EP2534118A1

EP2534118A1 - Conjugates of 18f carries having bioactive, organic compounds and the preparation thereof

Info

Publication number: EP2534118A1
Application number: EP11708685A
Authority: EP
Inventors: Matteo Scabini
Original assignee: APTENIA Srl
Current assignee: APTENIA Srl
Priority date: 2010-02-06
Filing date: 2011-01-17
Publication date: 2012-12-19
Also published as: WO2011095150A1; US20130041104A1; JP2013518830A; DE102010007097A1

Abstract

The invention relates to novel chemical compounds, which can be fluorinated with ¹⁸F under especially mild conditions. The novel chemical compounds thereby enable the use of a novel fluorination method according to the invention, wherein the substrate to be fluorinated is immobilized on a polymer during the fluorination. The method is characterized in that the method requires fewer and simpler manipulations than methods of the prior art. The occupational safety in the laboratory or hospital is thereby increased especially during work with the radionuclide ¹⁸F.

Description

Conjugates of F-carriers with bioactive organic compounds and their representation

Among the methods used in radiology, positron emission tomography (PET) is a preferred method for tracking disease courses and their therapy in many indications, for example in oncology. For this purpose, it is preferred to use the fluoroisotope ¹⁸ F, which is synthesized in a cyclotron. It is used to show labeled compounds that are selectively taken up by the pathologically altered tissue or that can selectively bind to abnormally altered cells. Such ¹⁸ F-labeled compounds are still referred to herein as PET "tracers". They allow the visualization of the tissue to which they bind or are incorporated by means of car radiography. Positron emission tomography (PET) with PET tracers enables the diseased tissue in the patient's body to be localized and determined, and among the positron-emitting radionuclides the fluorine isotope ¹⁸ F is preferred because it can be introduced into many organic compounds can be used as a PET 'tracer'. Advantageous for this is the relatively long half-life of 109.6 min. And a low-energy ß + emission (635 keV) of this nuclide.

The best known example of such a preparation is the 2- ¹⁸ F-fluorodeoxyglucose (FDG ¹⁸⁾ (J. Nucl. Med. 1978, 19, 1154-1161).

More recently, ¹⁸ F-labeled short, synthetic nucleic acids or peptides, so-called aptamers are used, which can selectively bind to the surfaces of pathologically altered cells. (Friebe, Matthias et al., PCT Int. Appl., WO2009033876 A1). For example, in oncology recently, aptamers have been used which have been prepared to bind tumor markers. Med. 2000, 78, 426-30; The Aptamer Handbook: Functional Oligonucleotides and Their Applications, Sven Klussmann (Editor) ISBN: 978-3-527-31059-3 March 2006, Wiley -VCH Verlag GmbH & Co. KGaA) With such novel aptamers, a more selective PET can be performed.

The labeling of organic molecules with radioactive ¹⁸ F often requires several wet-chemical stages, including some that must be performed above 100 ° C, as well as elaborate chromatographic steps. The conventional introduction of ¹⁸ F is therefore associated with high risks for the persons performing because of the high radioactivity. Another disadvantage of the use of the now firmly established ⁸ FDG are artifacts, which are caused by lack of selectivity of the diagnostic. So z. For example, ¹⁸ FDG is not only taken up by tumor tissue but also by active skeletal muscle. {Seminar in Nuclear Medicine 2004, XXXIV, 2, 122-133). The present invention relates to novel chemical compounds which can be fluorinated under particularly mild conditions. The goal is to obtain stable chemical bonds to fluorine atoms. They should be so stable under physiological conditions that the fluorinated compounds are suitable as "PET tracers".

Another goal is to ensure a high degree of occupational safety with a novel, inventive fluorination with minimal effort. This is done by minimizing the manipulation of radionuclides and concentrating the radioactive waste.

Another object of the invention is, for example, tumors bind to conjugate with ⁸ F with a generally applicable, safe, quick process bioactive molecules, the specific tissue types.

Thus, it is easier than before to use molecules as selective ¹⁸ F "PET" tracers.

