Ternary ligand complexes useful as radiopharmaceuticals

Details Ternary ligand complexes useful as radiopharmaceuticals Ternary ligand complexes useful as radiopharmaceuticals

2001-04-05

2003-03-18

Jones, Dameron L. (Department: 1616)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

C424S001110, C424S001650, C424S001730, C534S014000, C568S017000

Reexamination Certificate

active

06534038

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel highly functionalized phosphine ligands as ancillary ligands in radiopharmaceuticals which are useful as imaging agents for the diagnosis of cardiovascular disorders such as thromboembolic disease or atherosclerosis, infectious disease and cancer and kits containing the same. The radiopharmaceuticals are comprised of highly functionalized phosphine ligated
99m
Tc-labeled biomolecules that selectively localize at sites of disease and thus allow an image to be obtained of the loci using gamma scintigraphy. The invention also provides methods of use of the radiopharmaceuticals as imaging agents for the diagnosis of cardiovascular disorders such as thromboembolic disease or atherosclerosis, infectious disease and cancer.
BACKGROUND OF THE INVENTION
Radiopharmaceuticals are drugs containing a radionuclide, and are used routinely in nuclear medicine department for the diagnosis or therapy of various diseases. They are mostly small organic or inorganic compounds with definite composition. They can also be macromolecules such as antibodies and antibody fragments that are not stoichiometrically labeled with a radionuclide. Radiopharmaceuticals form the chemical basis for nuclear medicine, a group of techniques used for diagnosis and therapy of various diseases. The in vivo diagnostic information is obtained by intravenous injection of the radiopharmaceutical and determining its biodistribution using a gamma camera. The biodistribution of the radiopharmaceutical depends on the physical and chemical properties of the radiopharmaceutical and can be used to obtain information about the presence, progression, and the state of disease.
Radiopharmaceuticals can be divided into two primary classes: those whose biodistribution is determined exclusively by their chemical and physical properties; and those whose ultimate distribution is determined by their receptor binding or other biological interactions. The latter class is often called target-specific radiopharmaceuticals.
In general, a target specific radiopharmaceutical can be divided into four parts: a targeting molecule, a linker, a Bifunctional Chelator (BFC), and a radionuclide. The targeting molecule serves as a vehicle, which carries the radionuclide to the receptor site at the diseased tissue. The targeting molecules can be macromolecules such as antibodies. They can also be small biomolecules (Q): peptides, peptidomimetics, and non-peptide receptor ligands. The choice of biomolecule depends upon the targeted disease or disease state. The radionuclide is the radiation source. The selection of radionuclide depends on the intended medical use (diagnostic or therapeutic) of the radiopharmaceutical. Between the targeting molecule and the radionuclide is the BFC, which binds strongly to the metal ion via several coordination bonds and is covalently attached to the targeting molecule either directly or through a linker. Selection of a BFC is largely determined by the nature and oxidation state of the metallic radionuclide. The linker can be a simple hydrocarbon chain or a long poly(ethylene glycol) (PEG), which is often used for modification of pharmacokinetics. Sometimes, a metabolizeable linker is used to increase the blood clearance and to reduce the background activity, thereby improving the target-to-background ratio.
