JPH04506672A - metal complex - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] metal complex The present invention provides a novel radioactive metal complex and a method for using this complex, particularly in the context of cell labeling. Relating to therapeutic and especially diagnostic uses.

Radioactive indium and gallium when labeled to blood cells are suitable for clinical settings. It is widely used in clinical methods. Labeling of red blood cells is a pancreatic contrast or red blood For the measurement of sphere mass, platelet labeling is used to determine whether platelet survival and kinematics are impaired or focal. It has wide relevance in the diagnosis of sepsis and in the diagnosis of tumors and metastatic tissue.

Radioactive indium and gallium are generally used in the form of metal complexes.

That is, the present invention provides a neutral 3=1 ligand:metal (I[[) complex, where The trivalent metal cation is a radioactive isotope of indium or gallium; Each ligand separately has the following compounds; (1) 3-hydroxy-4-pyrone, with one or more pyrones bonded to a carbon atom of the ring Those substituted with one or more groups selected from oxy groups (however, 3- (excluding hydroxy-2-methyl-4-pyrone): or (2) (a) 3-hydro Roxypyridin-2-one, or (b) 3-hydroxypyridin-2-one and the hydrogen atom bonded to the nitrogen atom is an aliphatic acyl group, 1 to 6 carbon atoms aliphatic hydrocarbon group having atoms, or aliphatic acyl, alkoxy, cycloalco selected from xy, aliphatic amide, aliphatic ester, halogen and hydroxy group. Substituted with an aliphatic hydrocarbon group substituted with one or more substituents , and optionally (C) 3-hydroxypyridin-2-one, One or more hydrogen atoms bonded to a carbon atom is one of the above substituents, 1 to 6 carbon atoms an aliphatic hydrocarbon group having a child, or an aliphatic hydrocarbon group having alkoxy, silyl, Substituted by chloroalkoxy, aliphatic ester or hydroxy groups , or substituted with one or more halogen groups; The complex consists of the above complex.

A metal complex containing a certain ligand present in the metal complex of the present invention can be used to treat iron deficiency anemia. British Patent Nos. 2.111.766 and 2.128.998 are used for medical treatment. and No. 2°136,806. British Patent No. 2.117.766 No. 3 and No. 2.136.806 use different nomenclature; -Hydroxypyridin-2-one is called 3-hydroxypyridin-2-one. It is. However, these two names are used for a certain ring as shown in formula (V) below. They have the same meaning to indicate a system.

However, in order to obtain complexes for use in certain - therapeutic relationships, complexation of - with metals The suitability of the ligand for obtaining the complex for use in different therapeutic or diagnostic contexts does not indicate its value on complexation with another metal. In particular, the complex of the present invention Regarding the primary diagnostic use of the body, the problem to be solved by the present invention is , which is quite different from the problem with iron complexes. In iron complexes, the ligands are Iron must be released which is then recombined with apotransferrin.

For indium and gallium complexes, the complexes bind to cells and transmit signals. I have to be able to send it out.

The different requirements needed to use the ligand for the two purposes are Certain selected 3-hydroxypyridine-4-pyridines rather than sc-4-ones As shown in the recent literature on Ron and 3-hydroxypyridin-4-one . That is, the inorganic chemistry of Finnegan et al. - (Inarg, Chern, ), Engineering 987.26.2171-2176, and Matsguke et al., Inorganic Chemistry, 1988.27.3935-3939, various indium and gallium complexes characteristics are described. These studies demonstrated that 3-hydroxy-4-pyrone and 3 -Hydroxy-2-methyl-4-pyrone, as well as certain 3-hydroxypyridi suggests that ion-4-ones can be used to chelate these metals. There is. However, 3-hydroxy-2-methyl-4-pyrone (maltol) is The preferred ligand for use in the iron complex of Patent No. 2.128.998 is As discussed below, this is another substitution for use with indium and gallium. -Inferior to hydroxy-4-pyrone.

Preferred radioactive isotopes are those that emit X-rays or positrons. preferred Isotopes such as indium radioisotopes 111 and 113, especially 111 , and the gallium isotopes 66, 67, 68 and 72, especially 67 and 68 .

Indium-111 disintegrates by emitting gamma radiation of 17] and 245 keV. and has a half-life of 67.2 hours, making it particularly suitable for use in the present invention. Ru. Similarly, gallium-67 emits gamma radiation at 185 and 300 keV. It is particularly suitable because it disintegrates and has a half-life of 78°26 hours. gallium 66 and 68 are suitable positron emitters.

The metal ('III) complexes used in the present invention include indium and gallium in trivalent form. Contains. Metal(III) complexes are neutral, i.e. metal cations and There is an internal charge balance between the non-conjugated ligand and the non-conjugated Such electrical equilibrium is achieved by the presence of operably bound ion(s). There is no need to make it a state. That is, these ligands are -basic bidentate ligands, For the removal of protons from the hydroxyl group of the ligand of the compound forming the ligand (OH-0-) is formed. Therefore, - basic bidentate ligand: metal (Ill) The gold@(■) complex in a ratio of 3:1 is neutral.

The complexes according to the invention can be prepared with various variations of the three ligands of type (1) and (2). combinations may be included. That is, all three ligands in the complex are from type (1) , or type (2), and if necessary, these types of coordination Each child may choose a different one. Alternatively, the three ligands are , the two types may be selected in a 2:1 ratio. i.e. the same or Two ligands derived from two different 3-hydroxy-4-pyrones and one 3-hydroxypyridin-2-one, or the same or two different Two ligands derived from 3-hydroxypyridin-2-one and one 3-hydro It may also be a roxypyrone ligand.

However, particularly useful complexes contain three ligands of type (2), especially type (1). It is a complex. Advantageously, these ligands are the same.

For 3-hydroxy-4-pyrone ligands of type (1), these 3-hydroxy Droxy-4-pyrone may have one or more substituents, but if two groups Substitution with two groups is useful when at least one is an aliphatic hydrocarbon group. Substitution with one group rather than substitution with two or three groups, except that is preferred. The term aliphatic hydrocarbons herein refers to saturated or unsaturated acyclic or It means a cyclic group, and an acyclic group may have a branch, but especially a straight group. Make it chain-like. Methyl groups can be useful when extra substituents are present at the same time. Groups having 2 to 6, especially 3 to 5 carbon atoms are very useful. Ru. Saturated aliphatic hydrocarbon groups are preferred; these include cycloalkyl groups (cyclopropylene); cyclic groups (such as cyclopyl and cyclohexyl), or especially acyclic groups such as alkyl groups (methyl or ethyl) and especially propyl, butyl and pentyl (and with branched its congeners). Fats substituted by aliphatic hydrocarbyloxy groups The same applies to aliphatic hydrocarbyl groups present in substituents that are aliphatic hydrocarbon groups. (The aliphatic hydrocarbyloxy group may sometimes be a methoxy group). Ma Many aliphatic hydrocarbon groups are substituted by aliphatic hydrocarbyloxy groups. In this case, a methyl group may be used.

As used herein, the term "alkyl" refers to linear or branched chains. individual alkyl groups, such as propyl, mean only straight-chain groups. shall be tasted. The same applies to other general terms.

