DE3018472A1 - NEW PHTHALOCYANINTETRASULFONIC ACID METAL COMPLEXES AND COMPOSITIONS CONTAINING SAME FOR DETECTING TUMORS - Google Patents

Description

DR.-ING. WALTER ABITZ - ι. ™ »« *. ». . ^{14 May 198} °

DR. DIETERF, MORF DIPL.-PHYS. M. GRITSCHNEDER

I'OKtanRchrfit / Postal Address Pübfach 800109, 8000 Munich

_Pim _ _{EtraOe 28}

Patent attorneys Π ^{Telephone eB3222}

Telegrams: ChemlndUB Munich Telex: (0) 5 23992

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. UNIVERSITEDESHERBROOKE Boulevard de I ¹ Universite, Sherbrooke _f Quebec , Canada

New phthalocyanine tetrasulfonic acid metal - "'. Complex- and tumor detection compositions containing them

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description

The present invention relates to new organometallic complexes containing a short-lived, y-radiation emitting isotope metal. The invention also relates to the production of the new complexes from phthalocyanine tetrasulfonic acid and the short-lived, γ-radiation-emitting metal isotopes. The novel products according to the invention can be injected into the blood of mammals if they are dissolved or dispersed in a biologically sterile, aqueous medium which is essentially isotonic with the body fluids of the mammal, and you can then with their help and with conventional scanning methods or track. sampling malignant tumors or growths.

Radiochemistry has found wide application in the fields of medicine and biology. It has long been known that the introduction of compounds containing a radioisotope (or marked with a radioisotope) into organisms allows an insight into the anatomy, physiology and metabolic processes of the organism. These compounds, commonly referred to as radiopharmaceuticals, are particularly useful for diagnostic purposes, including studying the structure or function of internal organs such as the brain, kidneys or liver using radiation detectors. For diagnostic purposes, isotopes with a short half-life and an emission spectrum rich in γ-radiation (in contrast to α- or ß-radiation or particles) are preferred.

The metastable isotope Tc-99m has a half-life of 6 hours and an emission spectrum (99% γ radiation at

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140 KeV), which is particularly useful for diagnostic purposes in the Nuclear medicine is suitable. Thus, Tc-99m has a high specificity

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Activity, 5.28 10 millicuries per gram (mc / g) and a suitable rapid rate of disintegration; while the daughter product Tc-99 has a specific activity that is nearly nine orders of magnitude lower and a half-life that is nearly nine orders of magnitude longer. Due to the slow rate of decomposition of the relatively stable Tc-99, which has a low specific activity, to a pure decomposition product (ruthenium), no: '_-. Generates amounts of radiation that could be harmful to the organism to be examined or diagnosed, regardless of the biological route or the route of excretion of a Tc-99m radiopharmaceutical. For the researcher or medical professional, the emission spectrum of Tc-99m offers a high degree of accuracy in radio diagnostic measurements and calculations. Using selective elution from a molybdenum-99 (Mo-99) generator, the Tc-99m has recently become readily available in hospitals. The isotope Mo-99 produces the Tc-99m as a radioactive decay product.

Although Tc-99m compounds are therefore considered to be ideal radiopharmaceuticals are to be considered for the diagnosis, the provision or selection of Tc compounds or complexes in the With regard to organ specificity and tolerable toxicity values a difficult task. Obvious are connections with a low LD 50 value undesirable for use in humans or animals, even in the small amounts, which are required for diagnosis. Compounds with insufficient "in vivo" stability can be used as diagnostic tools be insufficient because radioactive ions or other chemical species with an insufficient or undesired Organ specificity can be released. Stable connections, which regardless of their stability in general in the organism are distributed, or which do not reach a desired destination in the organism, are also for many examinations or organ function or structure examinations, for example liver and gall bladder examinations, are not very suitable.

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For such examinations of organ functions, compounds that are specific for a particular organ are, however, by means of these are not excreted (or, if they are excreted, easily absorbed), likewise inadequate.

