Tumor imaging agents, methods and kits

Details Tumor imaging agents, methods and kits Tumor imaging agents, methods and kits

1997-05-01

2001-02-13

Jones, Dameron (Department: 1616)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001110, C424S001650, C536S027600, C536S027700

Reexamination Certificate

active

06187286

ABSTRACT:

The present invention is in the field of nuclear medicine. More specifically, the invention relates to diagnostic imaging of tumors.
BACKGROUND OF THE INVENTION
Clinical imaging technology plays a significant role in diagnosis of injuries and disease processes. Many parts of the human body can now be examined for diagnostic purposes using a variety of imaging techniques. Radiography has long been used to image body parts through which externally generated x-rays are transmitted. Computerized axial tomography (CAT) provides cross-sectional x-ray images of a plane of the body. Specific tissues or organs may be targeted in positron emission tomography (PET), single photon emission computed tomography (SPECT), and gamma scintigraphy. In PET, SPECT, and gamma scintigraphy, radiopharmaceutical agents capable of being sequestered (concentrated) to some degree in the target tissue or organ are internally administered to the patient, and images are generated by detecting the radioactive emissions from the concentrated radiopharmaceutical agent. Some of the radiopharmaceutical agents currently used for imaging include nuclides such as
201
Tl,
99m
Tc,
133
Xe, and the like; chelates of nuclides; radiolabeled metabolic agents such as
11
C-deoxy-D-glucose,
18
F-2-fluorodeoxy-D-glucose, [1-
11
C]- and [
123
I]-&bgr;-methyl fatty acid analogs,
13
N-ammonia, and the like; infarct avid agents such as
99m
Tc-tetracycline,
99m
Tc-pyrophosphate,
203
Hg-mercurials,
67
Ga-citrate, and the like; and radiolabeled ligands, proteins, peptides, and monoclonal antibodies. Whole cells such as erythrocytes, platelets, leukocytes, and other cells may also be labeled with a radionuclide and function as radiopharmaceutical agents.
The amount and type of clinical information that can be derived from PET, SPECT, and gamma scintigraphic images is related in part to the ability to concentrate the radiopharmaceutical agent in the target tissue or organ. Although many radiopharmaceuticals are available for clinical use, the resolution of the image generated may be limited depending on various factors. The resolution of a particular imaging agent for imaging diseased or injured tissue depends in part on the affinity of the radiopharmaceutical for the site of injury or disease as compared to its affinity for surrounding healthy tissue.
Radiopharmaceuticals are used to diagnose and treat tumors.
D. R. Elmaleh, et al. (1984)
Proc. Natl. Acad. Sci. USA
81, 918-921 discloses
99m
Tc-labeled Ap
4
A (
99m
Tc-Ap
4
A) used to image tumors implanted into rats. The method used to chelate the
99m
Tc to the Ap
4
A in this study yielded a mixture, in which
99m
Tc was attached to the Ap
4
A-dinucleotide and which also may have contained unchelated
99m
Tc. This study was based on the premise that some human tumor cells are permeable to exogenous ATP and ADP, and that these cells incorporate the intact nucleotides in intracellular pools, in contrast to normal cells. Ap
4
A was shown to permeate into hepatoma cells but not into a number of untransformed mammalian cell lines. In addition to accumulating in implanted tumors, the
99m
Tc-Ap
4
A in the 1984 study also accumulated in kidney, liver, bone, muscle, and lung.
SUMMARY OF THE INVENTION
Radionuclide-labeled nucleotide polyphosphates accumulate with high specificity in tumors, and one embodiment of the invention generally features tumor imaging agents which include a radionuclide associated with a nucleotide polyphosphates, the latter being a targeting moiety. The imaging agent has an improved ratio of targeted to untargeted radioactivity, as a result of the use of a co-eluant such a mannitol.
In another embodiment, the invention provides a tumor imaging agent that includes a radionuclide associated with a nucleotide polyphosphate targeting moiety. The imaging agent typically is eluted with an eluant as described herein, and the formulation of the agent may include traces of that agent.
