Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Patent
1993-01-29
1996-07-23
Wu, Shean C.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
534 14, 424165, 424173, A61K 5104, A61K 5106, C07F 1300
Patent
active
055387128
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
The invention relates to the object characterized in the claims, i.e., cyclopentadienylcarbonyl.sup.99m Tc complexes, agents containing these complexes, their use as diagnostic agents as well as process for the production of these complexes and agents.
Radioactive metal ions, mostly bound to a complexing agent, have for some time been used for in vivo diagnosis. Among them, technetium-99m (.sup.99m Tc), because of its almost ideal physical properties for this purpose--good absorption of radiation in corresponding detection devices (gamma camera, SPECT devices) relative to a lower absorption in the human organism and easy availability by a molybdenum/technetium generator--is the radionuclide most often used in clinical nuclear medicine. Its short half-life of 6.02 hours guarantees an only slight exposure of the patient to gamma radiation, particularly since also the daughter nuclide technetium-99 has only a negligible residual radiation. But, a drawback of technetium is its complicated and still not completely known complex chemistry. Technetium can be present in a number of oxidation stages (+7 to -1), which can greatly change the pharmacological properties by changing the charge of a complex. It is therefore necessary to synthesize complexes which bind the technetium in a defined oxidation stage and to prevent redox reactions, which could lead to a redistribution of the pharmaceutical agent. A number of such .sup.99m Tc complexing agents are already known and are clinically used. In the case of neutral complexes, systems, in which the .sup.99m Tc is bound between 2-4 nitrogen atoms and 0-2 sulfur atoms (N.sub.2 S.sub.2, N.sub.3 S, propylenamine oxime and isonitrile complexes), are often involved. But, often the insufficient stability of these .sup.99m Tc complexes is a significant drawback (Hung, J. C. et al.; J. Nucl. Med. 29: 1568 [1988]). In clinical use, therefore, e.g., HM-PAO (hexamethyl-propylenamine oxime) has to be administered within 30 minutes after its labeling with .sup.99m Tc-pertechnetate, so that the amount of by-products, which reduce the diagnostic informative value, does not become too high.
Also, other previously known attempts to couple chelating agents to substances selectively accumulating per se can thus far be considered as unsatisfactory. If functional groups of the complexing agent are used to bind to any low-molecular or polymeric molecule, a weakening of the complex stability often results, i.e., a diagnostically intolerable portion of the radioisotope is released from the conjugate (Brechbiel, M. W. et al., Inorg. Chem. 25: 2772 [1986]) and thus interferes with the physical measurement and as a result the diagnostic value.
In the previously clinically used compounds (e.g., MAG 3 [EP 0250013], ECD [EP 0279417] or HM-PAO [EP 0123504]), the complex, whose exclusive function actually should be to make possible the physical measurement via its .gamma.-radiation, also determines the biological distribution. Thus, these complexes are unsuitable for coupling to low-molecular molecules selectively accumulating in the organism. Further, these complexing agents contain functional groups, which can interact in an undesirable manner with the living organism.
Therefore, there exists an urgent need for stable, easily accessible complexes, which are coupled to various compounds selectively accumulating per se in the organism and whose concentration behavior is determined only by these low-molecular organic molecules.
According to the invention, this object is achieved by compounds of general formula I ##STR2## in which X stands for a carbonyl group or a direct bond, hydrocarbon radical, which optionally contains one to three carbonyl groups and/or one to three carboxy groups and/or a C.sub.1-3 alkyl, a phenyl or benzylcarboxylic acid ester and/or an NR.sub.1 R.sub.2 radical, in which R.sub.1 and R.sub.2 are the same or different and stand for hydrogen, deuterium, a straight-chain or branched C.sub.1-6 alkyl, a desoxysaccharide or a desaminoergoline radical, hydrogen
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Chemical Abstracts, Band 60, No. 7, 30 (Mar. 1964), E. O. Fischer et al.: romatic complexes of metals. LXXIII. Acylation of cyclopentadienylrhenium tricarbonyl and cyclopentadienyltechnetiumtricarbonyl", sieh Zusammenfassung No. 8060g, & J. Organometal. Chem. 1(2), 191-9 (1963).
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Schulze Paul E.
Wenzel Martin
Chapman Lara E.
Institut Fur Diagnostikforschung GmbH/an der Freien Universitat
Wu Shean C.
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