Chemistry: electrical current producing apparatus – product – and – Having polarity safety feature
Patent
1988-02-29
1989-03-07
Maples, John S.
Chemistry: electrical current producing apparatus, product, and
Having polarity safety feature
534 14, 2605024P, A61K 4902, C07F 938
Patent
active
048104868
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to bone-seeking complexes of technetium-99m, methods of preparing said complexes and compositions for use in the preparation of said complexes.
In April 1971, G. Subramanian and J. G. McAfee described (Radiology, 99, 192-6) a bone scanning agent prepared by reducing pertechnetate TcO.sub.4 -with stannous chloride in the presence of tripolyphosphate. The resulting labelled complex gave good skeletal uptake but suffered from several disadvantages, the most important of which were a 24-hour delay between injection and scanning (so that high levels of radioactivity were required in order to obtain adequate instrument response), and the instability of the tripolyphosphate with respect to hydrolysis.
An intensive search in the 1970's for better phosphate- and phosphonate-based bone scanning agents has resulted in a large number of publications and several commercial products. The most widely used compound is methylene diphosphonate (MDP), the complex of which with tin and Technetium-99m is the subject of U.S. Pat. No. 4032625. Recent introductions to the market have included hydroxymethylene diphosphonate (HDP), which is the subject of European Patent Application No. 7676; and 1,1-diphosphonopropane-2,3-dicarboxylic acid (DPD), which is described in German O.S. No. 2755874.
A successful bone scanning agent requires inter alia high and rapid uptake of the agent in bone with rapid clearance from the blood and soft tissues such as muscle of that part of the agent not taken up in the bone. In order to achieve scans of high definition, current bone agents normally require an interval of two hours or even more between injection of the agent into the patient and performance of the scan. (The word "scan" is here taken to include gamma-camera imaging techniques). Even small reductions of the interval between injection and scanning are highly desirable and could lead to worthwhile increases in convenience to the patient and the physician and in the efficiency in the running of nuclear medicine units.
The present invention arises from our discovery of some new bone-scanning agents based on the use of some bis-phosphonic acid compounds which additionally contain one or more sulphonic acid groups.
In a first aspect, the present invention provides a composition for the preparation of a bone-scanning agent which comprises a mixture of a bis-phosphonic acid having the general formula ##STR1## wherein: R.sup.1 and R.sup.3 may be the same or different group selected from H, --SO.sub.3 H and a lower aliphatic group which may optionally contain one or more hereto atoms and which contains at least one --SO.sub.3 H group; and lower alkyl optionally substituted by one or more polar groups; --SO.sub.3 H and lower alkyl optionally substituted by one or more polar groups; and when n is 1, R.sup.1 and R.sup.3 cannot both be H; or a non-toxic salt thereof together with a reducing agent for pertechnetate ions.
In a second aspect, the present invention provides a method of preparing a technetium-99m-labelled bone scanning agent comprising adding technetium-99m, as an aqueous solution of pertechnetate ions to a composition comprising a mixture of a bis-phosphonic acid compound of the formula I above, or a non-toxic salt thereof, and a reducing agent for pertechnetate ions.
In a third aspect, the present invention provides a bone-seeking composition which comprises an aqueous solution of a complex of technetium-99m and a bis-phosphonic acid compound having the formula I above or a non-toxic salt thereof.
The bis-phosphonic acid complexing agent of the formula I above is either a gem-bisphosphonate (in the case where n=0) or a vic-bisphosphonate (in the case where n=1). The gem-biphosphonates have the general formula II ##STR2## wherein R.sup.1 is --SO.sub.3 H or a lower aliphatic group, which may optionally contain one or more hetero atoms, and which contains at least one --SO.sub.3 H group and R.sup.2 is H, --OH, --NH.sub.2, --NHMe, --NMe.sub.2 or a lower alkyl group optionally substituted by one or more polar gr
REFERENCES:
patent: 3965254 (1976-06-01), Tofe et al.
patent: 4104366 (1978-08-01), Schmidt-Dwuyer et al.
patent: 4504462 (1985-03-01), Van Duzee et al.
Griffiths David V.
Kelly James D.
Amersham International plc.
Maples John S.
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