Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1998-03-06
2001-12-18
Jones, Dameron L. (Department: 1623)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001810, C424S001850, C424S001650, C424S001730, C424S009400, C536S028400
Reexamination Certificate
active
06331287
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the fields of biochemistry and medicine. More particularly, the present invention relates to compositions for use in imaging cancer or infectious disease.
BACKGROUND OF THE INVENTION
Imaging of cellular proliferation in vivo using radiolabeled analogues of nucleosides such as [
131
I]-IUdR and [
11
C]-thymidine is plagued by extensive catabolism of the parent compounds following intravenous administration, limiting uptake into the DNA of tumor tissues. Such catabolic events include dehalogenation, cleavage of the sugar moieties from the base, and ring opening of the base. In vivo assessment of such events requires complex mathematical models to interpret kinetic data obtained in imaging studies.
Mathematical models currently being designed to interpret positron emission tomography (PET) kinetic data obtained from [
11
C] thymidine studies in tumors are generally cumbersome, in large measure due to the presence of significant levels of short-term catabolism of thymidine with subsequent production of several radiolabeled byproducts in plasma and tissue {Martiat, P. H., et al., “In vivo measurement of carbon-11 thymidine uptake in non-Hodgkin's lymphoma using positron emission tomography”,
J. Nucl. Med.,
29:1633-1637 (1988); Shields, A. F., et al., “Short-term thymidine uptake in normal and neoplastic tissues: Studies for PET,”
J. Nucl. Med
., 25:759-764 (1984); Shields, A. F., et al., “Cellular sources of thymidine nucleotides: Studies for PET”,
J. Nucl. Med
. 28:1435-1440 (1987); Wong, C.Y.O., et al., “[
11
C]-Thymidine PET imaging as a measure of DNA synthesis rate: A preliminary quantitative study of human brain glioblastoma”,
J. Nucl. Med
., 35:9P (1994); Mankoff, D. A., et al., “Graphical analysis method for estimating blood-to-tissue transfer constants for tracers with labeled metabolites”,
J. Nucl. Med
., 35:34P (1994a); Mankoff, D. A., et al., “Tracer kinetic model to quantitative imaging of thymidine utilization using [
11
C]-thymidine and PET”,
J. Nucl. Med
. 35, 138P (1994b)}. Though potentially less complex, modeling of the kinetic behavior of ring labeled thymidine is likewise non-trivial {Shields A. F., et al., “Use of [
11
C]-thymidine with PET and kinetic modeling to produce images of DNA synthesis”,
J. Nucl. Med
., 33:1009-1010 (1992); Mankoff, D. A., et al. (1994a, b), supra}. In the case of imaging studies with radioiodinated IUdR using conventional nuclear medicine techniques, in addition to significant dehalogenation it has also been demonstrated that UdR, once formed, may be converted to TdR in mammalian systems and subsequently incorporated into DNA {Commerford, S. L., et al., “lododeoxyuridine administered to mice is de-iodinated and incorporated into DNA primarily as thymidylate”,
Biochem. Biophys. Res. Comm
., 86:112-118 (1979)}.
