Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – X-ray contrast imaging agent
Patent
1993-09-24
1996-01-09
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
X-ray contrast imaging agent
534 15, 534 16, 556 8, 556 31, 556 61, 540474, 514836, A61K 4904
Patent
active
054826993
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP92/00698 filed Mar. 27, 1992.
The present invention relates to the use in diagnostic imaging, in particular X-ray, ultrasound and scintigraphy of contrast agents comprising complexes of multinuclear moieties, and to contrast media containing such complexes.
All diagnostic imaging is based on the achievement of different signal levels from different structures within the body. Thus in X-ray imaging for example, for a given body structure to be visible in the image, the X-ray attenuation by that structure must differ from that of the surrounding tissues. The difference in signal between the body structure and its surroundings is frequently termed contrast and much effort has been devoted to means of enhancing contrast in diagnostic imaging since the greater the contrast between a body structure and its surroundings the higher the quality of the images and the greater their value to the physician performing the diagnosis. Moreover, the greater the contrast the smaller the body structures that may be visualized in the imaging procedure, i.e. increased contrast can lead to increased spatial resolution.
The diagnostic quality of images is strongly dependent on the inherent noise level in the imaging procedure - and the ratio of the contrast level to the noise level can thus be seen to represent an effective diagnostic quality factor for diagnostic images.
Achieving improvement in such a diagnostic quality factor has long been and still remains an important goal. In techniques such as X-ray and ultrasound, one approach to improving the diagnostic quality factor has been to introduce contrast enhancing materials, contrast agents, into the body region being imaged.
Thus in X-ray for example early examples of contrast agents were insoluble inorganic barium salts which enhanced X-ray attenuation in the body zones into which they distributed. More recently the field of X-ray contrast agents has been dominated by soluble iodine containing compounds such as those marketed by Nycomed AS under the trade names Omnipaque and Amipaque.
Much recent work on X-ray contrast agents has concentrated on aminopolycarboxylic acid (APCA) chelates of heavy metal ions and, recognising that effective imaging of many body sites requires localization at the body sites in question of relatively high concentrations of the metal ions, there have been suggestions that polychelants, that is substances possessing more than one separate chelant moiety, might be used to achieve this.
However we have now found that contrast enhancement may be achieved particularly effectively by the use of multinuclear complexes, that is complexes wherein the complexed moiety itself comprises two or more contrast enhancing atoms. Thus, for X-ray or ultrasound the complex would comprise two or more heavy metal atoms and for MRI the complex would contain two or more metal atoms with paramagnetic properties.
For the sake of clarity, the word "atom" is used to refer to ionic and covalently bonded forms and not simply to isolated uncharged atoms. Moreover it will be understood that the complexed moiety, while it is polynuclear, will not generally be so large as to be considered to be a particle itself. Thus it will generally have maximum dimensions 500 .ANG. or less, e.g. of 80 .ANG. or less, especially 40 .ANG. or less. More particularly, the multinuclear entity will have a distinct, characteristic and reproducible overall structure and atom content and is thus quite distinct from a fragment or microcrystal of for example a metal oxide which in contrast will have a lattice containing very many of the unit cells of the crystal structure. The multinuclear entity on the other hand cannot itself be larger than the size of its unit cell.
Thus viewed from one aspect the invention provides a diagnostic imaging contrast medium comprising a physiologically tolerable multinuclear complex of formula I be the same or different is a contrast enhancing metal atom covalently bonded to at least one atom B where u is non-zero; each B which may be the
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Almen Torsten
Berg Arne
Chang C. Allen
Droege Michael
Dugstad Harald
Hollinden Gary E.
Nycomed Salutar Inc.
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