The use of metallic radionuclides offers many opportunities for designing new radiopharmaceuticals by modifying the coordination environment around the metal with a variety of chelators. The coordination chemistry of the metallic radionuclide will determine the geometry of the metal chelate and the solution stability of the radiopharmaceutical. Different metallic radionuclides have different coodination chemistries, and require BFCs with different donor atoms and ligand frameworks. For “metal essential” radiopharmaceuticals, the biodistribution is exclusively determined by the physical properties of the metal chelate. For target-specific radiopharmaceuticals, the “metal tag” is not totally innocent because the target uptake and biodistribution will be affected by the metal chelate, the linker, and the targeting biomolecule. This is especially true for radiopharmaceuticals based on small molecules such as peptides due to the fact that in many cases the metal chelate contributes greatly to the overall size and molecular weight. Therefore, the design and selection of the BFC is very important for the development of a new radiopharmaceutical.
A BFC can be divided into three parts: a binding unit, a conjugation group, and a spacer (if necessary). An ideal BFC is that which is able to form a stable
99m
Tc complex in high yield at very low concentration of the BFC-Q conjugate. There are several requirements for an ideal BFC. First, the binding unit can selectively stabilize an intermediate or lower oxidation state of Tc so that the
99m
Tc complex is not subject to redox reactions; oxidation state changes are often accompanied by transchelation of
99m
Tc from a
99m
Tc-BFC-Ln-Q complex to the native chelating ligands in biological systems. Secondly, the BFC forms a
99m
Tc complex which has thermodynamic stability and kinetic inertness with respect to dissociation. Thirdly, the BFC forms a
99m
Tc complex with a minimum number of isomers since different isomeric forms of the
99
MTc-chelate may have significant impact on the biological characteristics of the
99m
Tc-BFC-Ln-Q complex. Finally, the conjugation group can be easily attached to the biomolecule.
In simple technetium complex radiopharmaceuticals such as
99m
Tc-sestamibi, [
99m
Tc(MIBI)
6
]
+
(MIBI=2-methoxy-2-methylpropyl-isonitrile) and
99m
Tc-bicisate, [
99m
TcO(ECD)] (ECD=l,l-ethylene dicycteine diethyl ester), the ligand (MIBI or ECD) is always present in large excess. The main factor influencing the
99m
Tc-labeling kinetics is the nature of the donor atoms and the radiolabeling conditions. For receptor-based target specific radiopharmaceuticals, however, the use of large amount of BFCA-Ln-Q may result in receptor site saturation, blocking the docking of the
99m
Tc-labeled BFC-Ln-Q, as well as unwanted side effects. In order to avoid these problems, the concentration of the BFC-Ln-Q in the radiopharmaceutical kit has to be very low (10
−6
-10
−5
M). Otherwise, a post-labeling purification is often needed to remove excess unlabeled BFC-Ln-Q, which is time consuming and thus not amenable for clinical use. Compared to the total technetium concentration (~5×10
−7
M) in 100 mCi of [
99m
Tc]pertechnetate (24 h prior-elution), the BFC-Ln-Q is not in overwhelmingly excess. Therefore, the BFC attached to the biomolecule must have very high radiolabeling efficiency in order to achieve high specific activity, the amount of unlabeled BFC-Ln-Q conjugate used to synthesize the radiopharmaceutical. Various BFCs have been used for the
99m
Tc-labeling of biomolecules, and have been extensively reviewed (Hom, R. K. and Katzenellenbogen, J. A.
Nucl. Med. Biol.
1997, 24, 485; Dewanjee, M. K.
Semin. Nucl. Med.
1990, 20, 5; Jurisson, et al
Chem. Rev.
1993, 93, 1137; Dilworth, J. R. and Parrott, S. J.
Chem. Soc. Rev.
1998, 27, 43; Liu, et al Bioconj.
Chem.
1997, 8, 621; Liu, et al
Pure
&
Appl. Chem.
1991, 63, 427; Griffiths, et al
Bioconj. Chem.
1992, 3, 91).
The use of hydrazines and hydrazides as BFCs to modify proteins for labeling with radionuclides has been recently disclosed in Schwartz et al U.S. Pat. No. 5,206,370. For labeling with technetium-99m, the hydrazino-modified protein is reacted with a reduced technetium species, formed by reacting [
99m
Tc]pertechnetate with a reducing agent in the presence of a chelating dioxygen ligand. The technetium is bonded through what are believed to be hydrazino or diazenido linkages with the coordination sphere completed by the coligands such as glucoheptonate and lactate. Bridger et al European Patent Application No. 93302712.0 discloses a series of functionalized aminocarboxyl

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