The short-term catabolism of [
11
C and
14
C-methyl]-thymidine have been extensively studied {Conti, P. S., et al., “Tumor imaging with positron-emission tomography (PET) and [
11
C]-thymidine: Determination of radiolabeled thymidine metabolites by high pressure liquid chromatography (HPLC) for kinetic data analysis”,
Radiology
, 173:P402 (1989); Conti, P. S., et al., “Analysis of nucleoside metabolism during positron emission tomography (PET) imaging studies of brain tumors with carbon-11 labeled thymidine (TdR)”, 199
th Meeting of American Chemical Society
, Boston, Mass., Apr. 22-27 (1990)}. Such studies have demonstrated that significant catabolism occurs once thymidine has been administered intravenously, with the notable radiolabeled products being thymine, dihydrothymine, beta-ureidoisobutyric acid, and beta-aminoisobutyric acid. The latter constitutes the most abundant radiolabeled species in plasma and tissues by 10 minutes post-injection. While [
11
C]-CO
2
is the most abundant radiolabeled species in plasma following administration of ring labeled thymidine {Shields, A. F., et al., “Comparison of PET imaging using [
11
C]-thymidine labeled in the ring-2 and methyl positions”,
J. Nucl. Med
., 31:794 (1990); Shields A. F., et al., “Contribution of labeled carbon dioxide to PET imaging of [
11
C]-labeled compounds”,
J. Nucl. Med
., 31:909 (1990)}, radiolabeled thymine, dihydrothymine, and beta-ureidoisobutyric acid also are present, albeit in lesser amounts. Despite its extensive catabolism, it has been demonstrated that [
11
C]-thymidine has utility in tumor imaging in both animal models and patients {Larson, S. M., et al., “Positron imaging feasibility studies. I: Characteristics of [
3
H]-thymidine uptake in rodent and canine neoplasms: Concise Communication”,
J. Nucl. Med
., 22:869-874 (1981); Conti, P. S., et al., “Potential use of carbon-11 labeled thymidine (TdR) for studying the effect of therapy on prostatic adenocarcinoma in vivo”, 32
nd Annual Meeting of the Radiation Research Society
, Orlando, Fla., Mar. 25-29 (1984); Conti, P. S., et al., “Comparative uptake studies of radiolabeled thymidine in the Dunning R3327H fast-growing and R3327H slow-growing prostate adenocarcinomas in vivo”, 79
th Meeting of the American Urological Association
, New Orleans, La., May 6-10 (1984); Conti, P. S., et al., “Carbon-11 labeled alpha-aminoisobutyric acid, 2-deoxy-D-glucose and thymidine as potential imaging agents for prostatic and renal malignancies”,
Surgical Forum
, 36:635-637 1985); Conti, P. S., et al., “Multiple radiotracers for evaluation of intracranial mass lesions using PET”,
J. Nucl. Med
., 32:954 (1991); Shields, A. F., et al.(1984, 1987, 1990b, c), supra; Shields A. F., et al., “Utilization of labeled thymidine in DNA synthesis: Studies for PET”,
J. Nucl. Med
., 31:337-342 (1990); Martiat, P. J., et al. (1988), supra; Strauss, L. G. et al., “The applications of PET in clinical oncology”,.
J. Nucl. Med
., 32:623-648 (1991); Schmall B., et al, “Tumor and organ biochemical profiles determined in vivo following uptake of a combination of radiolabeled substrates: Potential applications for PET”,
Amer. J. Phys. Imag
., 7:2-11 (1992); Wong, C.Y.O., et al. (1994), supra; Vander Borght T., et al., “Brain tumor imaging with PET and 2-[
11
C]-thymidine”,
J. Nucl. Med
., 35:974-982 (1994)}.
There is thus a long-felt need in the art for a suitable partially or non-catabolized imaging agent (e.g., nucleoside analog) for use in, e.g., tumor proliferation studies with PET. Except for limited catabolism, an ideal tracer should share the other in vivo characteristics of thymidine, including cell transport, phosphorylation by mammalian kinase, and incorporation into DNA. In particular, development of a partially or non-catabolized thymidine analog would greatly simplify imaging and modeling approaches and potentially provide higher tumor to target ratios due to more selective incorporation of radiotracer.
It is an object of the present invention to provide compositions and methods which do not suffer from the drawbacks of the heretofore-known compositions.
SUMMARY OF THE INVENTION
The present invention is directed to compositions and methods that can be used for in vivo imaging of proliferating cells. The composition includes an imaging agent, which is a 2′-deoxy-2′-fluoro-D-arabinofuranosyl pyrimidine nucleoside analog, and a physiologically acceptable carrier or adjuvant. The imaging agent is labeled with a positron emitting radioisotope, such as [
11
C] or [
18
F]. A unit dose of imaging agent is a non-toxic amount of the 2′-deoxy-2′-fluoro-D-arabinofuranosyl pyrimidine nucleoside analog, which is capable of localizing in proliferating cells and being detected in vivo.
The method of imaging proliferating cells in vivo includes the steps of administering a unit dose of the imaging agent, which has been labeled with a positron emitting radioisotope like [
11
C] or [
18
F]. The imagin
Alauddin Mian M.
Conti Peter S.
Fissekis John D.
Fulbright & Jaworski L.L.P.
Jones Dameron L.
University Advanced Bio-Imaging Associates
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