The novel fluorination process and conjugation process according to the invention is carried out on a specific polymer. In this case, first the substrate to be fluorinated is immobilized on a polymer. Subsequently, the fluorination of the immobilized substrate is carried out on a solid phase. Excess radionuclides are eluted from the polymer. Finally, the conjugation reaction is carried out with a bioactive compound that can bind specific types of tissue, eg tumors. In the conjugation reaction, a Staudinger reaction, the final ¹⁸ F-labeled "PET tracer" is cleaved off the solid phase.

The carrier:

The conjugation reaction or labeling reaction takes place on a carrier "Pol" which is insoluble in aqueous and organic solutions (Scheme 1). The preferred carrier materials are such that the functional groups and / or molecules conjugated to them can react with other molecules, regardless of whether the carrier is immersed in their organic or in aqueous solutions. (Scheme 1)

Scheme 1

Scheme 1: The insoluble support "Pol" with the groups L ¹ , L ² and L ⁴ ; M ¹ is a heteroatom (preferably P on which a Staudinger coupling can take place, X ¹ is an acylatable group, preferably SH, NH or OH Pol:

Herein "Pol" (Scheme 1) is an insoluble organic or inorganic polymer, metal surface or macromolecular surface on which organic and aqueous media chemical reactions can be performed.

Among the organic polymers, for. For example, the following materials can be used as homo- or mixed polymer in all possible variations: polystyrene, polyethylene, polypropylene, polyphenylene, polyacrylamides, polyacrylic esters, polyamides, polysulfones, oligosaccharides z. As dextran, PEG, polypropylene glycol and all partially or exhaustively fluorinated derivatives of the aforementioned materials.

Z was polymers are preferably similar or -identisch the "pole" Tentagel ^® (Rapp Polymere GmbH, Ernst-Simon-Str. 9, D-72072 Tubingen, Germany), the polymer body "molding injection" by generated. B. (Mimotopes Pty Ltd, 1 1 Duerdin Street, Clayton Victoria 3168, Australia, www, mi motopes. Com) or materials that consist of ferromagnetic substances. L ¹ :

With the aforementioned support materials, the group "L ¹ " is covalently bound or by strong ionic or Van der Waals interactions.

L consists of 1 -200 carbon atoms and / or 0-200 heteroatoms, which can occur in aromatic cycles, heteroaromatic cycles, aliphatic cycles, hetero-aliphatic cycles aliphatic chains. For L ¹ , heteroatoms from the following list can be used in all possible combinations: F, Cl, Br, I, S, O, N, Se, Te, Si, Al, Ge, P, As, Sb, B, Li, Na , K, Cs, Ca, Mg, Sr, Ba, Fe, Ce, Sn, H and their isotopes.

L ² :

L ² consists of 1 -200 carbon atoms and / or 0-200 heteroatoms, which can occur in aromatic cycles, heteroaromatic cycles, aliphatic cycles, heteroaliphatic cycles aliphatic chains and heteroaliphatic chains. For L ² , heteroatoms from the following list can be used in all possible combinations: F, Cl, Br, I, S, O, N, Se, Te, Si, Al, Ge, P, As, Sb, B, Li, Na , K, Cs, Ca, Mg, Sr, Ba, Fe, Ce, Sn, H and their isotopes.

However, the general formulas -CR groups L ² are preferably ¹² R ¹³ - or (-CR ² R ¹³ - CH ₂ -), where the radicals R ¹² and R ¹³ H or short alkyl groups having up to 20 carbon atoms as well as phenyl, and their partially or exhaustively fluorinated derivatives.

In a specific embodiment, the C atoms of the radicals R ¹² and R ¹³ are bridged together and part of a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ring and its heterocyclic derivatives containing O and S atoms. See formulas XI and XII. (Scheme 2)

Scheme 2

Scheme 2: Some preferred groups L ² X ¹ :

X ¹ represents an acylatable group. These also include compounds in which L -X ^{1 can be involved} in a heterocycle having 1-10 carbon atoms and / or 0-10 heteroatoms. The heteroatoms used herein are N, S, O. In a preferred embodiment X ¹ SH, OH, NH are their silylated or stannylated derivatives.