If 3-hydroxy-4-pyrone contains a substituted aliphatic hydrocarbon, this group , fluoro group, hydroxy group and aliphatic hydrocarbyloxy group. It is desirable to include a substituent.

Alternatives to using aliphatic hydrocarbon groups as substituents in 3-hydroxy-4-pyrone or in addition, a fluoro-substituted aliphatic hydrocarbon, e.g. 5, 9 The above-mentioned general or substituted with one or more fluoro groups, such as may use certain types of aliphatic hydrocarbon groups. fluoro-substituted aliphatic The hydrocarbon group preferably contains 1, 3 or 5 fluorine atoms, with special examples is L L, 2.2.2-pentafluoroethyl group and 3.3.3-triph It is a fluoropropyl group.

Alternatives to using aliphatic hydrocarbon groups as substituents in 3-hydroxy-4-pyrone or in addition, a hydrocarbyloxy-substituted aliphatic hydrocarbon group. Hydroxy-substituted aliphatic carbons may also be used, and to a lesser extent, hydroxy-substituted aliphatic carbons. Hydrogen radicals, especially hydrogen atoms substituted at the carbon atom of the aliphatic group attached to the pyrone ring. Chill groups or other aliphatic hydrocarbon groups may also be used. Substituted aliphatic hydrocarbons contains substituents other than fluoro, there is usually only one hydrocarbyloxy group Or a hydroxy group is present.

It is particularly useful to substitute the 6-position or especially the 2-position, or both positions. , when the ring is substituted by a larger substituent, -CO-C(OH) It is advantageous to avoid substitution on the α carbon atom of the system. This system is indium or One of the relatively large aliphatic hydrocarbons that occurs when complexing with gallium. in close proximity may induce steric hindrance and prevent complex formation.

Examples of hydroxypyrones which provide ligands that can be used in the complexes according to the invention are of the formula (r ), and certain useful hydroxypyrones have formulas (II), (m) and (1■) has.

In the formula, each R is individually represented by (compound 3-hydroxy-2-methyl-4-pi alkyl or cycloalkyl groups (with the exception of The group contains 3 or 5 fluoro, alkoxy or hydroxy groups, e.g. substituted by ethyl, broyl, isopropyl, butyl or pentyl groups ), its fluoro-substituted derivative groups containing 3 or 5 fluorine atoms (especially 1. 1.2.2.2-pentafluoroethyl or 3.3.3-trifluoropropyl ), or cl-4 alkoxy-substituted derivative groups thereof (especially methoxymethyl, ethoxymethyl, propoquine methoxy or butoxymethyl), and n is 1.2 or It is 3. Preferred compounds are 2-alkyl, 2,6-dialkyl, 2-fluoro loalkyl, 2-alkoxyalkyl, 2-hydroxyalkyl or 6-alkyl It is an alkyl-substituted compound with 2-hydroxy.

Among these compounds are 2-ethyl-3-hydroxy-4-pyrone; 2-(1'-methylethyl), 2-propyl, 2-butyl and 2-pentyl family [ethyl-maltol, isopropyl-maltol, propyl-maltol, Petit Lou Maltre and bench roof / l / tall; IL R = CzHs, CH ( CHs)zcHs or (CH2)sCH3] is its 1', 1', 2° , 2°, 2'-pentafluoroethyl and 3', 3', 3-trifluoropropyl [II, R''CF!CFs and R=CH 2CH2CF sco.

Also particularly useful are compounds of formula (m) in which R is an alkoxymethyl group and 6 R at the position is an alkyl group, and the R group at the 2nd position is an alkyl or 1-hydroxyalkyl group. Compounds of formula (IV) which are a radical such as 3-hydroxy-6-medoxymethyl- 4-pyrone, 6-ethoxymethyl-3-hydroxy-4-pyrone, 3-hydroxy C-6-bropoxymethyl-4-pyrone, 6-ptoxymethyl-3-hydroxy -4-pyrone, 2-ethyl-3-hydroxy-6-methyl-4-pyrone, 3-hyperone Droxy-6-methyl-2-propyl-4-pyrone, 2-butyl-3-hydroxy C-6-methyl-4-pyrone, 3-hydroxy-2-hydroxymethyl-6-methane thyl-4-pyrone, 3-hydroxy-2-(1-hydroxyethyl)-6-methy -4-pyrone, 3-hydroxy-2-(l-hydroxypropyl)-6-methy -4-pyrone, 3-hydroxy-2-(1-hydroxybutyl)-6-methyl -4-pyrone.

For 3-hydroxypyridine-2-one ligands of type (2), these are , British Patent No. 2.111.766 (U.S. Patent No. 4.550.101 and Patent Application (corresponding to Sho 58-49677) or British Patent No. 2.136.8 No. 06 (corresponding to U.S. Patent No. 4.810.491 and Japanese Patent Application No. 59-57186) ) may be derived from the types of hydroxyviridinones described in . former is an aliphatic hydrocarbon in which the hydrogen atom bonded to the nitrogen atom has 1 to 6 carbon atoms. one or more hydrogen atoms bonded by a radical or to a nitrogen atom of 1 to 6 carbon atoms also substituted by the same or different aliphatic hydrocarbon radicals with atoms 3 -hydroxy-2-one. In the latter case, the hydrogen atom is replaced with an aliphatic monomer. Compounds composed of only hydrogen groups (substituted hydroxypyridine in the prior patent) 3-hydroxypyridine-2-o defined by formula (2), except for Including. Note that 3-hydroxypyridin-2-one has an alkoxy group and a cyclo It may contain a loalkoxy group, and the compound according to British Patent No. 2.136.806 The aliphatic hydrocarbon groups of the carbon and nitrogen atoms of the ring contain one or more halide compounds. It may be substituted with a rogene group. Can be used in complexes according to the invention Hydroxypyridine providing the ligand has the formula (V) has. Here, X and Y are the nitrogen atom of 3-hydroxypyridin-2-one and and the substituents defined above as substituents for carbon atoms. And n is 0.1.2 Or 3.

The preferred nature and position of the substituents on hydroxyviridinone are generally found in each of the aforementioned patents. It is as described in . That is, the substitution present in hydroxyviridinone The aliphatic hydrocarbon radicals advantageously contain 1 to 8, especially 3 to 6 carbon atoms. or may have one or more substituents as indicated. However, the number of substituents is preferably one. However, unsubstituted aliphatic hydrocarbon groups A relatively simple hydroxyviridine according to British Patent No. 2.118.176 containing A preferred class of compounds is a hydrogen atom bonded to a nitrogen atom, since non-ions are very useful. is substituted by an aliphatic hydrocarbon group having 1 to 6 carbon atoms, or one or more hydrogen atoms bonded to a carbon atom of the same or another lipid having 1 to 6 carbon atoms. 3-hydroxypyridin-2-one substituted by an aliphatic hydrocarbon group Ru. Preferences regarding the aliphatic hydrocarbon groups present in these hydroxyviridinones The new conditions are as described above for hydroxypyrone, with the methyl group attached to the ring carbon. Advantageously used for substituting elementary atoms, higher alkyl groups and cycloalkyl The groups mentioned above, especially for hydroxypyrone, can be used for substitution of nitrogen atoms in the ring. Particularly useful.

