Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Patent
1996-04-09
1999-12-07
Dees, Jose' G.
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
534 14, A61K 5104, C07F 500
Patent
active
059978430
DESCRIPTION:
BRIEF SUMMARY
PRIOR ART DISCUSSION
U.S. Pat. No. 4,615,876 discloses neutral technetium complexes of diaminedioxime (or bis aminooxime) ligands having 2 to 4 carbons in the bridging group. The emphasis is on PnAO which forms stable, relatively lipophilic technetium complexes. PnAO analogues and derivatives are disclosed for various radiopharmaceutical applications including brain imaging and myocardial metabolism studies (using PnAO-fatty acid conjugates). The only butylene-bridged ligand complex prepared was the parent Tc-BnAO which was shown to be neutral, stable and less lipophilic than Tc-PnAO. ##STR1##
Volkert et al..sup.(1) (1984) studied the radiolabelling and rat biodistribution of the .sup.99m Tc complexes of EnAO, PnAO and BnAO. .sup.99m Tc-BnAO was found to exhibit insignificant brain uptake (0.12% injected dose at 30 sec pi) whereas with Tc-EnAO and Tc-PnAO the figures are 0.74% and 1.3% respectively. Consequently subsequent radiopharmaceutical development focused on PnAO ligands and desmethylated PnAO analogues have been patented as technetium brain imaging agents (U.S. Pat. No. 4,789,736 and U.S. Pat. No. 4,818,813).
Budsky et al..sup.(2) (1990) outline a synthesis of the BnAO analogue shown (n=4). Therefore, despite the fact that Tc-BnAO was first disclosed in 1984, no radiopharmaceutical applications for this ligand system have been described. ##STR2##
Jurisson et al..sup.(3) (1987) characterised the technetium complexes of a series of diaminedioxime ligands with n=2 to 5. X-ray crystal structures of the .sup.99 Tc complexes confirmed that both EnAO and PnAO.sup.(4) give technetium complexes with a Tc(V) monoxo core, whereas PentAO has a Tc(V) dioxo core. .sup.99 Tc-BnAO was not crystallographically characterised, but infra-red data suggested a dioxo core.
Troutner et al..sup.(5) (1986) disclosed the technetium complex of an EnAO analogue with expanded chelate rings, H.sub.2 dddo. The complex was found to be less lipophilic than Tc-PnAO. ##STR3## 2 Hypoxia Imaging
Radiopharmaceuticals which selectively concentrate in hypoxic cells are highly desirable since they could permit the diagnosis of potentially salvageable tissue which is at risk of infarction. Organs of interest for imaging would include heart and brain. Certain tumours are also known to be hypoxic, hence a hypoxia-specific radiopharmaceutical could also be used for the diagnosis and radiotherapy of tumours. It is also believed that hypoxia-selective radiopharmaceuticals could be useful for the detection of peripheral vascular disease.
Various nitro-heteroaromatic compounds including radiosensitisers such as misonidazole are known to be trapped in hypoxic cells. Preferred examples are 2-nitroimidazoles. .sup.18 F-radiolabelled and radioiodinated misonidazole analogues have been described for hypoxia imaging and include .sup.123 I-iodoazomycin arabinoside (IAZA).sup.(6,7) and .sup.18 F-misonidazole.sup.(8).
The preferred isotope for radiopharmaceutical imaging is .sup.99m Tc by virtue of both its availability and imaging characteristics. Prior art attempts to design a radiometal (e.g. .sup.99m Tc, .sup.186 Re or .sup.188 Re) hypoxia agent were based on a conjugate of a radiometal ligand and a hypoxia-localising moiety, such as a nitroimidazole.
Thus EP 417870 claims nitroimidazole conjugates of diaminediphenol and PnAO ligands. A .sup.99m Tc complex of a diaminediphenol-nitroimidazole conjugate is disclosed which has a hypoxic/oxic ratio of 2:8 in an in vitro cell model. EP 441491 A1 discloses boron-capped tris (dioxime) "BATO" technetium complexes in which the boronic acid moiety is functionalised with a nitroheteroaromatic hypoxia-localising moiety.
EP 544412 A2 claims a range of diaminedioxime (n=2-5) and N.sub.2 S.sub.2 diaminedithiol ligands functionalised with at least one hypoxia-localising moiety. Such hypoxia localising groups are described in detail on pages 7-10 and claims 18-22 of the application. The localising groups described encompass a wide range of nitroheterocycles. The supporting Examples are limited to 2 particular ligand s
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39th Annual Meeting of the Society of Nuclear Medicine, Los Angeles, California, USA, Jun. 9-12, 1992. Linder K.E. et al., `Chemistry of a Technetium-PNAO-Nitromidazole Complex that Localizes in Hypoxic Tissue`& J. Nucl. Med., vol. 33, No. 5 Suppl., pp. 919, 1992, see Abstract No. 400.
39th Annual Meeting of the Society of Nuclear Medicine, Los Angeles, California, USA, Jun. 9-12, 1992. Di Rocco R.J. et al., `Imaging Regional Hypoxia with a New Technetium-Labeled Imaging Agent in Rabbit Myocardium After Occlusion of the Left Anterior Descending Coronary Artery` & J. Nucl. Med., vol. 33, No. 5 Suppl., pp. 865, 1992. see Abstract 171.
J. Med. Chem., 1994, vol. 37, No. 1, pp. 9-17, Linder K.E. et al., `TcO(PnAO-1-(2-nitroimidazole))[BMS-181321], a new technetium-containing nitroimidazole complex for imaging hypoxia: synthesis, characterization, and xanthine oxidase-catalyzed reduction`, see the whole document.
Archer Colin Mill
Burke James Frederick
Canning Lewis Reuben
Edwards Barbara
King Adam Charles
Amersham International plc
Dees Jos,e G.
Hartley Michael G.
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