M ¹ :

M ¹ is a trivalent atom bearing a lone pair of electrons, including P, As, Sb, and Bi.

L ⁴ is a radical consisting of 1-200 carbon atoms and / or 0-200 heteroatoms, which can occur in aromatic cycles, heteroaromatic cycles, aliphatic cycles, heteroaliphatic cycles, aliphatic chains and heteroaliphatic chains.

L ⁴ may contain heteroatoms from the following list: F, Cl, Br, I, S, O, N, Se, Te, Si, Al, Ge, P, As, Sb, B, Li, Na, K, Cs, Ca , Mg, Sr, Ba, Fe, Ce, Sn, H and their isotopes. The general polymeric conjugation reagent III. In the first step, the carrier "I" is loaded with a labeled compound or with a compound "IV" which can be fluorinated according to the invention.

The radical X ^{1 of} the material described in formula I can be esterified with an ¹⁸ F-labeled carboxylic acid or a carboxylic acid molecule which can be labeled with ¹⁸ F. Examples of ¹⁸ F-labeled known carboxylic acids or their acylatable derivatives "II" (Scheme 3) are listed in the following publications (Bayer Schering Pharma Aktiengesellschaft, Germany, PCT Int Appl., 2008, 236 pp. Application: WO 2007-EP8042, 20070907. Priority: EP 2006-90166 20060908; EP 2007-90079 20070423.9 or Mu et al., Angew. Chem. Int. Ed., 2008, 47, 4922-4925)

Scheme 3

Scheme 3: The acylation of support "I" with an already existing ⁸ F-labeled acid

In this way, a general polymeric conjugation reagent can be obtained. A particular advantage of the described method is that the general polymeric conjugation reagent "III" can be packed in a chromatography column. All of the chemical transformations described below can thus be carried out in this one chromatography column with excess of the adding reagent. In this way, high yields can be achieved and excess reagents and by-products can be eluted by washing with appropriate solvents. Alternatively, the polymer body "III" may have been produced by "injection molding" and immersed in the appropriate reagents for subsequent conversions. Excess reagents can easily be washed off by immersion in rinse solutions. The inventive method of the method to obtain general polymeric conjugation reagent "IM" is carried out by acylation of the carrier "I" with a carboxylic acid according to the invention or its acylierungsfähiges derivative "IV". It carries at least one functional "X ² " group into which ¹⁸ F can be introduced. Out of that way representable carrier "V", the conjugation reagent "III" can easily be obtained subsequently. (Scheme 4)

Compounds of the general formula "IV" can be prepared analogously to the following literature specifications. (Andreas Gansaeuer et al., J. Am. Chem. Soc., 2005, 127, 1622-11623, Li Ming Gao et al, J. Biol., Inorg. Chem., 2007, 2, 959-967).

Scheme 4 n = 1-2

Scheme 4: The acylation of support "I" with an unlabelled acid "IV" bearing a group into which ⁸ F can be selectively introduced.

Scheme 5 shows a fluoroaffine group which can be used in the present invention.

Scheme 5:

n = 1, 2

Scheme 5: The fluoraffinic group based on an element of the 4th group of the periodic table (M ² = Ti, Zr, Hf)

Here, "Z" is a group of the type R ¹ -R ⁹ which carries a (C = O) Q group and represents the remainder of L 3 without the fluorophilic group.

R -R ⁹ :

The radicals R-R ⁹ are independently variable from one another H atoms or organic radicals consisting of 1 -200 carbon atoms and / or 0-200 heteroatoms, which in aromatic cycles, heteroaromatic cycles, aliphatic cycles, heteroaliphatic cycles, aliphatic chains and heteroaliphatic chains may occur. Adjacent residues may also be bridged by bridges of carbon and heteroatoms.

As hetero atoms, the following may be used: F, Cl, Br, I, S, O, N, Se, Te, Si, Al, Ge, P, As, Sb, B, Li, Na, K, Cs, Ca, Mg , Sr, Ba, Fe, Ce.