Some Tc compounds or complexes have been developed for special investigations. For example, a liver-specific 99m-Tc-6,8-dihydrothioctic acid complex was developed with which one can gain valuable insight into liver function by measuring the radioactivity emanating from the liver, gall bladder, intestine and the excretions of the organism or patient being examined ( U.S. Patent 3,873,680). It has been found that technetium-99m in conjunction with organic calcium chelates in the presence of iron (II) sulfate is a suitable aid for getting an idea of the kidneys, for kidney function tests and for other vascular tests (US Pat. No. 3,446,361 ). A preparation of ethane-1-hydroxy-1,1-diphosphonate in an acidic solution of tin (II) chloride, mixed with 99m-TcO _{4, has been} proposed for use in radiographic bone skeleton examination methods (US Pat. No. 3,735,001). The brain and kidneys can be examined with an iron complex labeled with Tc-99m (US Pat. No. 3,787,565). It is also known that macroaggregates of serum albumin labeled with Tc-99m are useful in the study of lung function (U.S. Patents 3,803,299 and 3,862,299). Various other compounds of technetium-99m have been suggested for numerous other purposes, such as in U.S. Patents 3,812,264, 3,852,413, 3,863,004, and 3,683,066.

In J. Nucl. Med. _5, 462 (196.4) it was reported that with Co-57 labeled derivatives of tetraphenylporphyrin sulfate are, however, not useful in the detection of cerebral tumors in the detection of other tumors. Almost 40% of the Co-57 was in the separated state, which was partly failure of localization of a radioisotope in tumors explained.

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Despite these developments, there remains a need for radiopharmaceuticals that are rapidly and selectively concentrated in particular tissues. It seems extremely desirable to have available radiopharmaceuticals which have an affinity for malignant tumors or tumor cells in order to be able to make an early tumor diagnosis and metastasis diagnosis.

It is also known that phthalocyanines and in particular the tetrasulfonic acid derivatives of phthalocyanines show a behavior similar to that of naturally occurring porphyrins. Phthalocyanine is a heterocyclic ring compound that consists of four benzisoindole nuclei that are connected to one another via nitrogen bridges. It is known that these compounds form stable chelates with metal ions and certain metal oxides. Metal phthalocyanines can be made by replacing the central ion of lithium phthalocyanine with the desired metal. One such class of metal phthalocyanines, which have been prepared, the actinide and lanthanide and rare earth-phthalocyanines, and in particular the sulfonated Urany! Phthalocyanine which a locally determinable in U.S. Patent 3,027,391 as useful in the treatment Swelling can be described by direct injection of uranyl phthalocyanine into the swelling of the animal.

It is obvious that these sulfonated heavy metal phthalocyanines can only be used meaningfully if When the tumor has been located by other means and they are only useful for the therapeutic treatment of the already localized tumor, either when the parent heavy metal is a ratio-active nuclide, the tumor being destroyed by the radiation, or when that Heavy metal is a fissile or neutron-activatable nuclide. Unfortunately, this procedure cannot locate a tumor, but only make it more radioactive Treatment can be used, and thus with its help not the presence of a tumor and its being discovered

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Treatment can be done by other means, such as surgical removal.

As it is well known that the main problem with malicious Growths or swellings as early as possible Discovery exists, so appropriate treatment as early as possible as possible, it seems extremely desirable to have a safe radioactive method available for this type of detection.

According to the invention, it has now been found that malignant tumors can easily be detected by using new complexes of short-lived, γ-radiation-emitting metal isotopes and phthalocyanine tetrasulfonic acid. It has been found that these new complexes are particularly valuable because of their affinity to malignant growths or tumors to determine the presence, the local situation and the size of the malignant growths or tumors by means of usual radioactivity scan method.

The short-lived T-radiation emitting metal isotopes that can be combined with phthalocyanine tetrasulfonic acid to form the novel radiopharmaceutical complexes of the present invention are technetium-99m, gallium-67, gallium-68, mercury-197, copper-64, chromium-51 , Cobalt-57, indium-111 and zinc-62. Preferred complexes for examinations in which the result can be seen within 12 hours are technetium-99mphthalocyanine tetrasulphonic acid and gallium-68-phthalocyanine tetrasulphonic acid, since technetium-99m and gallium-68 are easily available from a generator when required and also because of the short duration Half-life of 6 hours or 68 minutes. Although technetium-99m is currently the most widely used isotope in clinical practice, gallium-68 is becoming equally important because of recent developments in tomographic positron instrumentation. For .Areas of application in which the results within longer periods of time of up to 120 hours after

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To be visible after the injection, complexes with metal isotopes are used with a half-life of about 3 days preferred, including gallium-67-phthalocyanine tetrasulfonic acid and Indium-111-phthalocyanine tetrasulfonic acid.

