Synthesis method of < 18 > F-flurbiditaban labeled precursor

Abstract

The invention provides a synthesis method of an < 18 > F-flurbipataban labeled precursor (compound 7), which comprises the following steps: by taking 4-nitrophenylacetic acid (compound 8) and p-hydroxybenzaldehyde (compound 9) as initial raw materials, carrying out condensation under the action of piperidine to obtain 4-nitro-4 '-hydroxystilbene (compound 10), then carrying out phenolic hydroxyl group etherification and tert-butyldimethylsilyl protection to generate a compound 12, and finally, carrying out reaction on the compound 12 and the compound 13 to obtain the < 18 > F-flurbipataban labeled precursor (compound 7). The preparation method comprises the following steps: reducing nitryl into amino, carrying out tert-butoxy carbon group protection and N-methylation, removing tert-butyldimethylsilyl, and finally carrying out methylsulfonylation to obtain a labeled precursor 2-[2-(2-{4-[(E)-2-{4-[tert-butoxy carbonyl methyl amino]-phenyl}-vinyl]-phenoxy}-ethyoxyl)-ethyoxyl]-ethyl methanesulfonate (compound 7). According to the route, substitution reaction selectivity is avoided, the synthesis yield is improved, operation is easy, separation and purification are easy, and the obtained product is high in purity.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis and relates to the synthesis of radioactive fluorine-labeled precursor compounds, and in particular to radioactive drugs. 18 A new synthetic route for F-fluorobitaban labeling precursors. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] 18 F-Flubitaban is a diphenylethylene radioactive diagnostic reagent developed by Piramal Imaging. It was approved for marketing in Europe by the European Commission on February 24, 2014, and in the United States by the U.S. FDA on March 19 of the same year. The trade name is It was officially approved for marketing by the National Medical Products Administration (NMPA) on September 15, 2023. It is the first Aβ-PET imaging agent approved in China for the diagnosis of Alzheimer's disease, and can achieve early, accurate and non-invasive diagnosis of Alzheimer's disease.

[0004] Patents WO2006066104A2 and CN101123995B and literature (Nuclear Medicine and Biology, 32, (2005): 799–809) reported 18 Synthesis method of F-flubitaban labeled precursor (Compound 7). 4-Methylamino-4'-hydroxystilbene (Compound 1) and 2-[2-(2-chloroethoxy)ethoxy]ethanol (Compound 2) are used as starting materials, and 2-[2-(2-{4-[2-(4-methylaminophenyl)-vinyl]-phenoxy}-ethoxy)-ethoxy]ethanol (Compound 3) is generated by substitution reaction, and the hydroxyl group and amino group of Compound 3 are protected by TBS (tert-butyldimethylsilyl) and Boc (tert-butyloxycarbonyl) to obtain Compound 5, and the tert-butyldimethylsilyl group is removed under the action of tetrabutylammonium fluoride (TBAF), and finally the compound 2-[2-(2-{4-[(E)-2-{4-[tert-butyloxycarbonylmethylamino]-phenyl}-vinyl]-phenoxy}-ethoxy)-ethoxy]-ethyl methanesulfonate (Compound 7) is obtained by mesylation. The synthetic route is as follows:

[0005]

[0006] The literature reports that the total yield is 54%, but in the actual preparation process, the raw material 4-methylamino-4'-hydroxystilbene (compound 1) in the first step reaction has two reaction sites, namely the phenolic hydroxyl group and the methylamino group. It is difficult to obtain a high yield of intermediate 3 in its reaction with 2-[2-(2-chloroethoxy)ethoxy]ethanol (compound 2), resulting in a total yield of less than 20%; at the same time, the O-substituted and N-substituted products have similar polarity and are not easy to separate and purify. Summary of the invention

[0007] In order to solve the above problems, the present invention provides a 18 The method for synthesizing F-fluorobitaban labeled precursor has the advantages of high yield, simple preparation, easy separation and purification, etc.

[0008] In order to achieve the above object, the present invention adopts the following technical solution:

[0009] The first aspect of the present invention provides a 18 The synthesis method of F-fluorobitaban labeling precursor is synthesized by the following route 18 F-fluorobitaban labeled precursor;

[0010]

[0011] The specific steps of the route include:

[0012] (1) 4-Nitrophenylacetic acid (Compound 8) and p-hydroxybenzaldehyde (Compound 9) undergo condensation reaction under the action of piperidine to generate 4-nitro-4'-hydroxystilbene (Compound 10);

[0013]

[0014] (2) The intermediate compound 10 and 2-[2-(2-chloroethoxy)ethoxy]ethanol (compound 2) undergo a substitution reaction at the phenolic hydroxyl group in the presence of potassium iodide and a base to generate 2-[2-(2-{4-[2-(4-methylaminophenyl)-vinyl]-phenoxy}-ethoxy)-ethoxy]ethanol (compound 11);

[0015]

[0016] (3) The intermediate compound 11 is reacted with tert-butyldimethylsilyl chloride to protect the side chain hydroxyl group to obtain the intermediate compound 12;

[0017]

[0018] (4) The nitro group of the intermediate compound 12 is reduced to an amino group under the action of a reducing agent to generate the intermediate compound 13;

[0019]

[0020] (5) Using di-tert-butyl dicarbonate and an organic base to protect the amino group of intermediate 13 to obtain intermediate compound 14;

[0021]

[0022] (6) Using sodium hydride as a base, iodomethane was used to N-methylate the intermediate 14 to obtain the intermediate compound 5;

[0023]

[0024] (7) Under the action of tetrabutylammonium fluoride (TBAF), the tert-butyldimethylsilyl group of intermediate 5 is removed to obtain intermediate compound 6;

[0025]

[0026] (8) Mesylation of the side chain hydroxyl group of intermediate 6 to obtain labeled precursor 7;

[0027]

[0028] In some embodiments, the molar ratio of 4-nitrophenylacetic acid, p-hydroxybenzaldehyde, and piperidine is 1-1.5:1:1-2;

[0029] In some embodiments, the condensation reaction temperature is 140°C-145°C.

