Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2000-07-28
2003-11-25
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009361, C424S009363, C424S009364
Reexamination Certificate
active
06652835
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to contrast agents for diagnostic imaging. In particular, this invention relates to novel multimeric compounds which exhibit improved affinity for physiologically relevant targets, such as proteins, and surprisingly improved relaxivity properties upon binding. The compounds comprise:
a) two or more Image Enhancing Moieties (“IEMs”)
b) two or more Target Binding Moieties (“TBMs”), providing for in vivo localization and multimer rigidification;
c) a scaffold framework for attachment of the above moieties (“scaffold”);
d) optional linkers for attachment of IEMs to the scaffold (“linker”).
This invention also relates to pharmaceutical compositions comprising these compounds and to methods of using the compounds and compositions for contrast enhancement during imaging.
BACKGROUND OF THE INVENTION
Diagnostic imaging techniques, such as magnetic resonance imaging (MRI), X-ray, nuclear radiopharmaceutical imaging, ultraviolet-visible-infrared light imaging, and ultrasound, have been used in medical diagnosis for a number of years. Contrast media additionally have been used to improve or increase the resolution of the image or to provide specific diagnostic information. In some cases, such as imaging with ultrasound, the introduction of contrast media has been recent.
To be effective, the contrast media must interfere with the wavelength of electromagnetic radiation used in the imaging technique, alter the physical properties of tissue to yield an altered signal, or, as in the case of radiopharmaceuticals, provide the source of radiation itself. MRI and optical imaging methods are unique among imaging modalities in that they yield complex signals that are sensitive to the chemical environment. While the signal from X-ray or radionuclide agents remains the same whether the agents are free in plasma, bound to proteins or other targets, or trapped inside bone, certain contrast agents for MRI and optical imaging will have different signal characteristics in differing physiological environments. An optical dye may exhibit changes in its absorbance, reflectance, fluorescence, phosphorescence, chemiluminescence, scattering, or other spectral properties upon binding. It is important that the contrast agent be sufficiently sensitive and present at high enough concentration so that signal changes can be observed.
Attempts to Improve Contrast by Increasing the Number of IEMs
Targeted agents should deliver meaningful concentrations of the imaging moiety to the target so that sufficient improvement in the signal is observed during the course of imaging. Achieving sufficient sensitivity is a significant problem for MRI in particular, where concentrations in the range of 10-1000 micromolar (&mgr;M) of the image enhancing moiety are required to produce an adequate signal. The problem can be further complicated for targeted agents if the desired target is present at low concentrations. For example, in order to image biological receptor targets that are present at less than &mgr;M concentrations, greater signal enhancement is required at the target site to provide sufficient image contrast. Increased contrast has been approached by using (1) drug delivery vehicles to provide high local concentrations of the contrast agent, (2) multiple IEMs in a single contrast agent, [see, for example, Martin V. V., et al.,
Bioconjug. Chem.,
6: pp. 616-23 (1995); Shukla, R. et al.,
Mag. Reson. Med.,
35: pp. 928-931 (1996); Ranganathan, R. S., et al.,
Invest. Radiol.,
33: pp. 779-797 (1998)], or (3) particular IEMs of defined structure with improved signal enhancement properties. The ideal targeted contrast agent should efficiently combine IEMs and improved signal enhancement properties.
To incorporate a high number of image enhancing moieties into a contrast agent, large concentrations of low molecular weight contrast agents have been packaged within suitable drug delivery vehicles, such as polymerized vehicles or liposomes [Bulte J. W., et al.,
J. Magn. Reson. Imaging,
9: pp. 329-335 (1999)]. Unfortunately, these materials are difficult to direct to a target.
To increase the number of the image enhancing moieties, investigators have, for example, created polymers, dendrimers, and organic compounds in association with multiple IEMs. High numbers of IEMs, such as Gd(III) chelates for MRI, can be covalently attached to polymers [Schuhmann-Giampieri, G. et al.