The novel compounds according to the invention can either by that of Weber et al. in Inor. Chem. 4, 469 (1965) Condensation method or by the direct marking method.

The condensation process consists essentially in the fact that you monosodium sulfophthalic acid with the short-lived, 7-radiation-emitting metal isotope in nitrobenzene at 200 ⁰ C or at a higher temperature in an inert gas atmosphere in the presence of a reducing agent composed of hydroxylamine, urea and ammonium chloride and in the presence of a catalyst such as for example ammonium molybdate, condensed. The reaction mixture is ^{heated to about 90 °} C. and concentrated in a stream of nitrogen. The condensation takes place when the residue is heated to 235 ° C. or a higher temperature, depending on the selected metal isotope, for about half an hour.

Nevertheless, this method has the disadvantage that a mixture of labeled isotopes of tetrasulfophthalocyanine complexes is obtained and these must be purified to remove unreacted starting materials, such as the reactants and the free metal isotope, so that a certain time is lost, which is a disadvantage when a metal isotope with a very short half-life of around 3 hours. There is then a race against time instead of performing the desired injection procedure on the patient to be examined. Still, this is the im Only procedures available at the moment when an isotope of metal such as technetium is used, which for the direct marking process because of its chemical properties is not particularly suitable.

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Λ.

As an alternative to this, the products according to the invention can also be obtained by the direct marking process. In this process, the tetrasulfophthalocyanine obtained by the sulfonation of phthalocyanine is separated off in order to obtain the main component, which is then labeled directly with the desired metal isotope using known processes. This method is preferably used with metal isotopes other than technetium. In the direct marking process, the metal isotope is added to an aqueous solution of tetrasulfophthalocyanine and the whole is ^{heated to 100 °} C. for 10 to 30 minutes after the pH has been adjusted to a neutral or slightly basic value.

The new phthalocyanine tetrasulfonic acid complexes with the short-lived, Metal isotopes emitting γ-radiation are suitable for diagnosing the presence of tumors in the animal body after they have been injected into the blood.

Phthalocyanines and the analogous sulfonated compounds are non-toxic, and even their complexes with toxic metals lead to non-toxic metal complexes. Furthermore, since the actual amount of short-lived metal isotopes required for scanning purposes in animals is negligibly small, it has been shown that the corresponding phthalocyanine tetrasulfonic acid complexes are not associated with any noticeable, adverse pharmacological effect when administered to animals for the purpose of tumor detection will.

The present invention is illustrated by the following examples explained in more detail.

example 1

Manufacture of technetium 9 gm-phthalocyanine tetrasulfonic acid (Tc-99m-PcTs )

To a freshly eluted pertechnetate ( ¹¹¹ TcOj) solution (2 ml, containing 50-150 μCi ¹¹¹ Tc, obtained from a

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Mo / ⁱⁿ Tc generator) is Mononatriumsulföphthalsäure mg (8,04,

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3x10 "" inol), urea (6 mg, 10 mol) and 0.1 ml of a solution containing 6x10 m / l ammonium molybdate ((NH.), Mo ₇ O ₂₄ · 4H ₂ O) and 10 m / l ammonium chloride were added . After the addition of hydroxylamine (8.34 mg, 12x10 ~ mol), which reduces the pertechnetate, presumably to technetium oxide (TcO ₂ ) _r , the mixture is heated to 90 ° e and concentrated in a stream of nitrogen. The residue is heated to 235 ° C. within 25 minutes so that condensation takes place. The mixture is then allowed to cool to room temperature, the residue is taken up in 1 ml of water and the whole is poured into a weak anion exchange column (1 ml Amberlite ®IR-45- (OH), filled into a 1 ml plastic syringe, column A) . The column is washed with distilled water (9 ml) and eluted in the opposite direction with 0.1 N sodium hydroxide (10 ml). The eluate is passed directly over a cation exchange column (0.5 ml Amberlite® 12-120 (H), column B), and five 2 ml fractions are obtained. The purified Tc-99mPcTs (10% yield, based on the ratio activity of the original pertechnetate sample) is collected in the third fraction (fraction III, column B). After the adjustment, de $ pH to 7 with 0.1 N hydrochloric acid (about 0.1 ml), the preparation is ready for injection into test animals.

