DD291327A5 - MYOCARDYTE TECHNETIUM COMPLEX COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Abstract

The invention relates to singly cationic complexes of technetium which, as potential radiopharmaceuticals, preferentially accumulate in myocardial tissue. The intention of the invention is to bind singly positively charged lipophilic technetium complexes which preferentially accumulate in the myocardium and have a low accumulation rate in adjacent organs such as, for example, the liver. The object includes a process for the production of the complexes found. The object is achieved according to the invention with singly positively charged technetium complex compounds which enter the myocardium and have the general formula [TcL<1>nL<2>m]<+> in which the ligand L<1> is a polydentate sulphide or a polydentate ether, and the ligand L<2> is a monodentate, neutral or basic complexing agent which is either a halide or pseudohalide ion or an organic complexing agent. The combination of the polydentate and of the monodentate complexing agent is chosen so that the charge transferred by the total of the donor atoms to the metal is one unit less than the number of charges on the technetium. Concerning the process, the object is achieved by reacting the complexing agent L<1> with the second complexing agent L<2> either simultaneously in a mixture or in a subsequent reaction in acidic, aqueous or aqueous-alcoholic solution at room temperature with a technetium compound and with a reducing agent.

Description

R ^e -A

with A = OH, SH, NH ₂ , NR ⁷ ₂ , SR ⁷ , PR ⁷ ₂ , -NC and R ⁶ , R ⁷ = H, alkyl, aryl, cycloalkyl, heteroaryl.

2. myocardial complex according to claim 1, characterized in that the complexing agents L ¹ and L ^{2 are} a polydentate thioether and a monodentate thiol.

3. A process for the preparation of complex compounds according to claim 1, characterized in that the complexing agent L ¹ with the second complexing agent L ² either simultaneously in a mixture or in a subsequent reaction in acidic, aqueous or aqueous-alcoholic solution at normal temperature with a technetium compound and a Reducing agent is reacted.

field of use

The invention relates to simple cationic complexes of technetium, which are preferentially roasted as potential radiopharmaceuticals in myocardial tissue.

Characteristic of the known technical solutions Technetium compounds are used as radioactive diagnostic agents for functional and localization of the myocardium

used. The prerequisite for successful drug development is the availability of technetium compounds which, due to their chemical properties, have the biodistribution pattern required for the diagnostic purpose.

Up to now, myocardial uptake has been found predominantly in those technetium complexes which are positively charged and in

where the complexing agent contains organic radicals.

Tc-isonitrile compounds and Tc-DMPE compounds have hitherto been used to assess the perfusion of the heart muscle

[DMPE = bis (dimethylphosphino) ethane] in clinical use.

The ^Wm Tc-hexa MIBI as a Favored Representative of the Isonitrile Complexes (K. McKusick, BL Holman, AG Jones et al., J. Nucl. Med.

[1986] 878) is characterized by a high and constant cardiac uptake, disadvantageous is the initial storage in the lung.

⁹⁹ Tc-DPO as Clinically Applied DMPE Compound (W.Mohnike, J. Schmidt, F. Uhlich, S. Seifert, R. Syra, R. Coin,

NucCompact 18 [1987] 184) is rapidly extracted from the blood, but its high constant affects unfavorably Liver uptake.

^99m Tc-BATO complexes (AD Nunn, EN Treher, T. Feld, J. Nucl. Med. 27 (1986) 893) and various ^99m Tc-arenes (DW Wester,

D. L. Nosco, J. R. Coveney, R. T. Dean, J. Nucl. Med. 27 [1986] 894) are in clinical testing. They could sign up for

a routine application so far not enforce.

When designing new complexes of technetium, it is important that technetium be used as the transition metal

has a high affinity to soft donor atoms. So are preferably complexing agents with sulfur and phosphorus atoms to

Formation of complex compounds with technetium suitable. Sulfur-containing complexing agents are dominated by those containing thiol groups. Implementation of technetium with Complexing agents containing thioether groups are described in (G.F.E.Morgan, J.Pope, J.R.Thornoack, A.E. Theobald, 2nd Intern. Symp. On Technetium, Padua 1986, 65; S.Truffer, E.lanoz, P.Lerch, M.Kosinski, Inorg. Chim. Acta 149 [1988] 217; N.Bryson, J.C.Dewan, J.Lister-Lames, A.G. Jones, A. Davison, Inorg. Chem. 27 [1988] 2154). Of the Tec complexes of these Complexing agents which contain, in addition to one or more thioether groups, amino groups as further complex-forming units

However, no myocardial involvement is known.

Tridentate dithiols with an ether or thioether group give only in the presence of a second monodentate thiol

neutral complexes of technetium (V) (H.J.Pietzsch, H. Spies, S. Hoffmann, Inorg. Chim. Acta 165 [1989] 163) and are thus not myocardial.

Object of the invention

The aim of the invention is the provision of technetium complex compounds, which were preferably enriched in heart muscle with low liver accumulation, as well as their simple production,

Explanation of the essence of the invention

The invention has for its object to find simply positively charged lipophilic Technetiumkomplexe, which are preferably enriched in the myocardium and a low accumulation rate in adjacent organs such. As the liver, and thus can serve for the diagnosis of myocardial damage. The object includes a method for producing the complexes found.