X ²

X ² is a group which can be substituted by fluoride. These include z. The following heterocycles in unsubstituted or substituted form: imidazole, triazoles, tetrazole, thiazole, benzimidazole, benzotriazole, indole, imidazoles, aniline, pyrazole, pyrrolidone, acetanet, azepine, benzodiazepine, piperidine, purine, morpholine, piperazine, triazine, oxazole, Hydantoin, aziridine, pyrrolidine, pyrrole, hexamethyeneimines, azaindole or a group whose conjugated organic or inorganic acids have a pKa <12. Including corresponding substituted with halogens, pseudohalogens and nitro groups substituted phenoxy, alkoxy, thiophenoxy or thioalkoxy groups. Further, OH, SH, Cl, Br. And I. Q:

Q is a leaving group for acylations or a group that is capable of acylation by reaction with coupling reagents commonly used for esterification. (Methods of Organic Chemistry, E. Müller ed., Volume XV / 1-2, "Synthesis of peptides", Georg Thieme Verlag 1974) These include the following heterocycles in unsubstituted or substituted form: imidazole, triazoles, tetrazole, thiazole, benzimidazole, Benzotriazole, indole, imidazoles, aniline, pyrazole, pyrrolidone, azetane, azepine, benzodiazepine, piperidine, purine, morpholine, piperazine, triazine, oxazole, hydantoin, aziridine, pyrrolidine, pyrrole, hexamethyeneimines, azaindole, hydroxysuccinimide, oxybenzotriazole or a group whose conjugated organic or inorganic acids have a pKa <12. Including correspondingly substituted with halogens, pseudohalogens and nitro groups substituted phenoxy, alkoxy, thiophenoxy or thioalkoxy groups. Furthermore, the groups OH, SH, Cl, Br, F and I.

The fluorination on solid phase:

It is particularly advantageous when the column material "V" is reacted with highly radioactive, eg ¹⁸ F-labeled compounds or ¹⁸ F ^" , the radioisotope being immobilized on the column material. Here, the advantage of the residue "L ³ " in compounds "IV" and "V" to bear, which allows the introduction of the ¹⁸ F by substitution of the group (s) "X ² " under conditions that tolerates the support material.

Preference is given here an organolith "L ³ " to which an element of the 4th or 14th group of the periodic table is chemically bonded. That element of the 4th Group or 14 are the one or two leaving group (s) "X ^2", which is substitutable with fluoride under mild conditions (are).

The case of the element of the 4th group of the periodic table with M ² = Ti, Zr, Hf is shown in Scheme 5. The substitution of fluoride for a preferred leaving group X ² in Scheme 5 is described below. (Laurianne Bareille et al., Eur. J. Inorg. Chem. 2005, 2451-2456)

The fluorination is carried out with fluoride ions, because all ¹⁸ F-labeled compounds are preferably derived from the K ¹⁸ F shown in the cyclotron.

During fluorination, the column jacket protects the operator. Excess radioactive material can be washed by the polymer and is very concentrated and easily separable at the column exit. Thus, the conjugation reagent "III" can be surely obtained. (Scheme 6)

Scheme 6

n = 1 -2

Scheme 6: Fluorination of support "V". (Substitution of X ² by ⁸ F) Also, the carrier "III" of the present invention can be either packed as a chromatography column or transported to the site as a macroscopic polymer body by "injection molding" without danger to personnel, increasing its clinical application flexibility , The fluorinated support whose fluoroaffine group is an element of the 4th group of the Periodic Table is shown in Scheme 7.

Scheme 7

Scheme 7: The fluoraffinic group of compound "V". Here, fluorine can attach to an element of the 4th group of the periodic table to form a very strong bond.

The conjugation of a bioactive molecule:

Essential to the method of the invention is the atom M of the carrier "III" (Scheme 3, 4) which allows Staudinger coupling with a bioactive organiazide "VI" which selectively binds to specific cells, e.g. Tumor cells, can bind (Scheme 8).

