Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
1998-06-12
2001-11-06
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009363, C424S009364, C424S009400, C534S015000
Reexamination Certificate
active
06312664
ABSTRACT:
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 localized areas of the contrast in either a positive or negative maiser. 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 per fusion, 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:
R
1
{—R
2
(—R
3
)
m
}
n
(I)
The symbol R
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
2
and R
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 in 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
3
for purposes of convenience, but will refer to both the ligands which combine with the paramagnetic metal cations to form the paramagnetic complexes, and to the complexes themselves.
The spacer R
2
can be any of a wide variety of molecular structures, and will be at least bifunctional to permit attachment to both R
1
and R
3
, optionally through linkage groups. Preferred spacers are those which are cleaved in vivo by the biological environment within a relatively short period of time. Spacers with multiple binding functionalities at the complex end (i.e., the R
3
end) will accommodate a multitude of complexes, in which case m will have a value exceeding 1. Spacers of this type serve an amplifying function in a manner similar to that of the backbone, although to a lesser extent. Other spacers useful in the invention will have only a single functionality at either end, in which case the value of m will be 1. Useful spacers will be those which are non-toxic and non-immunogenic, while those which are particularly useful will be those which have further properties which benefit the construct when administered as MMCM. In addition to the property of in vivo cleavability mentioned above, a property of prominent interest is hydrophilicity. Still other useful properties are the ability to lower antigenicity and to increase molecular weight. Spacers with still further properties can be utilized to advantage as well, as will be readily apparent to those skilled in the art.
The ligands represented by R
3
include any ligand useful as an MR imaging contrast enhancement agent which can be attached to a spacer. These include known ligands which have been modified or derivatized in any of a variety of ways to achieve a functional group which will permit attachment to the spacer.
Further features and advantages of the invention will become apparent from the description which follows.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
Referring to Formula I above, pharmaceutical agents of the present invention are those in which:
R
1
is a polymeric backbone group which is non-toxic and non-antigenic;
R
2
is a group which includes at least four atoms bonded together and adjoining R
1
to R
3
;
R
3
is a complex of a ligand and a paramagnetic metal cation capable of altering contrast in magnetic resonance imaging;
n is at least 3; and
m is at least 1.
The spacer R
2
may be either a straight-chain or a branched-chain structure. Preferred R
2
groups are those which include a straight chain within their structures, either as the entire spacer group or as the backbone of a branched-chain group. The straight chain may be a chain of carbon atoms or of carbon atoms interrupted with one or more hetero atoms such as oxygen atoms, sulfur atoms or nitrogen atoms. The bonds forming the chain may be single bonds or double bonds, although single bonds are preferred. The length of the chain is not critical and may vary widely, depending on the desired relationship between the molecular weight of the construct and the number of paramagnetic groups included on the construct. Best results will generally be obtained with chain lengths ranging from 4 atoms to 1,000 atoms, with preferred chains being those of 6 atoms to 100 atoms, and the most preferred being those of from 10 atoms to 50 atoms. The chain as thus described is the backbone of the spacer itself, and does not include atoms, groups or side chains bonded to the serially bonded atoms forming the backbone. It does however include linking groups at the chain termini joining the chain to R
1
and R
3
, when such linking groups are present.
In certain embodiments of the invention, the spacer will be hydrophilic in character to impart hydrophilicity to the construct. The spacer may thus be any hydrophilic group among those known in the art. Examples are polyalkylene glycols, optionally substituted with groups which may or may not add to their hydrophilic character. Among polyalkylene glycols, polyethylene glycol is a preferred example. Examples of the optional substitutions are alkyl groups, alkoxy groups and hydrox
Brasch Robert C.
Mann Jeffry S.
Nitecki Danute E.
Hartley Michael G.
The Regents of the University of California
Townsend and Townsend / and Crew LLP
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