Organic compounds -- part of the class 532-570 series – Organic compounds – Radioactive metal containing
Patent
1985-08-23
1989-07-25
Terapane, John F.
Organic compounds -- part of the class 532-570 series
Organic compounds
Radioactive metal containing
424 11, 423 2, 423 49, A61K 4902, C07F 1300
Patent
active
048515159
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the preparation of radiopharmaceuticals, and in particular to the preparation of technetium-99m (.sup.99m Tc)--labelled radiopharmaceuticals.
Radiopharmaceuticals are diagnostic or therapeutic agents by virtue of the physical properties of their constituent radionuclides. Thus, their utility is not based on any pharmacologic action. Most clinically used drugs of this class are diagnostic agents incorporating a gamma-emitting nuclide which, because of its physical or metabolic properties, localizes in a specific organ after intravenous injection. Images reflecting organ structure or function are then obtained by means of a scintillation camera that detects the distribution of ionizing radiation emitted by the radioactive drug. The principal isotope currently used in clinical diagnostic nuclear medicine is reactor-produced metastable technetium-99m.
Many methods have been described for the reduction of pertechnetate (.sup.99m TC.sup.VII O.sub.4.sup.-) in the preparation of .sup.99m Tc-radiopharmaceuticals. Reducing agents which have been used include stannous ion, electrolysis, ferrous ion, ferrous-ascorbate, formamidine sulphinic acid and sodium borohydride (Deutsch et a., 1983). These labelling procedures generally lead to the reduction of technetium to the Tc(IV) or Tc(V) oxidation state. In many cases the compound prepared contains the TcO moiety (Deutsch, 1979). Because of problems experienced with these reducing agents, the use of a substitution route for the production of .sup.99m Tc-radipharmaceuticals has been advocated (Deutsch & Barnett, 1980). The agents normally used for substitution reactions are TcOX.sub.5.sup.2- and TcX.sub.6.sup.6- (X=Cl, Br) in which technetium is in the Tc.sup.V and Tc.sup.IV valency states respectively.
The present inventors have investigated the preparation of .sup.99m Tc-radiopharmaceuticals containing the TcN moiety, and have discovered that the TcN moiety is extremely stable to hydrolysis and that the nitrido group remains firmly attached to the Tc atom throughout a number of substitution reactions.
According to the present invention, there is provided a novel group of compounds containing the TcN moiety, as well as methods for the preparation thereof and methods for the preparation of .sup.99m Tc-radiopharmaceuticals utilizing these compounds.
According to a first aspect of the present invention, there are provided compounds of the formula I: another alkali metal, or ammonium, and X represents a halogen group, particularly a chloro or bromo group.
The compounds of this aspect of the invention are characterized by the presence of the nitridotetrahalotechnetium-99m anion in which Tc is in the Tc.sup.VI valency state, and which has been found to have particular utility in the preparation of radiopharmaceuticals containing the TcN moiety.
In another aspect of this invention, there is provided a process for the preparation of compounds of the formula I as described above, which comprises reaction of a compound containing the .sup.99m Tc-pertechnetate anion (R[.sup.99m TcO.sub.4 ], wherein R represents a cation such as alkali metal, or ammonium), with an azide compound, such as sodium azide, in the presence of a hydrohalic acid, such as hydrochloric or hydrobromic acid.
In another aspect, there is provided a method of producing a .sup.99m Tc-labelled product, which comprises reacting a compound of the formula I with a ligand. Suitable ligands includes, for example, methylene diphosphonate (MDP), thiourea (TU), thiomalate (TMA), dimercaptosuccinate (DMSA), gluconate (GLUC), N-(2,6-diisopropylphenylcarbamoylmethyl)iminodiacetate (PIPIDA), N-(2,6-dimethylphenylcarbamoylmethyl)iminodiacetate (HIDA) ethane-1-hydroxy-1,1-diphosphonate (EHDP), diethylenetriaminepentaacetate (DTPA), and cysteine (CYS). Other ligands which may be used in accordance with the present invention include thiouracil, diethyldithiocarbamate, mercaptopyridine, mercaptopyrimidine, thiooxine, acetylacetone, pyridoxal, oxine, tropolone and tetracycline. Monoclonal antibodies which ma
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Baldas John
Bonnyman John
Terapane John F.
The Commonwealth of Australia
Thomas J. E.
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