In the same way and starting from the nitrate or chloride salt of gallium-67, copper-64, chromium-51, cobalt-57, indium-111 and zinc-62 one obtains the corresponding gallium-67-phthalocyanine-tetrasulphonic acid, copper-64-phthalocyanine-tetrasulphonic acid, Chromium-SI-phthalocyanine tetrasulfonic acid, cobalt-57-phthalocyanine tetrasulfonic acid, indium-111-phthalocyanine tetrasulfonic acid and Zinc-e ^ -phthalocyanine tetrasulfonic acid.

Example 2

In order to find out the chemical nature of the Tc-99m in the purified Tc-99m-PcTs fraction (example 1, fraction III of column B), a condensation experiment with Tc-99, the long-lived

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Decay Product of Tc-99m. Technetium-99 metal (49.5 mg, 0.5x10 mol) becomes more concentrated in a few drops Dissolved nitric acid, and then a small amount of urea is added to remove any nitrite (ENT) to destroy. After adding a small amount of hydroxylamine, the mixture is dried in vacuo and one is obtained light green solid. The material is dissolved in an aqueous solution of hydroxylamine (2 ml) containing 3-sulfophthalic acid

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(432 mg, 1.61 χ 10 mol), urea (600 mg, 10 mol), ammonium molybdate (7.4 mg, 6x10 mol) and ammonium chloride (53 mg, 10 mol) were added. The reaction mixture is heated covered with nitrobenzene (b.p. 210.9 ⁰ C) and in an oil bath under nitrogen. After the water has evaporated, the hydroxylamine decomposes, which can be seen in the sudden formation of gas. The color of the reaction mixture changes from light purple to black. After adding a further 5 ml of nitrobenzene, the mixture is kept under reflux conditions for 20 minutes. The black precipitate is collected, suspended in absolute methanol, filtered, washed carefully with absolute methanol and then dried. 235 g of a black powder are obtained. The specific activity (ß-decay of Tc-99) shows the presence of 15.3% Tc (w / w), or a 5.6% excess of Tc, calculated for a Tc: PcTs ratio of 1: 1. As a result, the preparation is either contaminated by Tc salts, apart from the Tc-99-PcTs complex, or the complex contains more than 1 mol of Tc per mol of PcTs.

Furthermore, a co-chromatography of a Tc-99-PcTs (1 mg) and a Tc-99m-PcTs preparation in the ion exchange system is also performed (see Example 1), followed by UV analysis of the purified Tc-99m-PcT (fraction III from column B). The UV spectrum shows characteristic absorption maxima at 685 and 595 nm together with a strong absorption band below 300 nm and a shoulder at 305 nm, reflecting the sulfophthalocyanine nature of the eluted material confirmed.

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Example 3

In vivo distribution of Tc-99m-PcTs (fraction III of column B, see example 1)

Female rats (2 kg) are injected i.p. with sodium Nembutal® (Pentobarbital, 30 mg / kg) anesthetized. The purified Tc-99m-PcTs fraction (2 ml, 30 µ Ci) is given i.v. in the edge or Administered lateral artery of the ear. The distribution of radioactivity is determined by scintillation counting with a Dyna®-IV Camera (Picker Nuclear) made visible. The camera is equipped and contains a high-resolution parallel collimator a matrix of 37 photoelectron tubes for an inherent resolution of 0.32 cm (1/8 ").

Five minutes after the injection it arrives in the heart and the Liver area to an enrichment of activity. The kidneys become visible while the bones and especially the bone joints the hind legs can also be perceived. Six hours after the injection there is a strong fixation in the liver, heart area, kidneys, and spleen were observed. The stability of the Tc-99m-PcTs complex is shown by the fact that no activity can be observed in the stomach, thyroid and salivary glands. In comparison, a scintillation measurement shows in a rabbit who was injected with a similar dose of activity in the form of the free pertechnetate ion that in contrast to the Tc-99m-PcTs experiment the stomach, the Salivary glands and thyroid are heavily marked.