For this purpose, the general reagent "III", which can be prepared according to Scheme 3 or according to the invention according to Scheme 6, is reacted with a bioactive substance "VI" which carries an azide group. (Scheme 8). Due to the Staudinger reaction taking place on the solid phase, the selectively recognizing, for example, tumor-binding, ¹⁸ F-labeled compound "IX" can be eluted from the support and used as a diagnostic and / or therapeutic agent.

Scheme 8

L ⁵

n = 1, 2

Scheme 8: The Staudinger reaction of carrier "III" with an organo azide "VI".

It is particularly advantageous in this case application of the polymeric conjugation reagent "III" to an exceptionally wide variety of tumor-binding bioactives "L ⁵ ""VI". (Scheme 8) Here, L ^{5 is} a bioactive substance which may consist of an oligonucleotide of 0-200 natural nucleotides or artificial analogues and isosters containing as internucleotide linkages: phosphorothioates, phosphorodithioates, phosphorotrithioates, phosphorotetrathioates, arsenates, thioarsenates, dithioasenates, trithioarsenates, tetrathioarsenates, fluorophosphates, Phosphorofluorothioates, phosphorofluorodithioates, phosphorofluorotrithioates, H-phosohonates, alkylphosohonates, arylphosphonates, H-phosphonothioates, alkylphosphonothioates, arylphosphonodithioates, H-phosphonodithioates, alkylphosphonodithioates, arylphosphonodithioates, H-phosphonotrithioates,

Alkylphosphonotrithioates, arylphosphonotrithioates, phosphoramides, phosphorodiamides, phosphorotriamides, phosphoroamidothioates, phosphoroamidodithioates, phosphorodiamidothioates, phosphorotriamidothioates, acetals, ketals, phosphine oxides, phosphine sulfides, silyl groups, carboxylic acid amides, triazoles, oxadiazoles, sulfates, sulfamides, sulfonamides, dissulfides, amine oxides, nitrones, and BH ₃ - Adducts of phosphites, thiophosphites, dithiophosphites, trithiophosphites, phosphoamidites, phosphodiamidites, triaminophosphines, phosphorothioamidites;

Alkylborane adducts of the phosphites, thiophosphites, dithiophosphites, trithiophosphites, phosphoamidites, phosphodiamidites, triaminophosphines, phosphorothioamidites or dialkylborane adducts of the phosphites, thiophosphites, dithiophosphites, trithiophosphites, phosphoamidites, phosphodiamidites, triaminophosphines, phosphorothioamidites furthermore trialkylborane adducts of the phosphites, thiophosphites, dithiophosphites, trithiophosphites, phosphoamidites, Phosphodiamidites, triaminophosphines, phosphorothioamidites in any combination.

However, the bioactive substance L ⁵ may also be a synthetic polymer selected from 0 to 50 units of the groups ethylene, propylene, ethylene glycol, propylene glycol, acrylic ester, acrylamide, pyruvate, caprolactam, styrene, polyamines of different chain length, a polymer represented by ROM whose arylated and alkylated derivatives are in all possible mixtures and combinations. This polymer may be substituted by aromatic cycles, heteroaromatic cycles, aliphatic cycles, heteroaliphatic cycles, aliphatic chains and heteroaliphatic chains, and the heteroatoms F, Cl, Br, I, S, O, N, Se, Te, Si, Al, Ge, P , As, Sb. B, Li, Na, K, Cs, Ca, Mg, Sr, Ba, Fe, Ce, Sn, H and their isotopes. Examples of such a synthetic polymer are described by Kleiner et al. J. Am. Chem. Soc. 2008, 130, 4646-4659, Heemstra et al. J. Am. Chem. Soc. 2009, 131, 11347-11349, Ura et al. Science (Washington) 2009, 325, 73-77.

The bioactive substance L ⁵ may also consist of a peptide or protein from 0-2000 amino acids whose analogs, stereoisomers or isosters and z. B. D-amino acids, ao-amino acids may have taurine derivatives and PNA building blocks. Furthermore, the bioactive substance L ^{5 may be} a carbohydrate of 0-50 saccharide building blocks, its analogs or stereoisomers.