Typically, the targeting moiety is a residue of a targeting precursor; for example, a targeting precursor is reacted with a labeling entity which includes the radionuclide and a chelator for the radionuclide. The imaging agent is the reaction product which includes a residue of the targeting precursor and the chelator, in association with the radionuclide. The association may involve one or more of: chelation, co-valent bonding or electrostatic bonding, or it may involve other forces or combination of forces which maintains the nucleoside in spatial proximity to a targeting molecule. The imaging agent may be the reaction product of the above defined targeting precursor with a radionuclide-containing moiety, and such reaction may involve the formation of a chelate or a co-valent reaction product, or a product in which both chelation and co-valent bonds are involved. Typically, the targeting precursor is a molecule of the formula A) or formula B), or dimers or trimers thereof such as the molecules of formulas C), or D):
A) Nu
1
-(p)
n
-X
B) Nu
1
-(p)
n
-X-(p)
m
-Nu
2
 wherein,
(1) each of Nu
1
-Nu
4
is an independently selected nucleoside;
(2) p is selected from the group consisting of a phosphate moiety, a phosphorothioate moiety, an alkylphosphonate moiety, a phosphorodithioate moiety, a phosphoramidate moiety, an aminoalkylphosphoramidate moiety, an aminoalkylphophotriester moiety, an aminoalkylphosphorothioamidate moiety, and a thiophosphate moiety;
(3) each of X, X
1
, X
2
, and X
3
is selected from the group consisting of an alkyl group, a halogenated alkyl group, a nitrogen-containing alkyl group, a sulfur-containing alkyl group, an alkylene group, a halogenated alkylene group, a nitrogen-containing alkylene group, and a sulfur-containing alkylene group;
(4) (n+m) is from 2 to 8;and (r+q) is from 2 to 8.
Other agents (or residues of them reacted with the targeting moiety) to promote chelation or bonding may be present in the imaging agent.
In a preferred formula according to B), X is not optional, and Nu, and Nu
2
are the same and are adenosine, guanine, cytidine, thymidine, uracil, or inosine. Preferably, at least one of Nu
1
-N
4
(most preferably each of Nu
1-Nu
4
) is adenosine. The preferred moieties for X (when it is present) are alkyl moieties or chloroalkyl moieties, and p is preferably a phosphate moiety. When X is not present, the radionuclide-containing structure may be chelated via an oxygen atom of the phosphates(). Preferably, the nucleoside is adenosine, p is a phosphate, n=2, and m=2.
The radionuclide (Z) which is ultimately associated or complexed with the targeting precursor may be
123
I,
99m
Tc,
18
F,
68
Ga,
62
Cu, and
111
In, although
99m
Tc is preferred. If the radionuclide is associated via an optional chelating structure (R), particularly for
99m
Tc, the chelating structure may be an —N
2
S
2
structure, an —NS
3
structure, an —N
4
structure, an isonitrile, a hydrazine, an HYNIC (hydrazinonicotinic acid) containing structure, a 2-methylthiolnicotinic acid containing structure, a phosphorus containing group, or a carboxylate group. In one specific embodiment, Z is
99m
Tc, and it is part of a
99m
Tc complex having the following formula:
where Ad is adenosine, p is PO
2
H, and R is a complexing moiety.
The above agents may be administered to image tumors tissue in a mammal. A specific imaging method detects tumors by administering the imaging agent to the mammal and detecting the spatial distribution of the agent. Differential accumulation of the agent is indicative of a tumor.
The invention also features kits for tumor imaging which comprises the imaging agent. The kit may include a chelating agent and/or an auxiliary molecule selected from the group consisting of mannitol, gluconate, glucoheptonate, and tartrate; and a tin-containing reducing agent, such as SnCl
2
or tin tartrate.


REFERENCES:
patent: 5476928 (1995-12-01), Ward et al.
patent: 5556982 (1996-09-01), Fritzberg et al.
patent: 5684148 (1997-11-01), Caruthers et al.
Elmaleh et al (1984), Proc. Natl. Acad. Sci., USA, vol. 81, pp.

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