Example 4

To increase the organ distribution of the Tc-99m-PcTs as a function of time will examine seven female Fisher 344 CRBL rats The purified radiopharmaceutical is injected via the tail vein (45 μCi in 0.2 ml saline per rat). The animals will killed and dissected after various periods of time. Samples of the liver, kidneys, lungs, muscles, the spleen and blood taken, weighed and the amount of

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Tc-99m in a Spectron®-100 multichannel analyzer that is calibrated to 140 KeV photons (Picker Nuclear). The values are in terms of Tc-99m decay and in terms of the weight differences of the individual animals are corrected or adjusted and the changes in the specific activities are made recorded. From this graph, some obvious distribution patterns can be derived. During the entire examination, a high specific activity is retained in the kidneys, which is a sign of that irreversible retention of the Tc-99m-PcTs in these organs is. The fixation in the liver with a maximum is also important Admission after 12 hours. The spleen and lungs are less active, although the specific activities are during remain constant throughout the experiment. Blood activity increases exponentially with an elimination half-life of 12 hours from. The uptake of Tc-99m-PcTs by the muscle is insignificant and is similar to activity of the blood.

These results indicate that kidney tissues have a strong affinity for Tc-99m-PcTs. A number of other organs, including the liver, spleen, lungs, and heart also hold back this product. The distribution pattern indicates considerable binding in the area of the reticulo-endothelial system at.

Example 5

The fixation or holding of the Tc-99m-PcTs by the various organs can also be derived from the excretion pattern of this radiopharmaceutical. The excretion of the Tc-99m is carried out with three male rats (Sprague-Dawley) . (each about 100 g) determined. To get a uniform pattern obtained, the animals are subjected to a cystectomy (J.P. Bonjour, HeIv. Acta 24, 24 (1966)). Every rat receives a dose of 0.4 μCi / g Tc-99m-PcTs into the tail vein in

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jets. The total activity of the animals is recorded at different time periods with a PHO-V camera (Searle), which is equipped with a high resolution parallel collimator is measured. The animals are squeezed into a narrow cage to keep their position in with respect to the detector. During the entire experiment the animals can eat and drink. The mean values obtained with the three animals are expressed as percentages Activity versus time after injection on a semi-logarithmic basis Paper applied.

The values are corrected for the decay of the Tc-99m and only represent the biological excretion of the Tc-PcT. A two-part curve is obtained which shows that within equilibrium distribution is obtained after 3 hours. The intersection of these two curves} coincides with the maximum uptake in the various organs and in the blood system together. It is evident that during the first three hours after the injection, about 20% of the Tc-99m comes directly from the Blood system to be excreted. The remaining Tc-99m is from the various target tissues released extremely slowly (0.5% per hour). These observations, along with the fact that in the stomach jr in the thyroid and salivary glands no activity occurs (example 3), indicates that no pertechnetate is released from the TcPcTs complex. It also points for an irreversible binding of the TcPcT in the receptor areas the target organs.

Example 6

To determine whether Tc-99m-PcTs are suitable as a tumor detection agent, the hormone-sensitive 13762 breast adenocarcinoma in female Fisher 344 / CRBL rats is used as a model. This Tumor is kept in the ascites form. However, when vaccinated subcutaneously or in soft tissue, it develops a solid tumor. Five animals (150 g each) are im Thigh inoculated with 0.5 ml of the ascites fluid (10 Cells). Three, six, eight and eleven days after vaccination will be

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injected Tc-99m-PcTs into the tail vein of the animals (500 μCi in 1 ml). The activity distribution in the animals is determined by scintillation scanning with a Dyna®-IV camera that is equipped with is coupled to a Cybernex® ordinator system (Chromemco). Selected images are saved on a magnetic disk registered, which allows their representation on a matrix of 128 χ 128 points. The activity of each point will be with Using eight colors that are repeated four times, represented an activity from 0 to 256 counts or pulses to cover. Aside from the overwhelming visualization of the scintillation scan, this procedure also allows quantitative study of the results.

The images available 3 and 6 days after tumor inoculation give only a slight increase in activity at the vaccination site. However, scan examinations 8 days after vaccination show the Animals with Tc-99m-PcTs showed a clear selective uptake of Tc-99m in the tumor. One of the animals is scintigraphed after the Iic examination killed and dissected. In the thigh, the tumor has turned into a solid, solid, vascularized, 0.5 cm. white nodules (25 mg) developed. The activity of the tumor is four times higher than that of a healthy one Muscle tissue removed from the thighs. Eleven days after vaccination, the tumor reaches a diameter of 1 cm (455 mg) and can be made just as easily visible with the new radiopharmaceutical (tumor / muscle ratio 5: 1).

