Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – X-ray contrast imaging agent
Reexamination Certificate
1999-04-02
2003-02-25
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
X-ray contrast imaging agent
C424S001110, C424S001650, C424S001690, C424S009100, C534S010000, C534S014000
Reexamination Certificate
active
06524554
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides novel radiopharmaceuticals useful for the diagnosis of infection, inflammation, and cancer, reagents and kits useful for preparing the radiopharmaceuticals, methods of imaging sites of infection and/or inflammation, and cancer in a patient, and methods of diagnosing cancer and diseases associated with infection or inflammation in patients in need of such diagnosis. The present invention also provides novel readiopharmaceuticals for treating cancer. The radiopharmaceuticals bind in vivo to the tuftsin receptor on the surface of neutrophils and monocytes which accumulate at the site of infection, inflammation, and in tumors.
BACKGROUND OF THE INVENTION
The rapid diagnosis of diseases associated with focal infection and inflammation is a currently unmet clinical need. Inflammation is the result of the detection of an abnormality in the body, such as infection, or a tumor, by white blood cells, including neutrophils and monocytes. White cells become activated and gravitate toward the site of the abnormality. When the white cells become fully activated they degranulate and release proteolytic enzymes as well as chemoattractants resulting in a chemotactic gradient and as a consequence the recruitment of additional white cells. The result is a concentration of activated white cells at the site. This localization provides a means for diagnosing diseases associated with infection and inflammation and cancer through the use of white cells labeled with an externally detectable radioisotope and gamma scintigraphy.
Two approaches have been taken to utilize this mechanism for imaging infection and inflammation. The first involves isolating white cells from a patient, labeling the white cells with a radioisotope and then reinjecting the radiolabeled autologous white cells into the patient. This approach has several drawbacks including the effect of the labeling methodology on the biological activity of the white cells manifest as a diminished number of competent white cells, and the hazards and inconvenience of handling the patient's blood. The second approach involves injecting into the patient a radiopharmaceutical that binds to activated white cells in vivo.
An example of the in vivo labeling approach is the use of radiolabeled monoclonal antibodies or fragments thereof that are directed against a white cell activation marker, as described in Morgan, Jr., U.S. Pat. No. 5,376,356. A white cell activation marker is an antigen on the surface of the white cell that is poorly expressed or not expressed at all until activation of the white cell. This approach suffers from the disadvantages associated wit h the use of many proteinaceous radiopharmaceuticals as diagnostics, namely, generally slow blood clearance which results in high background activity unless an inconveniently long period of time is allowed to pass between injection and imaging, and the possibility of an allergic reaction by the patient to a foreign protein.
It has been proposed that these problems can be overcome by using radiolabeled peptides that bind in vivo to surface receptors on activated white cells (Fischman et. al., Semin. Nucl. Med., 1994, 24, pp 154-168). The chemotactic peptide, fMLF, labeled with In111 or Tc-99m have been shown to accumulate at sites of infection in experimental animal models. However, the peptide fMLF is a potent agonist for the white cells and thus has limited clinical applicability in a diagnostic radiopharmaceutical. The limitations include the potential for serious deleterious effects to the patient, such as a severe drop in white blood cell count, resulting from the activation of the white cells upon injection of even small amounts of the potent agonist peptide.
An alternative approach based on the use of radiolabeled tuftsin receptor antagonists has been disclosed by Pollak, A., U.S. Pat. Nos. 5,480,970, 5,659,041, 5,662,885, and Goodbody, A., U.S. Pat. Nos. 5,569,745, and 5,679,642. These patents disclose the use of Tc-99m chelate conjugates of the tuftsin receptor antagonist Thr-Lys-Pro-Pro-Arg for imaging infection and inflammation. The chelators are diamidedithiols (N
2
S
2
) and triamidethiols (N
3
S). The chelator may optionally be attached to the tuftsin antagonist via a linking group. The chelators disclosed do not generally form Tc-99m complexes with high labeling efficiency; that is moderate-to-high concentrations of the antagonist-chelator conjugates are required to obtain high yields of the Tc-99m complexes under clinically practical conditions.
Co-pending U.S. Ser. No. 08/415,908, and U.S. Ser. No. 08/808,699, describe ternary ligand complexes of Tc-99m comprised of hydrazine modified peptides and two ancillary ligands. The peptides described bind to a variety of antigens including the GPIIb/IIIa receptor on activated platelets and the chemotactic peptide receptor on white cells. The Tc-99m complexes comprised of GPIIb/IIIa receptor antagonists are useful for imaging platelet deposition, such as thrombosis, and the Tc-99m complexes comprised of chemotactic peptide receptor agonists and antagonists are useful for imaging infection and inflammation. Co-pending U.S. Ser. No. 08/476,296 describes the stable hydrazone modified peptides as reagents for synthesizing these ternary ligand Tc-99m complexes.
It is the object of the present invention to provide novel radiopharmaceuticals for imaging infection and inflammation comprised of tuftsin receptor antagonists linked to hydrazine or stable hydrazone bonding units for Tc-99m. This invention also provides a novel means of imaging tumors using these radiopharmaceuticals. This invention further provides a novel means of treating tumors in a patient by administering radiopharmaceuticals of the present invention comprised of a beta-emitting isotope of rhenium.
SUMMARY OF THE INVENTION
The present invention provides novel radiopharmaceuticals useful for the diagnosis of infection and inflammation, reagents and kits useful for preparing the radiopharmaceuticals, methods of imaging sites of infection and/or inflammation in a patient, and methods of diagnosing diseases associated with infection or inflammation in patients in need of such diagnosis.
The radiopharmaceuticals bind in vivo to the tuftsin receptor on the surface of white cells which accumulate at the site of infection and inflammation.
The radiopharmaceuticals of the present invention are comprised of one to three pentapeptides, X
1
X
2
X
3
X
4
X
5
, independently attached to a metal chelator or bonding moiety, C
h
, to which is attached a Tc-99m, Re-186, or Re-188, optionally further comprising a linking group, L
n
, between the peptides and the chelator or bonding moiety. The peptides are comprised of a pentapeptide sequence that binds to the tuftsin receptor attached at the N-terminus to L
n
or C
h
. The interaction of the pentapeptide recognition sequences of the radiopharmaceuticals with the tuftsin receptor on white blood cells results in localization of the radiopharmaceuticals in sites of infection and inflammation, and in tumors.
DETAILED DESCRIPTION OF THE INVENTION
[1] Thus, in a first embodiment, the present invention provides a novel compound capable of direct transformation into a radiopharmaceutical, the compound having the formula:
C
h
—L
n
—(X
1
X
2
X
3
X
4
X
5
)
d
,
wherein:
X
1
is an amino acid independently selected from the group: threonine, serine, 3-hydroxyproline, and 4-hydroxyproline;
X
2
is an amino acid independently selected from the group: lysine, ornithine, arginine, 2-aminoethylcysteine, and glutamine;
X
3
and X
4
are amino acids independently selected at each occurrence from the group: proline, and homoproline;
X
5
is an amino acid independently selected from the group: lysine, ornithine, arginine, glutamine, and 2-amino-5-(2-imidazolin-2-ylamino)pentanoic acid;
d is selected from 1, 2, and 3;
L
n
is a linking group having the formula:
(CR
6
R
7
)
g
—(W)
h
—(CR
6a
R
7a
)
g′
—(W)
h′
—(CR
8
R
9
)
g″
—(W)
h″
—(CR
8a
R
9a
)
g′″
—(W
Edwards David Scott
Rajopadhye Milind
Bristol-Myers Squibb Pharma Company
Golian Paul D.
Jones Dameron L.
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