The substitution of carbon atoms in the ring of hydroxyviridinone is again not one but two or three. Preference is given to groups such as aliphatic hydrocarbon groups, but also particularly preferred 3-hydrocarbon groups. As droxypyridin-2-one, the ring carbon atom is N- without any extra substituents. Something has been replaced.

Special among 3-hydroxypyridin-2-ones containing substituted aliphatic hydrocarbon groups Useful for It is substituted with a group. These halogen-substituted aliphatic carbons The preferred conditions for the hydrogen group are the fluoro-substituted aliphatic hydrocarbon group of hydroxypyrone. This is almost as described above. However, in this case, aliphatic hydrocarbon groups and halo It is even more likely that both the gen-substituted hydrocarbon group and the , in which one group, e.g. an aliphatic hydrocarbon group, is present on a carbon atom and the other, e.g. a halo Each of the gen-substituted hydrocarbon groups is present on a nitrogen atom. Particularly useful certain hydro Xyviridinone has the formula m).・Here, R is an alkyl group or a cyclo Alkyl groups (these groups are substituted by 1, 3 or 5 fluoro groups) groups such as ethyl, n-propyl, isopropyl, butyl, pentyl or hexy ), or fluoro-substituted derivatives thereof containing 3 or 5 fluorine atoms (especially 1.), 2.2.2-pentafluoroethyl or 3.3.3- trifluoropropyl). Among these compounds, 1-ethyl-3-hydroxy Droxypyridin-2-one, 3-hydroxy-]-propylpyridin-2-one 3-hydroxy-1-(1'-methylethyl)-pyridin-2-one, 1- Butyl-3-hydroxybiridin-2-one and 3-hydroxy-1-pentylpi Lysin-2-ones are particularly useful.

Among the very wide range of ligands mentioned above, certain ligands or combinations thereof are It is particularly useful, and its implications have already been indicated. One aspect of the preferred complex n-octatool and trishydrochloride (20mM) at 20°C.

pH 7.4, Tris is 2-amino-2-hydroxymethylpropane-1,3 di is given by the value of the partition coefficient (Kpart) between It is expressed by the ratio (concentration in organic phase)/(concentration in aqueous phase). A preferred complex is The value of Kpart for each coordination donor compound is between 2 and 50, especially It is 8-40. and Kpar for the 3:1 indium (I[I) complex The value of t is between 5 and 100, especially between 30 and 70. 31 gallium (111) Corresponding ranges for complexes are 5-100 and 20-50. Kpart These ranges are given as a guide for preferred complexes; Ligands and /' or complexes with Kpart values that are not included may also be used.

The desirability of these Kpart values is contrary to the desirability of specific ligands mentioned above. It is being shown. Examples of particularly useful complexes according to the invention include Indium-111 complex and gallium of droxypyrone and hydroxyviridinone For example, (butyl-maltol) sr　n1ll and Ga67 (isopropyl-maltol) ) s I n1ll and Ga67 (3-hydroxy-6-propoxymethyl- 4-pyrone) s I n1ll and Ga67 (6-hydroxymethyl-3-hydro Roxy-4-pyrone) s I n1ll and G a67 (wherein R1 is butyl, pentyl or hexyl group).

Radioactive metal (Iff) complexes include hydroxypyrone and/or hydroxyviridino Advantageously, they are prepared by reaction of a radioactive metal ion with a ligand-donating agent. The latter is , derived from metal (Pl) salts, especially chloride salts. This reaction is advantageously suitable The process is carried out in a suitable mutual solvent, usually an aqueous medium. But if desired, water/solvent Mixtures or organic solvents such as ethanol, methanol, chloroform, or or mixtures of these solvents together and/or with water if appropriate. I can do it. In particular, while keeping the indium or gallium complex in solution, If at least a large part of the by-products, such as thorium, are separated by precipitation, , methanol or especially ethanol can be used.

The reaction is generally rapid and proceeds to substantial completion within a few minutes at 20°C. Ru. The complexes of the invention are often prepared in solution, but if desired, the complexes are prepared in a reaction mixture. by evaporation, lyophilization or, for further purification, crystallization from a suitable solvent. It is prepared in solid form.

As will be understood, by the reaction of the coordination donor compound(s) with the metal ion, The properties of the resulting metal complex depend on the proportions of these reactants and the pH of the reaction mixture. Dependent. That is, in order to produce the 3.1 ligand/metal (III) complex, hydro xypyrone and/or hydroxyviridinone coordination donor compound(s) and gold A solution is obtained by mixing with a genus salt in a molar ratio of at least 3:l, and the pH is in the range of 6 to 9. , for example, to 7 or 8. Hydroxypyrone and/or hydroxyviridi Non: Using a similar excess of metal (m) but with hydroxypyrone or hydroxy Adjustment of acidic pH to give mixtures of viridinone and metal salts such as metal (m) chlorides If this is not done, mixtures of 2.1 and 1:1 ligand:metal (■) complexes are obtained. It will be done. to ensure that all radiometal anions are bound in complex form with the ligand. In order to Comb, for example, 100:1 to 1000:1. However, if we change this ratio to 3=1 or If the above reaction conditions are maintained, the product is basically Generally, it would consist of a 3:1 ligand: gold rii, (m> complex.Ligand: When forming metal complexes, cold J non-radioactive metals are treated as radioactive metals. incorporation, it may be desirable to adjust the amount of ligand-donating compound accordingly. Ru. As a result, a non-radioactive complex is provided together with a radioactive complex.

In addition, when the complex contains various ligands, the coordination donor compound may include, if desired, Advantageously used in a ratio of 2:1 or 1;I, but in the case of complexes in which the ligands are heterogeneous Even when using a 2:1 ratio, a mixture of various 3:1 complexes is always obtained. the Therefore, a complex with homogeneous ligands is desirable.

The radioactive indium or gallium cation is preferably obtained from its chloride salt. It will be done. The amount of radiation required for the complex is often 1010-6Oi/7z g, but ultimately depends on the application for which the complex is used, as discussed below. do.

Therefore, the present invention provides a combination of ligand donor compound(s) and indium or gallium release compound(s). Neutral 3:1 coordination consisting of reacting a radioactive isotope with a trivalent cation Substituted 3-hydroxy-4-pyrone or 3-hydroxypyridin-2-o The subject matter is also a method for producing metal (I[[) complexes].

Certain substituted 3- including 2-trifluoromethyl-3-hydroxy-4-pyrone Hydroxy-4-pyrone is commercially available. For producing substituted hydroxypyrones An advantageous starting material for this is the elimination of 2,6-dicarboxy-3-hydroxy-4-pyrone. It is a 3-hydroxy-4-pyrone easily obtained by carboxylation. Immediately For example, by reacting 3-hydroxy-4-pyrone with an aldehyde, 1-hydroxy Inserting a sialkyl group at the 2-position and then reducing the group to form a 2-alkyl-3-hydrogen Roxy-4-pyrone. 2-ethyl-3-hydroxy-4- by this method The manufacture of Pyron et al. It is described in National Patent Application No. 310.410 (filed in 1960).

