Chlorin and bacteriochlorin-based aminophenyl DTPA and N2S2...

Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent

Reexamination Certificate

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C424S009600, C540S145000, C534S014000

Reexamination Certificate

active

06534040

ABSTRACT:

BACKGROUND OF THE INVENTION
Cancer is the second most common cause of death in the United States, accounting for 20% of all deaths. Until now, medicine has tried to overwhelm the cancer cell with brute force, slicing it out with surgery, zapping it with radiation, or poisoning it with chemotherapy. All too often, however, a few cells survive the onslaught and germinate, sometimes years later, into tumors that are impervious to treatment. If tumors can be diagnosed at early stages, it will certainly increase the survival rate of the cancer patients. Therefore, efforts are currently underway in our and various other laboratories to develop efficient tumor diagnostic imaging agents.
For many years, in vivo imaging of human anatomy was dependent upon the intravenous administration of radioactive atoms (nuclear medicine) or non-radioactive iodinated contrast media (various x-ray tests and computed tomography). However, over the last decade magnetic resonance imaging (MRI) has assumed a critical role in imaging, and, unlike x-rays or computed tomography, MR uses contrast media that contain paramagnetic ions, particularly Gadolinium [Gd(III)]. Paramagnetic ions are not themselves “seen” by the MR scanner. Rather, they affect the water in body tissue so as to increase the “signal” emitted by tissue when it is placed in a magnetic field.
By and large, MR contrast media have been neither disease-specific nor organ-specific. Injected intravenously, most are rapidly excreted by the kidneys by glomerular filtration. Although several liver-specific contrast media have been created, other organs have not been successfully targeted, and no tumor-avid MR contrast agents are available to date.
Because of the importance of detection of unknown primary tumor and metastatic disease in diagnostic oncology imaging, a tumor-avid MR contrast medium would have high implications for prognosis, therapy selection, and patient outcomes. The entire issue of cure versus palliation would be impacted.
In recent years several reports focused on certain Gd-based macrocycles as potential magnetic resonance imaging agents (e.g. Z. D. Grossman and S. F. Rosebrough, Clinical Radioimmunoimaging, Grune & Stratton Inc., 1988, incorporated herein by reference as background art) and
99m
Tc or
111
In chelated compounds as radiopharmaceuticals (e.g. H. D. Burns, R. F. Gibson, R. F. Dannals and P. K. S. Siegel (Eds.); Nuclear imaging in Drug Discovery, Development and Approval, Birkhauser, 1993, and G. B. Saha, Fundamentals of Nuclear Pharmacy, Springer-Verlag, 1 992, incorporated herein by reference as background art).
Since the approval of [Gd(DTPA)(H
2
O)]
2
in 1988, more than 30 metric tons of Gadolinium have been administered to millions of patients worldwide. Approximately 30% of MRI exams include contrast agents, and this percentage is projected to increase as new agents and applications appear. Gadolinium is also finding a place in medical research. Over 600 references to Gadolinium appear each year in the basic science literature. While other types of MRI contrast agents, namely an iron-particle-based agent and a manganese (II) chelate have been approved, Gd(III) remains the dominant material. The reasons for this include the direction of MRI development and the nature of Gd chelates. The signal intensity in MRI stems largely from the local value of the longitudinal relaxation rate of water protons, 1/T
1
, and the transverse rate 1/T
2
. Signal tends to increase with increasing 1/T
1
and decrease with increasing 1/T
2
. Pulse sequences that emphasize changes in 1/T
1
, are referred to as 1/
T1
-weighed, and the opposite is true for T
2
-weighed scans. Contrast agents increase both 1/T
1
and 1/T
2
to varying degrees, depending on their nature as well as the applied magnetic field. Agents such as Gadolinium (III) that increases 1/T
1
and 1/T
2
by roughly similar amounts are best visualized using T
1
-weighted images, because the percentage change in 1 /T
1
in tissue is much greater than that in 1/T
2
. The longitudinal and transverse relaxivity values r
1
and r
2
refer to the increase in 1/T
1
and 1/T
2
, respectively, per millimole of agent. T
1
agents usually have r
2
/r
1
ratios of 1-2, whereas that value for T
2
agents, such as iron oxide particles, is as high as 10 or more. Advances in MRI have strongly favored T
1
agents and thus Gadolinium (III). Faster scans with higher resolution require more rapid radio frequency pulsing and are thus generally T
1
-weighed, since the MR signal in each voxel becomes saturated. T
1
agents relieve this saturation by restoring a good part of the longitudinal magnetization between pulses. At the same time a good T
1
agent would not significantly affect the bulk magnetic susceptibility of the tissue compartment in which it is localized, thus minimizing any inhomogeneities which can lead to image artifacts and/or decreased signal intensity.
The other important and interesting characteristic of Gadolinium (III) chelates is their stability. They remain chelated in the body and are excreted intact. For example, the off-the shelf ligands like DTPA form complexes so stable that while the agent is in vivo, there is no detectable dissociation. Owing to their large size, lanthanides tend to favor high coordination number in aqueous media. Currently, all Gd(III)-based chelates approved for use in MRI are nine-coordinate complexes in which the ligand occupies eight binding sites at the metal center and the ninth coordinate site is occupies by a solvent water molecule.
Radiopharmaceuticals are drugs containing a radionuclide and are used routinely in nuclear medicine department for the diagnosis or therapy. Radiopharmaceuticals can be divided into two primary classes: Those whose biodistribution is determined exclusively by their chemical and physical properties (like iodine-131) and those whose ultimate distribution is determined by their biological interactions (like a radiolabeled antibody). The latter class includes more target-specific radiopharmaceuticals. A target-specific radiopharmaceutical consists of four parts: a targeting molecule, a linker, a chelating ligand and a radionuclide. The targeting molecule serves as the vehicle, which carries the radionucleide to the target site in diseased tissue. The radionuclide is the radiation source.
Metallic radionuclides offer many opportunities for designing new radiopharmaceuticals by modifying the coordination environment around the metal with a variety of chelators. Most of the radiopharmaceuticals used in conventional nuclear medicine are
99m
Tc labeled, because of its short half-life (6 hours) and ideal gamma emission (140 KeV). Millicurie quantities can be delivered without excessive radiation to the patient. The monoenergetic 140-KeV photons are readily collimated, producing images of superior spatial resolution. Furthermore,
99m
TC is readily available in a sterile, pyogen-free, and carrier-free state from
99
MO-
99m
TC generators. Its 6 h half-life is sufficiently long to synthesize the labeled radiopharmaceuticals, assay for purity, inject the patient, image, and yet short enough to minimize radiation dose. Another radionuclide successfully used is
111
In. The success of the pharmaceutical IN-DTPA-Octreotide (OCTREOSCAN), used for diagnosis of somatostatin receptor-positive tumors, has intensified the search for new target-specific radiopharmaceuticals. Compared to
99m
Tc, the half-life of
111
In is much longer (72 hours).
Certain porphyrins and related tetrapyrrolic compounds tend to localize in malignant tumors and other hyperproliferative tissue, such as hyperproliferative blood vessels, at much higher concentrations than in normal tissues, so they are useful as a tool for the treatment of various type of cancers and other hyperproliferative tissue by photodynamic therapy (PDT) (T. J. Dougherty, C. J. Gomer, B. W. Henderson, G. Jori, D. Kessel, M. Kprbelik, J. Moan, Q. Peng,
J. Natl. Cancer Inst
., 1998, 90, 889 incorporated here by reference as background art). However, most of th

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