Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Patent
1996-11-08
1999-11-02
Dees, Jose' G.
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
424 169, 424 93, 424 9361, 424 936, 424DIG16, A61K 5104, A61K 4900, A61B 5055
Patent
active
059764937
DESCRIPTION:
BRIEF SUMMARY
This invention relates to polychelants, as well as the corresponding bifunctional polychelants (eg site-directed macromolecular conjugates of the polychelants, and the chelates and salts thereof and their applications in medicine, especially in the field of diagnostic imaging.
The polychelates are especially suited for use in enhancing images of selected mammalian organs, tissues, cells, and the like, in vivo, using Magnetic Resonance Imaging (MRI), X-ray, gamma scintigraphy, and CT scanning, by virtue of their enhanced imaging properties and site specificity. The polychelants are also particularly well suited for use as intravascular contrast agents, blood pool agents, in these imaging modalities. As such they may be used in imaging blood vessels, e.g. in magnetic resonance angiography, in the measurement of blood flow and volume, in the identification and characterization of lesions by virtue of differences in vascularity from normal tissue, in the imaging of the lungs for the evaluation of pulmonary disease and in blood perfusion studies. The polychelants are also well suited for metal detoxification, therapeutic delivery of radioisotopes and diagnostic nuclear medicine applications.
Medical imaging modalities, such as MRI, X-ray, gamma scintigraphy, and CT scanning, have become extremely important tools in the diagnosis and treatment of illnesses. Some imaging of internal parts relies on inherent attributes of those parts, such as bones, to be differentiated from surrounding tissue in a particular type of imaging, such as X-ray. Other organs and anatomical components are only visible when they are specifically highlighted by particular imaging techniques.
One such technique with potential to provide images of a wide variety of anatomical components involves biotargeting image-enhancing metals. Such a procedure has the possibility of creating or enhancing images of specific organs and/or tumors or other such localized sites within the body, while reducing the background and potential interference created by simultaneous highlighting of non-desired sites.
Researchers have recognized for many years that chelating various metals increases the physiologically tolerable dosage of such metals and so permits their use in vivo to enhance images of body parts (see for example C. D. Russell and A. G. Speiser, J. Nucl. Med. 21: 1086 (1988) and U.S. Pat. No. 4,647,447 (Gries et al.)). However, such simple metal chelate image enhancers, without further modification, do not generally provide any particularly significant site specificity.
The attachment of metal chelates to tissue or organ targeting molecules, e.g. biomolecules such as proteins, in order to produce site specific therapeutic or diagnostic agents has been widely suggested.
Many such bifunctional chelating agents, i.e. agents which by virtue of the chelant moiety are capable of strongly binding a therapeutically or diagnostically useful metal ion and by virtue of the site-specific molecular component are capable of selective delivery of the chelated metal ion to the body site of interest, are known or have been proposed in the literature. Thus for example even relatively early publications in the field of MRI contrast agents, such as GB-A-2169598 (Schering) and EP-A-136812 (Technicare) suggested the use as contrast agents of paramagnetic metal ion chelates of bifunctional chelants.
The attachment of chelant moieties to site-specific macromolecules has been achieved in a number of ways, for example the mixed anhydride procedure of Krejcarek et al. (Biochemical and Biophysical Research Communications 77: 581 (1977)), the cyclic anhydride procedure of Hnatowich et al. (see Science 220: 613 (1983) and elsewhere), the backbone derivatisation procedure of Meares et al. (see Anal. Biochem. 142: 68 (1984) and elsewhere--this is a technique used by Schering in EP-A-331616 to produce site specific polychelates for use as MRI or X-ray contrast agents), and the linker molecule procedure used for example by Amersham (see WO-A-85/05554) and Nycomed (see EP-A-186947 an
REFERENCES:
patent: 5338532 (1994-08-01), Tomalia et al.
patent: 5364614 (1994-11-01), Platzek et al.
Carvalho Joan
Fellmann Jere Douglas
Garrity Martha
Margerum Lawrence
Dees Jos,e G.
Hartley Michael G.
Nycomed Salutar Inc.
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