The object is achieved according to the invention with simply positively charged myocardial technetium complex compounds of the general formula [TcL ¹ "L ² _m ] ⁺ in which the ligand L ^{1 is} a polydentate sulfide or a polydentate ether of the general formula

R ¹ -X - [(CR ² R ³ ) rn-Y] _n - (CH'R ³ ) _m -ZR ⁴

with X, Y, Z = O, S or NR ⁶ , where at least one thioether or ether moiety must be present in the molecule, and R ¹ ... R ⁴ = H, alkyl. Cycloalkyl, aralkyl, aryl, heteroaryl (for R ¹ R ⁴ = H is η a 2) or CH ₂ COOR ⁶ , CH ₂ CN, CH ₂ OR ⁸ with R ⁶ = H or alkyl, where R ^{1 is} R ⁴ or CR ² R ³ Jm can also be an alkylene, cycloalkylene or arylene radical and m = 2,3 or η = 0,1,2,3,4, and the ligand L ^{2 is} a monodentate, neutral or basic complexing agent, the either a halide or pseudohalide ion or an organic complexing agent of the general formula

R ^e -A

with A = OH, GH, NH ₂ , NR ⁷ ₂ , 3R ⁷ , HR ⁷ ₂ , -NC and R ^e , R ⁷ = H, alkyl. Aryl, cycloalkyl, heteroaryl. The combination of the multidentate and the monodentate chelating agent is chosen such that the charge transferred from the sum of the donor atoms to the metal is one unit lower than the charge number of the technetium (eg 2 for TcIIII) or O for Tc [I]). Both the thioether and the monodentate complexing agent can be carriers of the negative charge.

Advantageously, the complexing agent used is a mixture consisting of a polydentate thioether and a monodentate thiol.

With respect to the process, the object is achieved by reacting the complexing agent L ¹ with the second complexing agent L ² either simultaneously in a mixture or in a subsequent reaction in acidic, aqueous or aqueous-alcoholic solution at normal temperature with a technetium compound and a reducing agent. The process is preferably carried out such that technetate (VII) is mixed with excess tin dichloride in organic / aqueous solution in the presence of a mixture of both complexing agents dissolved in a water-miscible organic solvent.

Reduction may also be by the complexing agent itself, provided that it has reducing groups. The resulting compounds can be extracted from the aqueous phase with an organic solvent. The multidentate complexing agents L ¹ are, for example, open-chain, neutralo tetradentates, or neutral bidenutes, or dibasic tetradentates or cyclic neutral tetradentates thioethers or their oxygen analogues. The sulfur or oxygen may be partially replaced by nitrogen in the molecule, but the complexing agent must contain at least one thioether or ether moiety.

The additional monodentate complexing agent L ² is either a halide or pseudohalide or an organic monodentate neutral or basic complexing agent, e.g. A thiol, a substituted phosphine, a thioether or a substituted isonitrile.

All o. G. Residual groups are largely variable both in the multidentate and in the monodentate complexing agent and also include Rectte with functional groups, wio, for example, ester, ether or amino groups. The invention is advantageous in that the combination of second different complexing agent a large / izahl different compounds can be represented, which represent potential radiopharmaceuticals for the study of the heart muscle due to their special chemical properties. The variability is further increased by the fact that each complexing agent is variable by substitution on any residual groups. It is also possible to introduce reactive groups, for example hydrolysable ester groups, which may be advantageous with regard to the biological behavior of the compounds.

embodiments

The invention will be explained in more detail by way of example with reference to some concrete embodiments. According to the general formulas for the ligands L ¹ and L ² , the following variants may be mentioned as examples:

for the ligand L ¹

1 a: Et-S-CH ₂ CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -S-Et 1 · '· BU-S-CH ₂ CH ₂ -O-CH ₂ CH ₂ -O -CH ₂ CH ₂ -S-Bu 1c: Et-O-CH ₂ CH ₂ -S-CH ₂ CH ₂ -S-CH ₂ CH ₂ -O-Et 1d: Et-S-CH ₂ CH ₂ -S- CH ₂ CH ₂ -S-CH ₂ CH ₂ -S-Et 1 e: BIt-S-CH ₂ CH ₂ -S-CH ₂ CH ₂ -S-CH ₂ CH ₂ -S-Bu

for the ligand L ² 2a: EtSH 2b: isoprop-SH 2c: C ₆ H ₆ -SH 2d: P-CHOj-C ₆ H ₄ -SH

Taking into account the requirement that the charge transferred from the sum of the donor atom to the metal must be one unit lower than the charge of the technetium, whereby both the thioether and the monodentate complexing agent can be carriers of the negative charge, different combinations of ligands result L ¹ and L ² , of which the following are to be explicitly carried out:

A 1 d + 2 b = bis-isopropyl thiolato O.GA ^ -tetrathiatetradocinltechnetium dll) B 1d + 2c = bis (thiophenolato) (3,6,9,12-tetroxythate tetradecane technetium (III) C 1d + 2c = bispara- methoxythiophenolatol O.e.g.-tetrathiatetradecanltechnetium dll) D 1e + 2c = bisithiophenolatole-S.e.H.U-tetrathiaoctadecanhechnetium dll) To these exemplified target compounds involving the inventive method for To produce biodistribution studies, the procedure is, for example, as follows:

3 mg of ligand L ¹ (TTTD) and 5 mg of ligand L ² (isopropyl mercaptan) are dissolved in 4 ml of acetone. To this is added 1.6 pmol of ⁹⁹ % Tc-TcO ₄ and 2 ml of ^Mm Tc-TcO ₄ generator eluate. After addition of 2 mg of SnCl ₂ .2H ₂ O in 100 μΙ 0.1 N HCI the solution with extracted 3 ml of chloroform. The solvent is removed in a stream of nitrogen and the residue taken up in 0.5 ml of ethanol. It is then made up with 4 ml of propylene glycol, filtered and treated with 1.5 ml of water. The solution is ready for injection.

Following this procedure, when using the o.g. Ligand combinations the injectable preparations A to D

manufactured.

These preparations show in animal distribution studies in rats the marked uptake into the heart muscle shown in the table. Table: Organ distribution values according to i. v. injection to Wistar rats

organ zeitp.i. A Test preparation [% dose / g] C D [Min] 2.5 B 2.3 1.2 heart 5 2.2 1.8 2.0 0.6 30 2.0 1.6 1.9 0.6 60 1.6 1.5 3.4 0.7 blood 5 1.2 1.2 2.2 0.6 30 0.6 0.7 1.7 0.6 60 2.5 0.5 4.0 5.6 liver 5 2.0 3.9 2.5 3.5 30 1.5 2.2 2.1 2.5 60 2.0

Autoradiographic recordings of the rat heart show an activity storage preferentially in the left ventricular myocardium

in good contrast to the heart interiors.

In order to be able to carry out a clear chemical-physical characterization of the compounds according to the invention,

their representation in crystalline form is required. Such a preparation may, for. B. be done as follows:

30μs (148pmol) of KTcO ₄ dissolved in 5ml of water are solubilized with 60mg (222μιηοΙ) of ligand L '[3,6,9,12-tetrathiatetradecane (TTTD)] and 34mg (444μηηοΙ) of ligand L ² (isopropylmercaptan) in 8 ml of acetone.

After addition of a solution of 170 mg of SnCl ₂ 2 H ₂ O in 0.5 ml of 0.1 N HCl, the reaction mixture turns dark red. The solution will be

Stirred for 20 minutes at room temperature and then brought to dryness. The residue is extracted to remove the excess complexing agent with 3x 5 ml of ether, then taken up in 4 ml of acetone, filtered off unroasted product and the solution added with 6ml of water.

A total of 50 mg of KPF _{6 are} added to this solution over a period of 10 minutes with stirring. The fancy deep red Product is separated, washed first with 3x 1 ml of water, then with 5x 1 ml of ether, taken up in 3 ml of chloroform

and mixed with 3 ml of ether. The complex crystallizes in the form of black, compact crystals.

Yield: 41 mg (42%) The elemental analysis (C, H, S, Tc) corresponds to the composition [Tc (TTTD) (SR) ₂ ] PFe [bis (isopropylthiolato] (3,6,9,12-

tetrathiatetradecanltechnetiumdlDhexafluorophosphat). The presence of both the multidentate complexing agent and the monothiol in the complex are confirmed by IR and 'H NMR data.

Using the above-mentioned other possibilities of combining the ligands L ¹ and L ² are analogous Bis (thiophenolato) (3,6,9,12-tetrathiatetradecane) technetium (III) hexafluorophosphate and bis (para)

methoxythiophenolato) (3,6,9,12-tetrathiatetradecane) technetium (III) hexafluorophosphate and bis (thiophenolato) 5,8,11,14-tetrathiaoctadekanltechnetiumdlDhexafluorophosphat prepared and characterized spectroscopically.

Claims (1)

1. Simply positively charged myocardial technetium complex compounds of the general formula [TcL ¹ _n L ² _m l ⁺ , characterized in that L ^{1 is} a polydentate sulfide or a polydentate ether of the general formula R ¹ -X - [(CR ² R ³ ) rn-Y] _n - (CR ² R ³ ) _m -ZR ⁴ with X, Y, Z = O, S or NR ⁵ , wherein at least one thioether or ether moiety must be present in the molecule, and R ¹ ... R ⁴ = H, alkyl, cycloalkyl, aralkyl, aryl, heteroaryl (for R ¹ R ² = H is η> 2) or CH ₂ COOR ⁵ , CH ₂ CN, CH ₂ OR ⁵ , with R ⁶ = H or alkyl, where R ¹ R ⁴ or (CR ² R ³ Jm also an alkylene , Cycloalkylene or arylene and m = 2,3 or η = 0,1,2,3,4 and L ^{2 is} a monodentate, neutral or basic complexing agent containing either a halide or pseudohalide or an organic complexing agent of the general formula