Examples of the preparation of other substituted 3-hydroxy-4-pyrones are as follows. Hydrocarby 3-hydroxy-4-pyrone is, for example, 3-hydroxy-substituted pyrone as a benzyloxy group. - protect the hydroxy group and convert this protected compound to e.g. sodium hydride. to react with the corresponding alkyl halide in dimethylformamide using Therefore, from 3-hydroxy-6-hydroxymethyl-4-pyrone (kojic acid) It can be prepared. Next, deprotection is performed, for example For example, convert the benzyloxy group to hydroxy using concentrated hydrochloric acid and isolate the final product. Ru. Using this method, the novel compound 3-hydroxy-6-medoxymethythi 4-pyrone, 6-ethoxymethyl-3-hydroxy-4-pyrone, 3-hydro Roxy-6-bropoxymethyl-4-pyrone and 6-ptoxymethyl-3-hydro Roxy-4-pyrone has been prepared. In addition, hydrogen bonded to a ring carbon atom 3-Hydroxy-4-pyrone with two of the atoms substituted was also prepared from kojic acid. can do. - As an example, using thionyl chloride to convert kojic acid to the chloro congener Transform into a body. Next, this was reacted with zinc white and hydrochloric acid to form a 3-hydroxy-6-methane Chill-4-pyrone. Next, this is reacted with an appropriate aldehyde to obtain the corresponding 2 -hydroxyalkyl-3-hydroxy-6-methyl-4-pyrone. Sara by reaction with zinc/hydrochloric acid to give the corresponding 2-alkyl-3-hydroxy-6- Let it be methyl-4-pyrone. Using this method, the novel compound 2-ethyl -3-hydroxy-6-methyl-4-pyrone, 3-hydroxy-6-methyl-2 -propyl-4-pyrone, 2-butyl-3-hydroxy-6-methyl-4-pyro 2-hydroxymethyl-6-methyl-4-pyrone, 3-hydroxy-2-hyperone Droxyethyl-6-methyl-4-pyrone, 3-hydroxy-2-hydroxypyrone Lopyl-6-methyl-4-pyrone and 3-hydroxy-2-hydroxybutyl- 6-Methyl-4-pyrone was prepared.

Therefore, the present invention provides that one or more hydrogen atoms bonded to a carbon atom of a ring have a carbon atom number of 1 or more. C1-6 fatty acids substituted by ~6 aliphatic hydrocarbyloxy groups Substituted by an aliphatic hydrocarbon group, one or more other hydrogen atoms are sometimes of 3-hydroxy-4-pyrone substituted by an aliphatic hydrocarbon group of 6 In the manufacturing method, the 3-hydroxy group is protected and the aliphatic hydroxycarbyl group is Intermediates in which the xy group is replaced by the corresponding hydroxy-substituted aliphatic hydrocarbon group with aliphatic hydrocarbyl/1ride containing the corresponding aliphatic hydrocarbyl group. Provided is a method of preparation comprising reacting and then deprotecting the 3-hydroxy group. .

The present invention further provides C1-6 lipids which may be substituted with hydroxy groups. by aliphatic hydrocarbon groups (excluding 3-hydroxy-2,6-dimethyl-4-pyrone) to a method for preparing 3-hydroxy-6-methyl-4-pyrone substituted at the 2-position. (a) 3-hydroxy-6-methyl-4-pyrone with the corresponding formyl position C1-6 aliphatic hydrocarbon group (itself hydroxyl) 3-hydro substituted at the 2-position by (1-position substituted by a cy group) roxy-6-methyl-4-pyrone, or (b) After performing step (a), the hydroxy-substituted C1-0 aliphatic carbon 3 in which the hydroxide group is reduced and the 2-position is substituted by a C2-6 aliphatic hydrocarbon group -Hydroxy-6-methyl-4-pyrone is also provided. .

Some of the substituted 3-hydroxy+pyrone intermediates are novel compounds and are subject to the present invention. included in the range.

3-Hydroxyl 4-one is described in British Patent Nos. 2.117.776 and 2.13. 6.806 and variations thereof.

As will be appreciated, the above method is only one way to obtain the above compound. However, various modifications can be made by those skilled in the art.

Radiolabeled gold according to the invention! (III) The complex was used as a label for blood cells It is particularly useful in diagnosis in some cases. This involves targeting the desired blood cells in vitro. The blood cells then need to be reinfused into the patient. Labeled blood cells are circulated The location is determined by gamma scintillation counter or PET scan. can be monitored. Alternatively, when using cell survival studies, radioactive Within a predetermined time after injecting the labeled cells and measuring the radiation counts, another A blood sample can be taken from the patient.

As mentioned above, the labeling of different species of blood cells offers a variety of diagnostic uses. Served. That is, the radiolabeled gold g(III) complex according to the present invention , is advantageously used for the labeling of platelets, red blood cells and white blood cells. radioactively labeled The collected white blood cells can be used clinically to detect the location of tumors and inflammation. and , radiolabeled platelets are used to treat atherosclerotic lesions, small venous thrombi and To visualize the state in which platelets accumulate in veins and arteries in thrombophlebitis It can also be used. Another use for radiolabeled platelets is in the early stages of kidney transplant rejection. The purpose of this study is to provide instructions for evaluating the tromponogenicity of arterial grafts. radioactivity mark The circulation and distribution of recognized autologous lymphocytes can be visualized using the complexes of the present invention. can be analyzed. Labeling of red blood cells is useful in the following cases: imaging of heart defects, Study of gate wall motion (gatecl val, 1 motion), left ventricular pulsation Heat denatured for functional measurements, blood volume measurements, gastrointestinal bleeding studies and spleen imaging Diagnostically useful for labeling red blood cells.

Radioactive indium complexes such as complexes of +14 In and potentially gallium complexes. In addition to the use of diagnostic complexes, labeled lymphocytes are primarily used for the treatment of lymphocytes. It can be used for therapeutic purposes. Therefore, the complexes of the present invention have applications in the therapeutic field. It is also useful even if

The dose of red blood cells labeled with a radiolabeled metal (I[[) complex to be administered to a patient is: It depends on the radioisotope, red blood cell species, diagnostic purpose and detection method. However, the next Information is presented as a guide.

Indium-labeled white blood cells in adults to locate the disease The dose is 500-1000 μC1 (18,5 → 37 MBq). The embodiment of the present invention 300-100 (lμCi, especially for 600μCi) Amounts are generally adequate.

For the gallium complex of the present invention, 300 to 1000.2000 or 2500 μCi.

In particular doses of 500.1000 or 1500 μCi are generally suitable. Therefore, The usual adult dose of radioactive gallium-67 is 1 for the detection of tumors of the lymphatic system. 000 to 2000μC1 (37 to 74M Bq). by scanning technique For tumor visualization, 1500-2500μC1 (55.5-92.5MB The dose of q) is appropriate.

Uses for indium-111 and gallium-67 complexes in other labeling fields Quantities are subject to changes generally accepted in the literature as preferred in this field. This is the same as described above. In addition, the doses of other radioactive isotopes are The same is true for μCi (but not necessarily for the amount of complex).