J. Invest. Rad.,
26: pp. 969-974 (1991); Corot, C. et al.
Acta Rad.,
38:S412 pp. 91-99 (1997)] and dendrimers [Jacques, V., et al.,
J. Alloys Cmpd.,
249: pp. 173-177 (1997); Margerum, L. D., et al.,
J. Alloys Compd.,
249: pp. 185-190 (1997); Toth, E., et al.,
Chem. Eur. J.,
2: pp. 1607-1615 (1996)]. Polymeric agents typically comprise a mixture of species with a broad and complex molecular weight distribution. These heterogeneous properties adversely affect agent performance and make characterization difficult. Furthermore, it is synthetically difficult to selectively introduce TBMs along with multiple IEMs. Therefore there exists a need for well-defined, homogeneous molecules for use as contrast agents that can provide adequate image enhancement at a target.
Dendrimers (such as “Starburst dendrimers”, or “cascade polymers”) theoretically offer a single high molecular weight species onto which many IEMs can be covalently attached. [Fischer, M. et al.
Angew. Chem., Int. Ed. Eng.,
38/7: pp. 884-905 (1999); Weiner, E. C. et al.,
Mag. Reson. Med.,
31: pp. 1-8 (1994)]. However, dendrimers, like polymeric agents, present significant synthetic problems, especially when selectively introducing tissue-specific targeting groups.
Organic molecules have been synthesized with multiple image enhancing moieties. MRI contrast agents of this type are referred to herein as “multimeric chelates” or “multimers” and typically comprise 2-12 IEMs. [Shukla, R. et al.,
Mag. Reson. Med.,
35: pp. 928-931 (1996); Shukla, R. B., et al.,
Acta Radiol.,
412: pp. 121-123 (1997); Ranganathan, R. S., et al.,
Invest. Radiol.,
33: pp. 779-797 (1998)]. Advantages of multimeric chelates include: (1) they are homogeneous molecules in that they have a single size and structure, unlike polymers and dendrimers, (2) they can be readily synthesized and purified, and (3) targeting groups can be readily incorporated. Unfortunately, the ability of multimeric chelates to improve the MRI signal intensity has been disappointingly low. This is because the proton relaxation rate enhancement (or “relaxivity”), which correlates with signal enhancement, has decreased as the number of IEMs was increased. Therefore, contrast agents wherein the relaxivity does not decrease when the number of IEMs increases are needed to achieve greater signal enhancement at a target.
Attempts to Improve Contrast by Decreasing the Rotational of the Contrast Agent
Attempts have been made to increase the relaxivity of non-targeted multimeric MRI contrast agents by restricting rotational motion. Attempts to restrict rotational motion have focused on (1) decreasing the flexibility of the molecule or (2) restricting rotational motion through binding to a target.
For example, non-targeted agents have been synthesized with rigid frameworks to which multiple Gd(III) chelates are attached [Shukla, R. et al.,
Mag. Reson. Med.,
35: pp. 928-931 (1996); Shukla, R. B., et al.,
Acta Radiol.,
412: pp. 121-123 (1997); Ranganathan, R. S., et al.,
Invest. Radiol.,
33: pp. 779-797 (1998); Jacques, V., et al.,
J. Alloys Cmpd.,
249: pp. 173-177 (1997)]. However, these structures have several drawbacks. First, the relaxivities per Gd(III) ion that have been achieved for agents containing more than two chelates has been less than that observed for single chelates, such as MS-325. Therefore, local chelate motion could still be further reduced. Second, these agent are not targeted. More importantly, even if they were targeted, rigid multimer frameworks would greatly increase the unwanted background s
Amedio John
Caravan Peter
Dumas Stephane
Kolodziej Andrew
Lauffer Randall B.
Epix Medical, Inc.
Hartley Michael G.
LandOfFree
Targeting multimeric imaging agents through multilocus binding does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Targeting multimeric imaging agents through multilocus binding, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Targeting multimeric imaging agents through multilocus binding will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3139198