Finally, L ⁵ may be a bioactive low molecular weight molecule, a natural or artificial protein agonist, antagonist, enzyme inhibitor, or nucleic acid binder, a steroids group lipid, terpenes, macrolides, poliketides and / or their natural and artificial derivatives.

Scheme 9 shows a summary of the invention

Labeling method.

Scheme 9 n,

IX to the PET

flu

Scheme L9 shows the use of the labeling reagent "I" described in the invention packed in a column which can be esterified with carboxylic acids "II" and "IV". In case "II" the carboxylic acid is ¹⁸ F-labeled, in case "IV" it carries a fluoro-affine group. The latter can be fluorinated on the solid phase. The acylated carrier "III" can then with a tumor-binding substance z. B. an aptamer are conjugated with the "IX" is released. Examples:

Example 1) Preparation of a compound of the type "V" (XVIII) with a fluoro-affinic group:

Scheme 10

The titanocenecarboxylic acid (Gansaeuer, et al., J. Am. Chem. Soc., 2005, 127, 1622-1 1623) is converted into the acid chloride:

(313 mg, 1.0 mmol) of I was reacted with SOCl ₂ (1.0 mL) within one hour at room temperature. Excess SOCl ₂ is distilled off. The residue is then dissolved in CH ₂ Cl ₂ (5 mL) and added to a suspension of the mercaptomethylphosphinyltentagel (0.25 equivalents SH), (Hanyoung, Kim et al., Chem. Lett., 2006, 8, 1149-51) and DIPEA (120 mg, 5.0 mmol) in CH ₂ Cl ₂ (5 mL). The reaction mixture is shaken for 16 hours at room temperature. The resin is filtered off with DMF, dioxane, DCM and ether and then dried in a vacuum desiccator.

Example 2) Preparation of a compound of the "V" type with a fluoro-affinitive group

Scheme I l

XIX

The carboxylic acid chloride of Example 2 "XVII" (Gansaeuer et al., J. Am. Chem. Soc., 2005, 127, 1622-1 1623) is dissolved in CH ₂ Cl ₂ (5 mL) and added dropwise to a mixture of CH ₂ Cl ₂ (5 mL) NaH (5.00 mmol) and sarcosine tert. Butyl ester (1.20 mmol). The reaction mixture is stirred for 5 hours at room temperature. After filtration through Celite, the filtrate is evaporated in vacuo. The resulting solid is extracted with CH ₂ Cl ₂ (20 mL) and washed with a solution of 10 mL (1 N) NH ₄ Cl and NaCl. The organic phase dried over MgS0 ₄ and chromatographed on silica gel 60. The product fractions are dried in a vacuum desiccator.

Example 3) Cleavage of the tert. Butyl group of the sarcosine derivative from Example 3:

Scheme 12

XXII

The tert-butyl ester is cleaved off with a saturated solution of HCl in dioxane.

Example 4) Immobilization of the compound from Example 3 on the support of the type 'Ί' (ΧΧΙΙΙ)

Scheme 13

The immobilization of the compound from Example 3 is carried out according to the procedure of Example 1.

Example 5) Fluorination of the carrier "V" of Example 1 to obtain a reagent of the general formula "III" (XXV) containing a fluoroaffinen group.

Scheme 14

XXV

The resin from Example 2 is for 30 min. treated with aqueous KF solution at room temperature. Subsequently, the resin is washed salt-free with water.

Example 6) Fluorination of the carrier "V" of Example 4 to obtain a reagent of the general formula "III" (XXVI) containing a fluoroaffine group.

Scheme 15

XXVI

The resin from Example 5 is for 30 min. treated with aqueous KF solution at room temperature. Subsequently, the resin is washed salt-free with water. Example 7) Preparation of a compound of the "II" type with a fluoraffinic group from an element of the 4 group:

The compound from Example 4 is for 30 min. treated with aqueous KF solution at room temperature. Subsequently, the compound is washed the resin salt-free with water.

