells; i.e. the large concentration of naturally-occurring ether lipids in the cell membranes relative to corresponding normal tissues. Although the precise mechanism of action is not fully understood, the prevailing hypothesis is that the phospholipid ether analogs become entrapped in tumor membranes. Accordingly, these compounds localize in tumor tissue and remain in place for diagnostic and/or therapeutic applications.
The selective retention of the radiolabelled phospholipid ether analogs described in the above patents has been demonstrated in a variety of rodent and animal tumors. Unfortunately, the data obtained from these studies has also demonstrated a relatively rapid clearance of the radiopharmaceutical compound from the blood, and an undesirable accumulation by non-target tissues. As noted above, non-target tissue uptake can decrease the efficacy of radiodiagnostic imaging by creating high background activity, or by causing excessive exposure of radiosensitive tissues to the injected radioactivity.
Accordingly, there remains a significant need in the art for radiopharmaceuticals which exhibit a rapid clearance from non-target tissues as well as an extended half-life in the blood plasma, while still retaining its specificity and avidity for neoplastic tissue. Such an agent should not only assist in the non-invasive imaging of primary tumors and metastases, but should also provide a potential cytotoxic agent for site-specific eradication of the tumor tissue.
SUMMARY OF THE INVENTION
The present invention solves the problems present in the prior art through the provision of improved radiolabelled phospholipid ether analogs of naturally-occurring phospholipid ether compounds, having the general Formula I:
where X is a radioactive isotope and n is an integer between 16 and 30. In a preferred embodiment of the present invention, X is a radioactive isotope of iodine, preferably selected from the group comprising
123
I,
125
I, and
131
I. It is further contemplated that X can be substituted at the ortho, meta or para position on the aromatic ring. In a preferred embodiment, the radioactive isotope is substituted at the para position.
Y is selected from the group comprising H, OH, COOH,
and OR, and Z is selected from the group comprising NH
2
, NR
2
, and NR
3
, wherein R is an alkyl or aralkyl substituent.
In accordance with a specific illustrative embodiment of the invention, the improved compound is 1-O-[18-(p-iodophenyl)octadecyl]-1,3-propanediol-3-phosphocholine.
In accordance with another specific illustrative embodiment, the improved compound is 1-O-[18-(p-Iodophenyl)octadecyl]-2-O-methyl-rac-glycero-3-phosphocholine:
In a further embodiment of the invention, the radiolabelled aralkyl side chain may be substituted directly onto the alkyl phosphocholine moiety in accordance with general Formula II:
where X is a radioactive isotope substituted at the ortho, meta or para position, preferably of iodine, n is an integer from 16 to 30, and Y is selected from the group comprising NH
2
, NR
2
and NR
3
, wherein R is an alkyl or aralkyl substituent.
In accordance with a specific illustrative embodiment of the invention, the improved compound is 18-(p-iodophenyl)octadecyl phosphocholine.
REFERENCES:
patent: 4925649 (1990-05-01), Counsell et al.
patent: 4965391 (1990-10-01), Counsell et al.
patent: 5087721 (1992-02-01), Counsell et al.
patent: 5347030 (1994-09-01), Counsell et al.
Akiyama et al., “AlCl,-N,N-dimethylamiline: A Novel Benzyl and Allyl Ether Cleavage Reagent,”Bull. Chem. Soc., Jpn.65:1932-1938 (1992).
Fouquent and Schlosser, “Improved Carbon-Carbon Linking by Controlled Copper Catalysis,”Agnew. Chem. Int. Ed.13:82-83 (1974).
Kotting et al., “Alkylphosphocholines; Influence of Structural Variation on Biodistribution at antineoplastically Active Concentrations,”Cancer Chemother. Pharm.30:105-112 (1992).
Pienta et al., Inhibition of Spontaneous Metastasis in a Rat Prostrate Cancer Model by Oral Administration of Modified Citrus Pectin,J. Natl. Cancer Inst.87:348-353 (1995).
Rampy et al., “Synthesis and Biological Evaluation of Radio-Iodinated Phospholipid Ether Analogs,”Nucl. Med. Biol.22:505-512 (1992).
Schlosser and Bossert, “The ‘Two-Fold Reaction’ Benchmark Applied to the Copper Catalyzed Assembling of 1,&ohgr;-difunctional Hydrocarbon Chains,”Tetrahedron47:6287-6292 (1991).
Tayck et al., Influence of the Walker 256 Carcinosarcoma on Muscle, Tumor, and Whole-Body Protein Synthesis and Growth Rate in the Cancer-Bearing Rat,Cancer Res.46:5649-5654 (1986).
Weichert et al., “Radioiodination Via Isotope Exchange in Pivalic Acid,”Appl. Radiat. Isot.37:907-913 (1986).
Choyke, “Imaging of prostate cancer,” Abdom Imaging 20:505-515 (1995).
Lohmeyer and Bittman, “Antitumor ether lipids and alklphosphocholines,” Drugs of the Future, 19(11):1
Counsell Raymond E.
Longino Marc A.
Pinchuk Anatoly N.
Rampy Mark A.
Weichert Jamey P.
Higel Floyd D.
Medlen & Carroll LLP
Shameem Golam M. M.
The Regents of the University of Michigan
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