When using indium ■ or gallium ■ complexes in vivo for diagnostic or therapeutic purposes British Patent Nos. 2.117.766, 2.128.998 or 2.13 6.806, with suitable diluents or carriers. Preferably, it is formulated as a product.

Labeling desired blood cells with the complex of the present invention can be performed as described in Examples 3 and 4. may advantageously be carried out by methods given in the literature for complexes of.

The present invention will be described below with reference to Examples. Among these, Examples 1 to 3 produce complexes. Concerning the above intermediates. Some of these intermediates are themselves novel; Within the scope of the present invention. The nmr signal is thought to be related to the signals of the ears. It originates from the protons that are present.

Example Example 1 3-hydroxy-6-medoxymethyl-4-pyrone with benzyl chloride A mixture with a 1.5 molar excess of potassium carbonate in dimethylformamide for 24 hours. By heating at 60°C, 3-benzyloxy-6-hydroxymethyl- 4-pyrone was prepared. 3-benzyloxy- in the obtained dimethylformamide In 6-hydroxymethyl-4-pyrone solution (10 g, 0.023 mol), in Domethane (14 g, 0.215 mol) was added and the solution was stirred for half an hour.

Add sodium hydride (2.6 g, 0.086 mol) and cool for 24 hours under nitrogen gas. Time mixed. The dimethylbormamide was then evaporated and the residue dissolved in water. I set it. After adjusting the pH to 12 using NaOH in IOM, dichloromethane (3X 150ml). Combine dichloromethane extract and anhydrous sodium sulfate The mixture was evaporated to dryness over aluminum. The resulting yellow solid was removed from hot ethanol. Recrystallization gave the title compound (5.8 g, 55%).

(2) 3-hydroxy-6-medoxymethyl-4-pyrone 3-benzyl-6-hyperone Droxymethyl-4-pyrone (8 g, 0.032 mol) in 100 ml of hydrochloric acid Refluxed for an hour. After cooling, the pH of the mixture was adjusted to 11 and then dichloromethane ( Extracted into 2X 50ml volume. The aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid and diluted with Extracted into lolomethane (3X 100 mA'). Combine the extracts and add anhydrous sodium sulfate. Evaporate to dryness over thorium. 3, 5 g (7 0%) white solid was recrystallized from toluene to give the title compound. Physical property value is as follows.

Melting point 79-80℃, ν,,, (nujol) 1650.1630.1595.1260.1220 ．． 1150.950cr'δH (d'-DMSO) 9.5 (In, sbr, OH), 8.1 (IH, s, 2-H), 6゜4 (LH, s, 5-El) .

4.3 (2H, s, CH2), 3J (3H, s, CHs) (B) Others 3-hydroxy-6-aerkoxymethyl-4-pyrone of Prepared. However, in step (1), a 5 molar excess of alkyl halide is used. did.

Yield in 6-nitoxymethyl-3-hydroxy-4-pyrone step (1): 8.2 g (73.3%), and yield in step (2) 4.2 g (80%) Melting point 73-74℃ ν,,, (nujol) 1650.1610.1265.1220.1100 ．． 900c+a-'δH (d'-DMSO) 9.15 (IH, sbr, OR ), 8.1 (LH, s, 2-H), 6.4 (IL s, 5-11).

4.3 (2Ls, CH2), 3.4 (2H, Q, CB2CH3), 1. 1(3t[,t,CEIs)3-hydroxy-6-broboxymethyl-4-pi Yield in Ron step (1) 8. Og (68%), and the yield in step (2) was 4 ．． 6 g (68,5%) Melting point 63-64°C ν,,, (nujol) 1650.1620.1580.1265.1210 ．． 1150.950cm-'δH (d'-DMSO) 9.1 (IH, b, O H), 8.1 (IH, s, 2-H), 6.4 (1, H, s, 5-H).

4.3 (2H, s, C) 12), 3.4 (21b, 42CB2CH3), 1 ．． 5 (2H, m, CLCHzCllg), 0.9 (3H, t, CH3) 6- Yield of ptoxymethyl-3-hydroxy-4-pyrone in step (1): 8.3 g (83%), and yield in step (2) 5.4 g (78.6%) Melting point 34 ~35℃ ν,,, (nujol) 1650.1630.1300.1210.1100 ．． 920cm-'δH (d'-DMSO) 9.1 (in, s, OH), 8 ．． 1 (IH, s, 2-H), 6.4 (IH, s, 5-11).

4.3 (2H, s, CHz), 3.4 (2L t, CEzCH2C1lIz CHs), 1.4 (2H, m, Ctt2CH□CH2CHs), 0.9 (3H , t, CHa) Wari Nijirishi Yu upper level ≦ Niro Tadato and 1 and ``shie, Yuyoni 2 and 3 of 3 -Preparation of hydroxy-2-(1-hydroxyalkyl)-6-methyl-4-pyrone (1) 3-hydroxy-6-chloromethyl-4-pyrone 3-hydroxy-6-hydroxy Droxymethyl-4-pyrone (50 g, 0.135 mol) in 500 mf redistilled salt The mixture was dissolved in thionyl chloride and left for 2 hours. The indicated compound is precipitated from solution and filtered. filtered and washed in petroleum ether. Recrystallization from B20 yielded 41.6% yield. The rate was obtained.

δH (d6-DMSO) 9.3 (1B, s, OR), 8. I(IH,s , 3H), 6.6 (Ill, s, 5-H).

4, 7 (2H, s, CH2) (2) 3-hydroxy-6-methyl-4-pyrone 3-hydroxy-6-chloromethane Chil-4-pyrone (20g, 0.125mol) was added to B20.150m/ and heated to 40°C. Zinc white (16.29g, 0.25mol) was added and the mixture was vigorously stirred at 60°C. Add concentrated hydrochloric acid (37 ml, 3 molar equivalents) over 1 hour. dripped.

The slurry was stirred at 60°C for 2-3 hours. Excess zinc is removed by high-temperature filtration, and the filtrate is The pH of the mixture was adjusted to 1 and extracted into dichloromethane (3×100 m/). merger The extracted extract was evaporated to dryness over anhydrous sodium sulfate to give the indicated compound. (12.9g, 86%).

Recrystallized from hot propatool. The melting point was 152-153°C.

ν, , (nujol) 1650.16]0. ]575.1220.115 0.920cm-'δH(d'-DMSO) 8.9(LH,s, Ofri, 8.0 (IH, s, 2-H), 6.3 (IH, s, 5-4).

2, 2 (3H, s, CH3) (3) 3-hydroxy-2-hydroxymethyl-6-methyl-4-pyrone 3-hydroxy Droxy-6-methyl-4-pyrone (9.4 g, 0.074 mol) in H201 100mj! added to. Formaldehyde (5.5mf, 0.074mol) was added to adjust the final pH of the mixture to 1. Stir the solution at 25°C for 24 hours. mixed. The pH was then adjusted to 1 and the indicated compound was precipitated (10 g, 86.2 %).

The following 2-hydroxyalkyl compounds can be prepared using the appropriate aldehyde in a 1:1 ratio: was prepared.