Example 8) Acylation of a compound by means of reagent "III" from Example 5 to give a compound of general formula "IX" (XXVIII). Scheme 16

5'-azido thymidine was reacted with reagent "III" from Example 5 analogously to the protocol of Hanyoung Kim, et al. Chem. Lett. 2006, 8, 1 149-51.

Example 9) Acylation of an Oligonucleotide Using Reagent "IM" from Example 6 to give a compound of general formula "IX" (XXX).

Scheme 17

To 0.01g of the resin of Example 6 are added to 2 ml of an aqueous buffer solution of 100 mg of an oligonucleotide carrying an azido group at the 5 'end. The fluorinated oligonucleotide diffuses out of the resin and can be isolated from the filtrate after one hour of filtration of the resin.

Example 10) Acylation of a peptide by means of the reagent "HI" from Example 6 to give a compound of the general formula "IX" (XXXIII).

To 0.01 g of the resin from Example 6, which is located in a column that can be closed at the outlet, are placed in 2 mL of an aqueous buffer solution of 100 mg of a peptide carrying an azide group. After incubation for one hour, open the outlet and elute the fluorinated oligonucleotide with physiological NaCl solution.

Claims

claims

1. Support with the general formula (V):

where Pol is an insoluble, organic or inorganic polymer, metal surface or macromolecular surface;

L is a group covalently bound by Pol or bound by strong ionic or van der Waals interactions, comprising 1-200 carbon atoms and / or 0-200 heteroatoms selected from the group consisting of F, Cl, Br , I, S, O, N, Se, Te, Si, Al, Ge, P, As, Sb, B, Li, Na, K, Cs, Ca, Mg, Sr, Ba, Fe, Ce, Sn, H and their isotopes;

M is a trivalent atom bearing a lone pair of electrons, in particular P, As, Sb or Bi; L ^{2 is} a group comprising 1-200 carbon atoms and / or 0-200 heteroatoms selected from the group consisting of F, Cl, Br, I, S, O, N, Se, Te, Si, Al, Ge, P, As, Sb, B, Li, Na, K, Cs, Ca, Mg, Sr, Ba, Fe, Ce, Sn, H and their isotopes;

L ^{4 is} a radical comprising 1-200 carbon atoms and / or 0-200 heteroatoms selected from the group consisting of F, Cl, Br, I, S, O, N, Se, Te, Si, Al, Ge, P, As, Sb, B, Li, Na, K, Cs, Ca, Mg, Sr, Ba, Fe, Ce, Sn, H and their isotopes;

X ^{1 represents} an acylatable group, in particular SH, OH, NH, their silylated or stannylated derivatives;

L ^{3 represents} a fluorophilic group based on an element selected from the 4th group of the periodic table consisting of titanium, zirconium, hafnium, and nine (R-R ⁹ ) independently variable hydrogen atoms or organic radicals Radicals of 1-200 carbon atoms and / or 0-200 heteroatoms include those in aromatic cycles, heteroaromatic cycles, aliphatic cycles, heteroaliphatic cycles, aliphatic chains, or heteroaliphatic chains are arranged, wherein the heteroatoms are selected from the group comprising F, Cl, Br, I, S, O, N, Se, Te, Si, AI, Ge, P, As, Sb. B, Li, Na, K, Cs, Ca, Mg, Sr, Ba, Fe, Ce;

X ^{2 represents} a group which is substitutable by fluoride, in particular the following heterocycles in unsubstituted or substituted form: imidazole, triazoles, tetrazole, thiazole, benzimidazole, benzotriazole, indole, imidazoles, aniline, pyrazole, pyrrolidone, azetane, azepine, benzodiazepine, Piperidine, purine, morpholine, piperazine, triazine, oxazole, hydantoin, aziridine, pyrrolidine, pyrrole, hexamethylene-imines, azaindole; n = 1-2.