The permanent or permanent fixation of the Tc-99m-PcTs in malignant diseases in the stage of tumor development, i.e. well before the vascularization phase, clearly shows the usefulness of the new radiopharmaceutical as a scanning or Detection agent for the early diagnosis of malignant tumors and their metastases.

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Example 7

Manufacture of GaIlium-67-phthalocyanine tetrasulfonic acid (Ga-67-PcTs) by direct labeling

Phthalocyanine is converted to the tetrasulfonic acid derivative by the method of RP Linstead and FT Weiss, J. Chem. Soc. 2975 (1950) transferred. 0.1 ml of the same buffer containing carrier-free gallium (67Ga ⁺⁺⁺ , 30-50 microcuria) and 40 micrograms of sodium citrate. The mixture is ^{heated to 100 °} C. for 10 minutes and then a sample of 10-25 microliters is applied to a silica gel thin-layer chromatography plate. After developing the plate in acetone: ethyl acetate: water: NH ₄ OH (7: 3: 3: 0.3), the autoradiogram reveals the presence of four radioactive zones with identical migration patterns as the developed blue major components of the unlabeled phthalocyanine tetrasulfonic acid preparation. Unreacted gallium remains at the starting point (84%), while 16% of the radioactivity comes from the Ga7 67-PcTs zones.

The Ga-67-PcTs are cleaned by applying the reaction mixture onto a silica gel column (2 × 0.5 cm), followed by elution with 1 ml of 0.9% saline. The preparation is then ready for use.

Using the same procedure and starting with the nitrate or chloride salt of gallium-68, copper-64, chromium-51, Cobalt-57, indium-111, mercury-197 and zinc-62 are obtained the corresponding gallium-ee-phthalocyanine tetrasulfonic acid, Copper-64-phthalocyanine tetrasulfonic acid, chromium-51-phthalocyanine tetrasulfonic acid , Cobalt-57-phthalocyanine tetrasulfonic acid, Mercury-197-phthalocyanine tetrasulphonic acid, indium-111-phthalocyanine tetrasulphonic acid and zinc-62-phthalocyanine tetrasulfonic acid.

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In summary, the invention relates to new phthalocyanine tetrasulfonic acid metal complexes with metals selected from the group consisting of technetium-99m, gallium-67, Gallium-68, Copper-64, Chromium-51., Cobalt-57, Indium-111, Mercury-197 and Zinc-62. It was found that this Complexes have an affinity for malignant tumors, and they are therefore useful for tracing such tumors and determining their size and location with the aid of a radiation imaging device.

End of description

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Claims (1)

Claims Phthalocyanine tetrasulfonic acid metal complexes with metals selected from the group consisting of technetium-99m, Gallium-67, Gallium-68, Copper-64, Chromium-51, Cobalt-57, Indium-111, Mercury-197 and Zinc-62. 2. Technetium 9gm phthalocyanine tetrasulfonic acid. 3. Gallium 67 phthalocyanine tetrasulfonic acid. 4. Containing metabolic radioactive tumor detection composition a radioactive phthalocyanine tetrasulfonic acid metal complex with a radioactive metal from the, group consisting of technetium-99m, gallium-67, Gallium-68, Copper-64, Chromium-51, Cobalt-57, Indium-111, Mercury-197 and Zinc-62, and a suitable liquid Carrier. 5. Composition according to claim 4, characterized in that it contains technetium-99m-phthalocyanine tetrasulfonic acid and contains a suitable liquid carrier. Composition according to claim 4, characterized in that that they are gallium-67-phthalocyanine tetrasulfonic acid and contains a suitable liquid carrier. Composition according to claim 4, characterized in that it is indium-111-phthalocyanine tetrasulphonic acid and contains a suitable liquid carrier. 0300A8 / 074S ORIGINAL INSPEOTED SHERU 4 5-WG η 8. Composition according to claim 4, characterized in that it is gallium-ee-phthalocyanine tetrasulfonic acid and contains a suitable liquid carrier. 030048/0745