Example 3: 2,6-dimethyl-3-hydroxy-4-pyrone and other 2-alkyl 820.100 m7? During ~ It was dissolved in Zinc white (1°7g, 0.026mol) was added and the mixture was heated to 60°C. Stir vigorously (stir). Add concentrated HCI (13 ml, 10 molar equivalents) dropwise over about 1 hour. I put it down. The slurry was stirred for 12 hours at 60°C. Excess zinc is removed by high temperature filtration. The pH of the filtrate was adjusted to 1 and extracted into dichloromethane (3X 50mr).

The combined extracts were evaporated to dryness over anhydrous sodium sulfate to give the indicated compound. (0.8g, 47%). Recrystallized from toluene, melting point 152-153℃ Met.

ν,,, (nujol) 1660.1630.1580.1220.1080 ．． 970.930cm-'δH (d'-DMSO) 8.5 (IH, sbr, OH), 6.2 (IH, s, 5-4+).

2.2 (6H, s, CH3CH3) (B) Corresponding 3-hydroxy-2-(1-hydroxyalkyl-6-methyl -Prepare other 2-alkyl-6-methyl-4-pyrones from 4-pyrone in the same manner. can do.

Example 4: Preparation of a 3:1 ligand:indium ■ and gallium ■ complex (A) ( Preparation of 3-gallium 67 complex (ethyl-maltol) U.S. Pat. No. 3,376,31 As described in Example 1 of U.S. Patent Application No. 310.141, referenced in Ethyl maltol was prepared as follows. Ethyl maltol is 20mM HEPES prepared in a seed solution with a concentration of 001M in 8% NaCl, pH 7.4-7.5. Manufactured. A more concentrated seed solution of ethyl maltol in 0.04N HCl It was dropped into the acidic solution of a (G a C1s). Put the resulting solution in pH 7.0. It was made into a sex.

Other substituted 3-hydroxy-4-pyrones were prepared similarly.

The synthesis of 1-ethyl-3-hydroxypyridin-2-one is described in European Patent No. 0941 No. 49, Example 1.

1-xf-3-4: Fo + dipyridin-2-one in 20mM HEPESl o, 8% NaCl, pH 7.4-7.5, into the seed solution at a final concentration of 0.01M. Prepared. 1-ethyl-3-hydroxypyridin-2-one solution at 0.04N In III (InC13) in HCI was added dropwise to an acidic solution. The resulting solution was adjusted to pH 7. , 0 neutrality.

Other 3-hydroxypyridine-2one complexes were similarly prepared.

In both cases of hydroxypyrone and hydroxyviridinone, the ligand is All radiometal cations are combined in a 3:1 complex with the coordination donor compound. For example, instead of a 3=1 molar ratio of coordination donor compound:salt, the molar ratio is 100:1 or more. or 1000:1 in large excess compared to the metal salt.

Example 50 Partition coefficient Using a molar ratio of 3:1 to 1 rnl of water saturated octan-1-ol in a glass test tube. 67Ga-(I[I) and “’” prepared as described in Example 1. By adding 1 mA' of solution of the I n-(n[) complex, the distribution coefficient of the complex is has been established. The system was allowed to stabilize at temperature for 15 minutes on a slowly rotating mixer. . After rotating the 6 tubes at 300 rpm (1500 g) for 10 minutes, 20 A 0 mA sample was taken, weighed using an analytical balance, and radioactivity was counted. Next The distribution coefficients p and c were calculated from the equation.

p, c, = (counts per 19J/octatools per gram)/(counts per minute) counts/gram of HEPES/saline) of various 3-hydroxy-4-pi Table 1 shows the distribution coefficient values obtained for the HP complexes.

Table 1 The distribution coefficients of the various coordination test donor compounds described in Examples 1-3 were also measured.

Coordination is achieved by dissolving the ligand in an aqueous solution of trischloride at pH 7.4. A solution of filtrate was prepared. Always use acid-washed glassware and After adding 10-4M aqueous solution 51III for 1 minute, 1.000 g, 30 seconds The aqueous mixture of n-octatool was centrifuged. The obtained two phases are each The samples were separated for concentration determination by spectrophotometry. Typical values obtained Table 2ζ2 is shown.

Table 2 knowledge Red blood cell labeling was performed using whole blood collected from normal adult volunteers.

First, spin the blood at 1500 rpI11 (400 g) for 15 minutes to remove blood. Removed.

The loaded blood cells were washed with an equal volume of heparinized saline and then removed by centrifugation. The brine was removed and the washing step was repeated. Pool the washed and loaded blood cells before use. Rotated briefly on mixer rotator. 1 m of washed blood cells for blood cell labeling experiments r was added to heparinized blood collection glass tubes. This blood cell'J, ml, 100 : Prepared as shown in Example 1 using a molar ratio of 1 to 1.000 + 1. 0.5 of a 3:1 3-hydroxy-4-pyrone complex solution of Ga(m) was added.

Attach a stopper to the multitube and use an open flat rotary mixer during the experimental period, except for short sample collection times when necessary. I placed it 1!1' on the sir. Samples of 100 μl of blood cell suspension were collected at various time intervals. and added to a clean glass test tube containing 2 ml of saline. Ten suspension samples The mixture was mixed for 5 minutes and centrifuged at 3000 rpm (1500 g) for 5 minutes. supernatant liquid Removed and the blood cells were washed again with saline. After removing the second saline wash, remove Lyse the blood cells using ionized water and adjust the final volume to equilibrate with the previous saline wash. adjusted. Set about 67Ga photon energy (95-300keV) Blood cells and the supernatant were counted using an automatic gamma counter equipped with a 100% automatic gamma counter.

The results are shown in attached Figure 1-5. Each figure incorporates red blood cells as a function of time. represents the percentage of Ga complexes present.

Figure 1 shows the data for Ga(II[)-(maltol)3 for comparison purposes. are doing.

FIG. 2 represents the data for "Ga(II[)-(ethyl-maltol)3].

Figure 3 represents data for 67Ga(II[)-(isopropyl-maltol)3. ing.

FIG. 4ft represents the data of "Ga(ml)-(butyl-maltol)3".

As can be seen from each figure, the complexes with higher alkyl groups are able to absorb 67Ga to red blood cells. Enable faster uptake and achieve more complete integration.

Figure 5 shows the uptake of 67Ga into red blood cells at 15 minutes for various complexes. The effect of ligand concentration is shown. Figures 1 to 4 are maltol, ethyl-maltol , conclusions for isopropyl-maltol and butyl-maltol 67Ga complexes. (The first one is for comparison purposes). This also makes it possible to It has been shown that complexes containing 67Ga groups increase the incorporation of 67Ga into red blood cells. Ru.