2. A carrier according to claim 1, wherein X ^{2 is} OH, SH, Cl, Br, I or a group whose conjugated organic or inorganic acids have a pKa <12, in particular according to halogens, pseudohalogens and nitro groups substituted phenoxy, alkoxy , Thiophenoxy or thioalkoxy groups.

3. Support with the general formula (III):

wherein

Pol stands for an insoluble, organic or inorganic polymer, a metal surface or macromolecular surface;

L ^{1 is} a group which is covalently bound by Pol or bound by strong ionic or Van der Waals interactions, comprising 1-200 carbon atoms and / or 0-200 heteroatoms selected from the group consisting of F, Cl, Br, I, S, O, N, Se, Te, Si, Al, Ge, P, As, Sb, B, Li, Na, K, Cs, Ca, Mg, Sr, Ba, Fe, Ce, Sn, H and their isotopes;

L ^{3 represents} a fluorophilic group based on an element selected from the 4th group of the periodic table consisting of titanium, zirconium, hafnium and nine (R ¹ -R ⁹ ) independently variable of each other or H atoms organic radicals of 1-200 carbon atoms and / or 0-200 heteroatoms, which are arranged in aromatic cycles, heteroaromatic cycles, aliphatic cycles ₍ heteroaliphatic cycles, aliphatic chains, or heteroaliphatic chains, wherein the heteroatoms are selected from the group comprising B, Li, Na, K, Cs, Ca, Mg, Sr, Ba, Fe, Ce;

F stands for the radioisotope ¹⁸ F, n = 1-2.

4. A bioactive substance which binds selectively to specific cells, in particular tumor cells, and has at least one fluorinated group with the general formula (IX):

(IX) wherein L ^{5 is} a bioactive substance comprising an oligonucleotide consisting of 0-200 natural nucleotides or artificial analogs and isosters; or a synthetic polymer consisting of 0 up to 50 units; or a peptide or protein consisting of 0-2000 amino acids, their analogs, stereoisomers or isosters; or a carbohydrate consisting of 0-50 saccharide units, its analogues or stereoisomers; or a low molecular weight molecule, a natural or artificial protein Agonist, antagonist, enzyme inhibitor or nucleic acid binder, or a steroid group lipid, terpenes, macrolides, polyketides and / or their natural and artificial derivatives;

L ^{3 represents} a fluorophilic group based on an element selected from the 4th group of the periodic table consisting of titanium, zirconium, hafnium, and nine (R-R ⁹ ) independently variable hydrogen atoms or organic radicals Radicals of 1-200 carbon atoms and / or 0-200 heteroatoms, which are arranged in aromatic cycles, heteroaromatic cycles, aliphatic cycles, heteroaliphatic cycles, aliphatic chains, or heteroaliphatic chains, wherein the heteroatoms are selected from the group comprising F B, Li, Na, K, Cs, Ca, Mg, Sr, Ba, Fe, Ce ;

F stands for the radioisotope ¹⁸ F.

5. A bioactive substance according to claim 4, wherein the fluorophilic group carries at least one fluorine atom which is bonded to a titanium atom.

6. A process for the preparation of a support according to claim 3, wherein the support according to claim 1 is reacted with ¹⁸ F-labeled compounds or with ¹⁸ F.

7. A process for producing a bioactive substance according to claim 4 or 5, wherein the carrier according to claim 3 is reacted with an organyl azide having the general formula (VI)

In which

L ^{5 is} a bioactive substance comprising an oligonucleotide consisting of 0-200 natural nucleotides or artificial analogs and isosters; or a synthetic polymer consisting of 0 up to 50 units; or a peptide or protein consisting of 0-2000 amino acids, their analogs, stereoisomers or isosters; or a carbohydrate consisting of 0-50 saccharide units, its analogues or stereoisomers; or a low molecular weight molecule, a natural or artificial protein agonist, antagonist, enzyme inhibitor or nucleic acid binder, or a lipid from the group of steroids, terpenes, macrolides, polyketides and / or their natural and artificial derivatives. 8: Kit comprising a carrier according to claim 3, which is protected transferable protected by its column casing.