Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2001-09-14
2004-03-23
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009363, C424S009364
Reexamination Certificate
active
06709646
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention relates to improved diagnostic agents for Magnetic Resonance Imaging (MRI) and optical imaging. These agents permit the sensitive detection of a specific bioactivity within a tissue. This invention also relates to pharmaceutical compositions comprising these agents and to methods of using the agents and compositions comprising the agents.
BACKGROUND OF THE INVENTION
Diagnostic imaging techniques, such as MRI, x-ray imaging, nuclear radiopharmaceutical imaging, ultraviolet/visible/infrared light imaging, and ultrasound imaging, have been used in medical diagnosis for a number of years.
Commonly used contrast materials include organic molecules, metal ions, salts or chelates, particles (particularly iron particles), or labeled peptides, proteins, polymers or liposomes. After administration, these agents may non-specifically diffuse throughout body compartments prior to being metabolized and/or excreted; these agents are generally known as non-specific agents. Alternatively, these agents may have affinity for a particular body compartment, cell, organ, or tissue component; these agents can be referred to as targeted contrast agents.
Contrast agent-enhanced diagnostic imaging procedures desirably increase the contrast between normal and pathological tissue in such a way as to provide two basic classes of information:
1) Detection Data. This includes data necessary to determine whether an abnormality is present in the imaged tissue and the degree to which it is present. The ability to provide this class of information relates to the “sensitivity” of the imaging procedure.
2) Differential Diaanosis Data. This includes data necessary to identify with precision the type of abnormality present. The ability to provide this class of information relates to the “specificity” of the imaging procedure. Specificity is necessary for making an accurate prognosis of the patient's condition and a plan of therapy. For example, although current procedures may be able to detect a tumor, generally they are inadequate to determine whether the tumor is benign or malignant, whether the tumor is likely to metastasize, or whether the tumor is responding to therapy. Such determinations require some knowledge of the specific biochemical state of the tissue.
A number of approaches have been presented to create targeted contrast agents. U.S. Pat. No. 4,880,008, incorporated herein by reference, describes MRI contrast agents which exhibit higher signal, or relaxivity, when they bind non-covalently to serum proteins, such as human serum albumin. For this class of agents, the relaxivity is related to the percent of the contrast agent bound to protein and is typically five to ten times higher than that observed for agents that do not bind proteins. In co-pending U.S. application Ser. No. 08/382,317 (filed Feb. 1, 1995), incorporated herein by reference, blood half life extending moieties (“BHEMs”) are added to the protein-binding contrast agents. The resulting agents exhibit enhanced or altered signal for a longer period of time in blood relative to agents lacking the BHEM, rendering these materials especially useful for vascular imaging.
U.S. Pat. No. 4,899,755, incorporated herein by reference, describes MRI contrast agents which are preferentially taken up in normal hepatocytes, resulting in contrast enhancement between normal and abnormal liver tissue.
Another targeting approach is based on conjugation of contrast agents to proteins, antibodies or other biomolecules which are known to interact with cell surface receptors, intracellular receptors, transporters, or other biochemical constituents. See, e.g., U.S. Pat. No. 5,171,563. However, such targeting usually involves a one-to-one interaction between the conjugated agent and the biochemical target, which is often present in relatively low concentrations (frequently nanomolar). Consequently, the number of targeted contrast agent molecules which accumulate in a particular tissue using this approach is limited. For imaging modalities where a significant concentration of agent molecules is often needed for detection (e.g., >1 uM), such as MRI and optical imaging, this “one-to-one” approach is generally too insensitive to be useful.
Attempts to image the biochemical state of tissues include radiopharmaceutical applications, where certain imaging agents are retained in a particular tissue. For example, the positron-emitting
18
F-labeled fluorodeoxyglucose is transported into the brain by passive diffusion, where it is phosphorylated and retained within brain tissue, resulting in an indication of glucose metabolism (see M. Blau,
Seminars in Nuclear Medicine
, Vol. XV, No. 4 (October), 1985). Similarly, a technetium-99 m labeled nitroimidazole is reported to be preferentially retained in ischemic heart (see Y. W. Chan et al., Proceedings of the 41st Annual Meeting of the Society of Nuclear Medicine, Jun. 5-Jun. 8, 1994,
J. Nuclear Medicine
(1994), Volume 35, Abstract No. 65, p. 18P). However, in these cases, the signal from the radiopharmacetical remains constant (i.e., each radioisotope has a characteristic, invariant decay and energy of the particles emitted) and is not affected by either biomodification or preferential retention in a tissue. The specificity and sensitivity of the information which can be obtained by this technique is limited.
There remains a need for contrast agents with improved specificity and sensitivity. In particular, there remains a need for targeted MRI and optical contrast imaging agents that exhibit enough signal enhancement or signal alteration in response to the presence of specific bioactivities to be useful in diagnosing the presence of those bioactivities.
SUMMARY OF THE INVENTION
The present invention provides novel improved diagnostic MRI and optical imaging agents for the sensitive detection of a specific bioactivity within a tissue, and pharmaceutically acceptable derivatives thereof. The imaging agents are prodrug contrast agents which are bioactivated in vivo in the presence of the specific bioactivity. Where the bioactivity is catalytic (e.g., stemming from enzyme activity), a large number of activated contrast agent molecules is generated for every unit of bioactive substance. The bioactivated form of the imaging agent exhibits increased binding affinity for one or more proteins compared to the prodrug, and this change in binding affinity causes a detectable change in the signal characteristics in the imaging agent. This detectable signal change increases the signal (or image) contrast between tissues which contain the targeted bioactivity and those which do not, which thus reflects the presence of the targeted bioactivity.
It is an object of this invention to provide novel compounds that are useful as contrast agents in MRI and optical imaging. It is also an object of this invention to provide pharmaceutical compositions comprising these compounds. It is a further object of this invention to provide methods for using these compounds and compositions comprising them in MRI and optical imaging.
DETAILED DESCRIPTION OF THE INVENTION
In order that the invention herein described may be more fully understood, the following detailed description is set forth.
The novel prodrugs of the present invention are designed with three constraints in mind: 1) they must have one or more specific sites in their structure that can become modified in vivo by a specific bioactivity; 2) the modified form of the imaging agent generated by this bioactivity must bind to one or more proteins to a greater degree than the prodrug; and 3) the signal characteristics of the imaging agent must be altered when it binds to a protein.
For the present invention, image contrast between normal and abnormal tissue generally requires the bioactivity in one of the tissues to be higher than that in the other. If abnormal tissue expresses a greater concentration of bioactivity than normal tissue, then abnormal tissue will convert more prodrug contrast agent to the activated form than will normal tissue (pro
Dumas Stephane
Dunham Stephen O.
Lauffer Randall B.
McMurry Thomas J.
Parmelee David J.
Epix Medical, Inc.
Fish & Richardson P.C.P.A.
Hartley Michael G.
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