Example 7: [''In(m)-C3-hydroxy-4-pyrone)3] Example 1 Using a molar ratio of 100:1~], 000:1 III n (III) 3,13-hydroxy-4-pyro prepared as shown in The effect of ligand concentration on the labeling of leukocytes by complexes suspended in buffer was investigated. It was performed using a leukocyte colony. White blood cells are measured in 60 m whole blood from normal adult volunteers. Retrieved from A'. Aspirate the blood into a 60ml syringe and add heparin (100 units/full). Anticoagulate with 10 ml of blood and hold the syringe on a ring stand for 1 hour. The red blood cells were precipitated by keeping the cells in an upright position. After 1 hour, most of the white blood cells are in the supernatant. It was discovered during a blood donation. Transfer the supernatant to a sterile plus using a 19g butterfly set. I pushed it out into the tick tube. 20mM HEPES-saline (0°8%) The leukocytes were washed twice using the same method and suspended in 5 ml buffer. white blood cell count and the difference was performed using a Coulter counter, and the suspension concentration of white blood cells was determined as 9×106 white blood cells. Blood cells were adjusted to 10.9 mA. Solution of the appropriate “’In(Ill) 3:1 complex 0, Labeling was performed by adding 1~] and incubating for 15 minutes. Incubation for 15 minutes After incubation, the leukocytes were washed twice with 2 ml of buffer. automatic gun with energy window Cells and each wash were counted using a micrometer.

Figure 6 shows the effect of ligand concentration on the incorporation of the complex into leukocytes, and the graph Labeling is as shown in FIG. These results are consistent with those containing higher alkyl groups. Regarding the gallium complex of Example 3, in that increased incorporation is obtained with the complex containing The result is similar to that of

Example 8: Effect of blood cell concentration on incorporation of radiolabeled complex “’In(I[[)-(2-butyl-3-hydroxypyridin-2-o The effect of leukocyte concentration was studied using the 3-complex. Label, isolate, and realize leukocytes. Counts were made using the method of Example 4. Butyl-maltol 3: I Ga (m) The effect of red blood cell volume was investigated using the complex. 100: 1-1000: The complex prepared for Example 1 using a molar ratio of 0.5 to 1, 2.3.4 or 5~] containing the washed and packed red blood cells prepared by Added to parinized blood collection glass tubes. 100μl volume of blood cell suspension, 5 ．． 15. Remove and add to the tube with 2 ml of 0.9% saline every 30 and 45 minutes. , washed, separated and counted using the method of Example 3.

Figure 7 shows the 0.OOOI of butyl-maltol 3:1”’n(III). The effect of leukocyte concentration on M concentration is shown. Culture time is 15 minutes. White Blood cell concentration did not have a significant effect on the percentage uptake of radiolabeled complexes. It was. These results demonstrate that the butyl-maltol 3:167Ga(I[[) complex compared to the study of red blood cell volume for the uptake of gallium-labeled complexes. (Results not shown).

Yamaki I stand + 9 mo, l Shij prisoner l 屹 B ■Ra mole 1 skin (xE-4) ! -----To metal rust body A neutral 3:l ligand:gold R(m) complex in which the trivalent metal cation is A radioactive isotope of indium or gallium, each with its own separate ligand. The following compound; (1) 3-hydroxy-4-pyrone with one or more ring carbon atoms attached a hydrogen atom is replaced by an aliphatic hydrocarbon group having 1 to 6 carbon atoms; or such groups include fluoro groups, hydroxy groups and aliphatic hydrocarbyl groups. Substituted with one or more groups selected from group oxy groups (however, 3 -Excluding hydroxy-2-methyl-4-pyrone<); or (2) (a) 3- Hydroxypyridin-2-one, or (b) 3-hydroxypyridin-2 -on, and the hydrogen atom bonded to the nitrogen atom is an aliphatic acyl group, 1 to 6 Aliphatic hydrocarbon group having carbon atoms, or aliphatic acyl, alkoxy, cycloa Select from lukoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups substituted with an aliphatic hydrocarbon group substituted with one or more substituents and optionally (C) 3-hydroxypyridin-2-one, One or more hydrogen atoms bonded to a carbon atom of the ring is one of the above substituents, 1 to 6 carbon atoms An aliphatic hydrocarbon group having an elementary atom, or an aliphatic hydrocarbon group having an alkoxy , cycloalkoxy, aliphatic ester or hydroxy group substituted or substituted with one or more halogen groups; Said complex is useful in therapy and especially in diagnosis, especially in the field of labeling of blood cells. It is useful.

international search report 1m-Mal ＾emta+mIIm PCT/GB 91/OO441 country international investigation report S^　46020

Claims (1)

