Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Patent
1995-07-28
1998-09-22
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
424 9364, 424 934, 424 935, A61B 5055
Patent
active
058110763
DESCRIPTION:
BRIEF SUMMARY
This invention resides in the field of contrast media for magnetic resonance imaging in medical procedures.
BACKGROUND OF THE INVENTION
Magnetic resonance (MR) imaging is a developing field with ever-expanding applications. Much of this expansion is attributable to the development of a wide array of contrast agents, which increase the contrast of the image by modifying localize areas of the contrast in either a positive or negative manner. The regions of localization vary considerably among the various types of contrast agents. These regions include specific tissues, organs, cells, antigens, and tumors, as well as the blood pool itself.
Of interest in the present invention are contrast agents used for imaging the blood pool and monitoring its movement. MR imaging assisted by such agents is useful for such procedures as assessments of relative tissue blood volume, estimation of tissue perfusion, and detection of abnormal capillary permeability. Clinical applications include assessments of myocardial and cerebral ischemia, pulmonary embolism, transplants, and neoplasia. To be useful as blood-pool markers, the contrast agents must remain in the pool rather than leaving it through such means as diffusion into extravascular compartments or glomerular filtration. A requisite property of contrast agents is therefore a relatively high molecular weight, generally on the order of 20,000 daltons or more, which prevents the agents from diffusing through normal capillaries and glomerular endothelium. Contrast agents of this type are thus referred to in the art as macromolecular contrast media, or "MMCM." A further advantage of MMCM is that the prolonged intravascular retention of these agents permits imaging of the blood pool in multiple body regions without repeated dosing, thereby eliminating the need for critical timing of the imaging. The enhancement of normal tissues with MMCM 5 minutes after administration, for example, is virtually identical to the enhancement 50 minutes after administration.
SUMMARY OF THE INVENTION
This invention resides in a novel class of MMCM constructs which include a plurality of paramagnetic complexes joined to a macromolecular or polymeric backbone through spacer groups. In prior art MMCM in which most of the high molecular weight resides in the polymeric backbone, the MMCM are generally polydisperse in molecular weight due to the polydispersity of the backbone. The spacer groups of the present invention provide a means of adding molecular weight to the construct in a manner which permits control of the molecular weight within a narrow range. In addition, the spacer groups offer an opportunity for adding to or modifying the physical and chemical characteristics of the construct. Still further, they provide additional functional groups for the attachment of paramagnetic complexes, thereby further amplifying the signal enhancement within a given molecular weight range.
The constructs of the invention have the following general formula:
The symbol R.sup.1 in this formula represents a multifunctional group or backbone providing a multitude of attachment sites for spacer groups. Polymers, including polypeptides, polysaccharides and others, are generally useful for this backbone. With its multitude of attachment sites, the backbone serves an amplifying function for the paramagnetic complexes.
The symbols R.sup.2 and R.sup.3 represent a spacer group and a paramagnetic complex, respectively, or the spacer group and a ligand which retains the paramagnetic metal cation and thus forms part of the paramagnetic complex. The symbol m represents the number of paramagnetic complexes attached to each spacer. This may be as low as 1, or greater. The symbol n represents the number of spacers, and their associated complexes, which are attached to the backbone, and this will generally be a number in excess of 1, preferably well in excess of 1. The term "ligand" will be used herein for R.sup.3 for purposes of convenience, but will refer to both the ligands which combine with the paramagnetic metal cati
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Brasch Robert C.
Mann Jeffry S.
Nitecki Danute E.
Hollinden Gary E.
The Regents of the University of California
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