Type S.sub.3 N.sub.2 chelators for radioactive isotopes, their m

Details Type S.sub.3 N.sub.2 chelators for radioactive isotopes, their m Type S.sub.3 N.sub.2 chelators for radioactive isotopes, their m

1996-03-08

2000-11-07

Dees, Jose G.

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

424 111, 424 165, 424 91, 534 14, A61K 5100, A61M 3614

Patent

active

06143275&

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION

This invention relates to new bifunctional chelating agents with intermittent chalcogen atoms, pharmaceuticals containing these compounds, their use in radiodiagnostics and radiotherapy, and methods for the production of these compounds and pharmaceuticals.


BACKGROUND OF THE INVENTION

It has been known for a long time that complexing agents for radioactive isotopes or their complexes with radio-active metals can be applied in radiodiagnostics and radio-therapy. Technetium-99m is the most frequently used radio-nuclide in radiodiagnostics because it is particularly well suited for in-vivo applications due to its favourable physical properties (no corpuscular radiation, low half-life of 6.02 h, good detectability by 140 keV .gamma.-radiation) as well as its low biological half-life and easy availability. The first step of forming complexes of technetium-99m is to gain pertechnetate from a nuclide generator; it is then converted to a lower oxidation number using appropriate reductants (such as SnCl.sub.2, S.sub.2 O.sub.4.sup.2-, etc.). This oxidation number is stabilized by an appropriate chelating agent. As technetium may have several oxidation numbers (+7 to -1) which may vehemently alter its pharmacological properties by changing the charge of the complex, it is necessary to provide chelating agents or complex ligands for technetium-99m that are capable of binding technetium in a specific oxidation number safely, firmly and stably to prevent undesirable biodistribution due to in-vivo redox processes or release of technetium from the radiodiagnostic agent which would impede the safe diagnosis of the respective diseases.
For example, cyclic amines (Troutner, D. E. et al.: J. Nucl. Med. 21, 443 (1980)) are regarded as suitable complexing agents for technetium and rhenium isotopes but their disadvantage is that they are only capable of binding technetium-99m in sufficient quantities from a pH value >9. N.sub.2 O.sub.2 systems (Pillai, M. R. A., Troutner, D. E. et al.: Inorg. Chem., 29, 1850 (1990)) are in clinical use. Non-cyclic N.sub.4 systems such as HMPAO have the great disadvantage of low complex stability. Tc-99m-HMPAO has to be applied immediately after labelling due to its low stability (Ballinger, J. R. et al., Appl. Radiat. Isot. 42, 315 (1991); Billinghurst, M. W. et al., Appl. Radiat. Isot. 42, 607 (1991)) to keep the portion of decomposition products low which have different pharmacokinetic and excretion properties. Such radiochemical impurities make detection of the diseases to be diagnosed more difficult. Any coupling of these chelates or chelating agents with other substances that accumulate selectively in centres of diseases cannot be broken by simple means so that these normally spread unspecifically in the organism.
N.sub.2 S.sub.2 chelating agents (Bormans, G. et al.: Nucl. Med. Biol., 17, 499 (1990)) such as ethylene dicysteine (EC; Verbruggen, A. M. et al.; J. Nucl. Med. 33, 551 (1992)) meet the requirement of sufficient stability of their respective technetium-99m complex but form radiodiagnostic agents of a purity greater than 690 only at pH values >9 of the complexing medium. N.sub.3 S systems (Fritzburg, A.; EPA 0 173 424 and EPA 0 250 013) yield stable technetium-99m complexes but have to be heated up to temperatures of ca. 100.degree. C. to insert the radionuclide.
Another disadvantage of N.sub.2 S.sub.2 and N.sub.3 S systems is that they are discharged too rapidly and without specific accumulation in the organism. Thus they are only used clinically, though to a limited extent, in renal function diagnostics. Their use is limited mainly because the demand has increased for substances that accumulate specifically in diseased tissues. This can be accomplished if one manages to link complexing agents easily with selectively accumulating substances while the latter retain their favourable complexing properties. But as it happens quite frequently that a certain reduction of complex stability is observed after coupling the complexing agent to such

REFERENCES:
Chemical Abstracts, vol. 118, No. 5, Feb. 1, 1993, Columbus, Ohio, US, abact No. 33497.
Chemical Abstracts, vol. 119, No. 13, Sep. 27, 1993, Columbus, Ohio, US, abstract No. 139794.
Tetrahedron, vol. 38, No. 14, 1982, Oxford, GB, pp. 2055-2060, T. Lodi et al., `Chiral Aminoacid Containing Acyclic Ligands-I. Syntheses and Conformations`.
Tetrahedron, vol. 38, No. 14, 1982, Oxford, GB, pp. 2061-2067, R. Marchelli et al., `Chiral Aminoacid Containing Ligands-II. Complexation of Alkaline Earth Cations`.
Bioconjugate Chemistry, vol. 2, Sep. 1992, Washington, US, pp. 353-366, James P. Dizio et al., `Progestin-Rhenium Complexes: Metal-Labeled Steroids With High Receptor Binding Affinity, Potential Receptor-Directed Agents For Diagnostic Imaging Or Therapy`

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