[Claims] 1. A neutral 3:1 ligand:metal(III) complex in which a trivalent metal cation is The ion is a radioactive isotope of indium or gallium, and the respective ligands is separately the following compound; (1) 3-hydroxy-4-pyrone with one or more ring carbon atoms attached a hydrogen atom is replaced by an aliphatic hydrocarbon group having 1 to 6 carbon atoms; or such groups include fluoro groups, hydroxy groups and aliphatic hydrocarbyl groups. Substituted with one or more groups selected from group oxy groups (however, 3 -hydroxy-2-methyl-4-pyrone); or (2) (a) 3-hydro; Roxypyridin-2-one, or (b) 3-hydroxypyridin-2-one in which the hydrogen atom bonded to the nitrogen atom is an aliphatic acyl group, 1 to 6 carbon atoms aliphatic hydrocarbon group having atoms, or aliphatic acyl, alkoxy, cycloalco selected from xy, aliphatic amide, aliphatic ester, halogen and hydroxy group. Substituted with an aliphatic hydrocarbon group substituted with one or more substituents , and optionally (c) 3-hydroxypyridin-2-one, One or more hydrogen atoms bonded to a carbon atom is one of the above substituents, 1 to 6 carbon atoms an aliphatic hydrocarbon group having a child, or an aliphatic hydrocarbon group having alkoxy, silyl, Substituted by chloroalkoxy, aliphatic ester or hydroxy groups , or substituted with one or more halogen groups; The said complex which is. 2. A neutral 3:1 ligand:metal(III) complex in which a trivalent metal cation is The ion is a radioactive isotope of indium or gallium, and the respective ligands is separately the following compound; (1) 3-hydroxy-4-pyrone with one or more ring carbon atoms attached a hydrogen atom is replaced by an aliphatic hydrocarbon group having 1 to 6 carbon atoms; or such groups are substituted with one or more fluoro groups (provided that (excluding 3-hydroxy-2-methyl-4-pyrone); or (2) (a) 3 -Hydroxypyridin-2-one, or (b) 3-hydroxypyridine- 2-one, in which the hydrogen atoms bonded to the nitrogen atom are an aliphatic acyl group, 1 to 6 aliphatic hydrocarbon group having carbon atoms, or aliphatic acyl, alkoxy, cyclo Selected from alkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy group. substituted with an aliphatic hydrocarbon group substituted with one or more selected substituents. and optionally (c) 3-hydroxypyridin-2-one, , one or more hydrogen atoms bonded to a carbon atom of the ring is one of the aforementioned substituents, 1 to 6 An aliphatic hydrocarbon group having a carbon atom, or an aliphatic hydrocarbon group having an alkoxy substituted by cy, cycloalkoxy, aliphatic ester or hydroxy group or substituted with one or more halogen groups; The said complex which is. 3. Claims in which the trivalent metal cation is In111 or In113 The complex according to item 1 or 2. 4. Claim 1 in which the trivalent metal cation is Ga67 or Ga68 The complex according to item 1 or item 2. 5. Claims in which each ligand is selected separately from compounds in type (1) The complex according to any one of Ranges 1 to 4. 6. Claims in which each ligand is given by the same compound in type (1) The complex according to item 5. 7. Compounds of type (1) are methyl, hydroxymethyl, methoxymethyl, ethyl oxymethyl, propoxymethyl, butoxymethyl, ethyl, 1-hydroxyethyl 1,1,2,2,2-pentafluoroethyl, propyl, isopropyl, 1 -Hydroxypropyl, 3,3,3-trifluoropropyl, butyl, 1-hydro by the same or different substituents selected from roxybutyl and pentyl groups. 3-hydroxy, in which one or more hydrogen atoms bonded to a ring carbon atom are substituted. The complex according to any one of claims 1 to 6, which is C-4-pyrone. 8. The compound is 3-hydroxy-2,6-dimethyl-4-pyrone, 2-ethyl- 3-hydroxy-4-pyrone, 2-(1',1',2',2',2'-pentaf (fluoroethyl)-3-hydroxy-4-pyrone, 3-hydroxy-2-propyl -4-pyrone, 3-hydroxy-2-(1'-methylethyl)-4-pyrone, 2 -(3,'3,'3'-trifluoropropyl)-3-hydroxy-4-pyrone or 2-butyl-3-hydroxy-4-pyrone according to claim 7. complex. 9. The compound is 3-hydroxy-6-methoxymethyl-4-pyrone, 6-ethoxymethyl Dimethyl-3-hydroxy-4-pyrone, 3-hydroxy-6-propoxymethylene -4-pyrone or 6-butoxymethyl-3-hydroxy-4-pyrone The complex according to claim 7. 10. The compound is 2-ethyl-3-hydroxy-6-methyl-4-pyrone, 3-hydroxy Droxy-6-methyl-2-propyl-4-pyrone or 2-butyl-3-hydro 8. The complex according to claim 7, which is roxy-6-methyl-4-pyrone. 11. The compound is 3-hydroxy-2-hydroxymethyl-6-methyl-4-pi Ron, 3-hydroxy-2-(1-hydroxyethyl)-6-methyl-4-pyro 3-hydroxy-2-(1-hydroxypropyl)-6-methyl-4-pyro or 3-hydroxy-2-(1-hydroxybutyl)-6-methyl-4-pi 8. The complex according to claim 7, which is ron. 12. Claims in which each ligand is selected separately from compounds in type (2) The complex according to any one of the ranges 1 to 4. 13. The assumption is that each ligand is provided by the same compound in type (2). The complex according to item 12. 14. The compound of type (2) is 3-hydroxypyridin-2-one, Hydrogen bonded to nitrogen by an aliphatic hydrocarbon group having 1 to 6 carbon atoms substituted, or such groups are substituted with one or more fluoro groups; or as needed. 3-hydroxypyridin-2-one, one or more of which is attached to a ring carbon atom hydrogen atom is substituted with the same or different substituent (the substituent is an aliphatic hydrocarbon group having 1 to 6 carbon atoms or is substituted with one or more fluoro groups). , 4, 12 or 13. 15. The aliphatic hydrocarbon group is methyl, ethyl, 2,2,2,3,3-pentafluor Oroethyl, n-propyl, isopropyl, 3,3,3-trifluoropropyl , and linear and branched butyl and pentyl groups. The complex according to item 4. 16. The compound is 1-ethyl-3-hydroxypyridin-2-one, 1-( 1',1',2',2',2'-pentafluoroethyl)-3-hydroxypyri Zin-2-one, 3-hydroxy-1-propylpyridin-2-one, 3-hydro Roxy-1-(1'-methylethyl)-(pyridin-2-one, 1-(3',3 ',3'-trifluoropropyl)-3-hydroxypyridin-2-one or Claim 15 which is 1-butyl-3-hydroxypyridin-2-one complex. 17. Any one of claims 1 to 16 for use in diagnosis or treatment Neutral 3:1 ligand:metal(III) complexes described in . 18. Claims 1 to 3, including a pharmacologically acceptable diluent or carrier. consisting of a neutral 3:1 ligand:metal(III) complex according to any of paragraph 16. Pharmaceutical composition. 19. A neutral 3:1 ligand according to any of claims 1 to 16: Atherosclerosis, consisting of radiolabeling red blood cells with metal(III) complexes Diagnostic methods for sclerosis, thrombocytopenia, venous thrombosis and thrombophlebitis. 20. A neutral 3:1 ligand according to any of claims 1 to 16: Treatment of abscesses, inflammations, and tumors consisting of radiolabeling lymphocytes with metal(III) complexes. Methods for detecting and treating tumors and metastatic sites. 21. A neutral 3:1 ligand according to any of claims 1 to 16: Treatment of arterial grafts consists of radiolabeling platelets with metal(III) complexes. A method for evaluating embogen formation and obtaining early indications for rejection of organ transplants. 22. A neutral 3:1 ligand according to any of claims 1 to 16: radiolabeled red blood cells, consisting of radiolabeling red blood cells with a metal(III) complex Red blood cells are used to contrast cardiac veins, study gated wall motion, and left ventricular pulsation. Diagnostic methods that measure function, measure blood volume, and image gastrointestinal bleeding and the spleen. 23. 3-Hydroxy-4-pyrone, one or more attached to a ring carbon atom hydrogen atom is formed by an aliphatic hydrocarbyloxy group having 1 to 6 carbon atoms. aliphatic hydrocarbon radicals having 1-6 carbon atoms substituted by things, and If necessary, one or more other atoms are aliphatic hydrocarbons having 1 to 6 carbon atoms. Those that are optionally substituted with elementary groups. 24.3-hydroxy-6-methoxymethyl-4-pyrone, 6-ethoxymethyl -3-hydroxy-4-pyrone, 3-hydroxy-6-propoxymethyl-4- Pyrone or 6-butoxymethyl-3-hydroxy-4-pyrone 3-Hydroxy-4-pyrone according to item 23. 25. C1-6 aliphatic hydrocarbon group or such group is substituted with a hydroxy group, 3-hydroxy-4-pyrone (however, 3 -hydroxy-2,6-dimethyl-4-pyrone). 3-hydroxy-6-methyl-4-pyrin substituted at the 2-position by Ron. 26.2-ethyl-3-hydroxy-6-methyl-4-pyrone, 3-hydroxy -6-methyl-2-propyl-4-pyrone or 2-butyl-3-hydroxy- 3-hydroxy-6 according to claim 25, which is 6-methyl-4-pyrone. -Methyl-4-pyrone. 27.3-hydroxy-2-hydroxymethyl-6-methyl-4-pyrone, 3- Hydroxy-2-(1-hydroxyethyl)-6-methyl-4-pyrone, 3-hydroxyethyl droxy-2-(1-hydroxypropyl)-6-methyl-4-pyrone or 3 -hydroxy-2-(1-hydroxybutyl)-6-methyl-4-pyrone , 3-hydroxymo-6-methyl-4-pyrone. 28. Corresponding 3-hydroxy-4-pyrone and/or 3-hydroxypyrido -2-one coordination donor compound(s) with an indium or gallium isotope of the complex according to claim 1, which comprises reacting with an elementary trivalent cation. Preparation method.