Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Patent
1997-01-17
1998-08-25
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
424 936, 424 9363, 424 9361, 534 10, 534 14, 534 15, 534 16, 540465, 540474, A61K 5104, A61B 5055, C07D25702, C07D22500
Patent
active
057980896
DESCRIPTION:
BRIEF SUMMARY
The invention relates to novel amphiphilic chelants to the chelates and salts thereof and particularly to their use as diagnostic image contrast enhancing agents.
It is well accepted in diagnostic imaging modalities, such as magnetic resonance imaging, X-ray imaging, scintigraphy, ultrasound and the like, that the use of contrast agents can lead to improved image contrast and higher diagnostic efficacy.
A large proportion of contrast agents that have been developed for imaging other than of the gut, have been extracellular agents which after injection leave the vascular space and are excreted by the kidneys by glomerular filtration. However in order to obtain diagnostically useful information of other organs it is desirable to develop target specific contrast agents which distribute preferentially to the desired target site and remain there for a time sufficient for image generation to be effected.
Among the primary internal organs, the liver plays a leading role in the processing and metabolising of toxins, particulates and macromolecules as well as being involved in the absorption and digestion of fat. Processed materials are released through the biliary system and finally excreted. The detection of both focal and diffuse liver diseases such as primary and metastatic cancers is thus of great importance and the development of contrast agents for the liver has received much attention (see Schuhmann-Giampieri, Invest. Radiol. 28: 753-761 (1993)).
To image the liver using contrast agents, three main approaches have been adopted. The first is simply to target the blood passing through the liver using ECF agents and fast imaging procedures or MRI blood pool agents, the second is to target the Kupffer cells of the reticuloendothelial system in the liver, and the third is to target the hepatocytes, the cells which account for over 90% of the liver.
The present invention is concerned with liver targeting contrast agents.
For MR imaging, paramagnetic metal chelate hepatobiliary agents such as Gd-EOB-DTPA and MnDPDP are under development by Schering and Nycomed Salutar respectively. The paramagnetic MRI imaging agent GdBOPTA has also been proposed for liver imaging by Bracco and arabinogalactan-coated ultrasmall superparamagnetic iron oxide (AG-USPTO) particles have been proposed by Advanced Magnetics.
Besides the normal concerns in relation to toxicity, a requirement for a hepatobiliary contrast agent to function adequately is that liver uptake should occur efficiently and that retention within the hepatobiliary system in a contrast inducing form should be for an adequate period for imaging to be effected.
It has now been found that surprisingly good liver uptake and prolonged hepatobiliary system retention is achieved with novel amphiphilic contrast agents comprising a chelate conjugated to an acid group carrying aryl function.
By way of example, one such chelate Gd-DO3A-DOBA (10-p-carboxyphenoxydecyl-1,4,7,10-tetraazacyclododecane-1,4,7-tri-acetic acid) achieves a significantly higher and more prolonged accumulation in the liver than does Gd-EOB-DTPA as may be seen from FIG. 2 of the accompanying drawings.
Thus viewed from one aspect the invention provides an amphiphilic compound of formula I at least one CH.sub.2 moiety is replaced by a group X.sup.1 (e.g. L may include a chain sequence, a X.sup.1 (CH.sub.2 CH.sub.2 X.sup.1).sub.u (where u is a positive integer) such as X.sup.1 CH.sub.2 CH.sub.2 X.sup.1, X.sup.1 CH.sub.2 CH.sub.2 X.sup.1 CH.sub.2 CH.sub.2 X.sup.1, X.sup.1 CH.sub.2 CH.sub.2 X.sup.1 CH.sub.2 CH.sub.2 X.sup.1 CH.sub.2 CH.sub.2 X.sup.1, etc), and wherein L is optionally interrupted by a metabolizable group M but with the provisos that the terminus of L adjacent Ch is CH.sub.2 and that the terminus of L adjacent Ar is X.sup.1 or a CH.sub.2 group adjacent or separated by one CH.sub.2 from a group X.sup.1 (thus for example the L--Ar linkage may be L.sup.1 --X.sup.1 --Ar, L.sup.1 --CH.sub.2 --Ar, L.sup.1 --X.sup.1 CH.sub.2 --Ar or L.sup.1 --X.sup.1 CH.sub.2 CH.sub.2 --Ar, where L.sup.1 is the residue o
REFERENCES:
patent: 5410043 (1995-04-01), Platzek et al.
Berg Arne
Varadarajan John
Watson Alan David
Hartley Michael G.
Hollinden Gary E.
Nycomed Salutar Inc.
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