[0030] In some embodiments, in step (2), the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, pyridine, triethylamine, diisopropylethylamine, etc.; the reaction solvent is selected from at least one of dimethylformamide, dimethylacetamide, acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, xylene, and chlorobenzene;

[0031] In some embodiments, the temperature of the substitution reaction is 60-150°C.

[0032] In some embodiments, in step (3), the reaction solvent is selected from at least one of dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide, and acetonitrile;

[0033] In some embodiments, in step (3), the reaction temperature is 0°C to room temperature (20-25°C).

[0034] In some embodiments, in step (4), the reducing agent is selected from zinc powder / ammonium chloride or palladium carbon / hydrogen;

[0035] In some embodiments, in step (4), the reaction solvent is selected from at least one of dichloromethane, tetrahydrofuran, ethyl acetate, methanol, and ethanol;

[0036] In some embodiments, in step (4), the reaction temperature is 20-25°C.

[0037] In some embodiments, in step (5), the organic base is selected from at least one of triethylamine, pyridine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine (DABCO), and N-methylmorpholine;

[0038] In some embodiments, in step (5), the reaction solvent is selected from at least one of dichloromethane, tetrahydrofuran, 1,4-dioxane, and acetonitrile;

[0039] In some embodiments, in step (5), the reaction temperature is 0°C to room temperature (20-25°C).

[0040] In some embodiments, in step (6), the reaction solvent is selected from at least one of dimethylformamide, dimethylacetamide, tetrahydrofuran, and 2-methyltetrahydrofuran;

[0041] In some embodiments, in step (6), the reaction temperature is 0°C to room temperature (20-25°C).

[0042] In some embodiments, in step (7), the reaction solvent is selected from at least one of dichloromethane, tetrahydrofuran, ethyl acetate, methanol, and ethanol;

[0043] In some embodiments, in step (7), the reaction temperature is room temperature (20-25°C).

[0044] In some embodiments, in step (8), the mesylation agent is selected from methanesulfonyl chloride or methanesulfonic anhydride;

[0045] In some embodiments, in step (8), the reaction solvent is selected from at least one of dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, and acetone;

[0046] In some embodiments, in step (8), the reaction temperature is 0°C to room temperature (20-25°C).

[0047] The second aspect of the present invention provides the above-mentioned method synthesized 18 F-Fluorobitaban labeled precursor.

[0048] Beneficial effects of the present invention

[0049] The synthetic route of the present invention avoids substitution reaction selectivity, improves route efficiency, is easy to separate and purify, is simple to operate, and has not only a high total yield but also a high purity of the obtained product. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention, and the exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute improper limitations on the present invention.

[0051] Figure 1 The synthetic route used in the specific embodiment;

[0052] Figure 2 is the mass spectrum of the labeled precursor (compound 7);

[0053] Figure 3 is the H NMR spectrum of the labeled precursor (compound 7);

[0054] Figure 4 is the NMR carbon spectrum of the labeled precursor (compound 7);

[0055] Figure 5 This is the HPLC purity diagram of the labeled precursor (Compound 7). DETAILED DESCRIPTION

[0056] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0057] The present invention will be further described in detail below in conjunction with specific embodiments. It should be noted that the specific embodiments are intended to explain the present invention rather than to limit it.

[0058] Example 1: Synthesis of Intermediate Compound 10

[0059] 4-Nitrophenylacetic acid (compound 8, 2.17 g, 12 mmol), p-hydroxybenzaldehyde (compound 9, 1.22 g, 10 mmol) and piperidine (1.28 g, 15 mmol) were added to a round-bottom flask, and the mixture was stirred and sealed at 140 °C for 4 hours. After the reaction, the mixture was cooled, a small amount of methanol was added and ultrasonically dissolved, and the mixture was poured into ice water to precipitate a solid. The filtered solid was purified by silica gel column chromatography to obtain the intermediate compound 10 (red solid, 1.98 g, yield 82%). 1H NMR (400MHz, CDCl3) δ8.20(d,J=8.9Hz,2H),7.58(d,J=8.9Hz,2H),7.44(d,J=8. 6Hz, 2H), 7.21 (d, J = 16.3Hz, 1H), 6.98 (d, J = 16.3Hz, 1H), 6.84 (d, J = 8.6Hz, 2H). 13 C NMR (101MHz, CDCl3) δ157.4,146.5,144.5,133.2,128.8,128.7,126.6,124.3,123.9,116.2.

[0060] Example 2: Synthesis of Intermediate Compound 11

[0061] Intermediate 10 (1.45 g, 6 mmol), 2-[2-(2-chloroethoxy)ethoxy]ethanol (compound 2, 1.21 g, 7.2 mmol), potassium carbonate (1.24 g, 9 mmol) and potassium iodide (50 mg, 0.3 mmol) were added to a round-bottom flask, and the reactants were dissolved in 20 mL of dimethylformamide. The reaction was stirred at 90 ° C for 4 hours. After the reaction was completed, 100 mL of ammonium chloride solution was added for dilution, and the mixture was extracted 3 times with 50 mL of ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove part of the solvent. Petroleum ether was added for pulping, filtered, and the solid was collected and dried to obtain intermediate compound 11 (yellow solid, 1.9 g, yield 85%). 1 H NMR (400MHz, CDCl3) δ8.20(d,J=8.8Hz,2H),7.59(d,J=8.8Hz,2H),7.48(d,J=8.7Hz,2H),7.21(d,J=16.3Hz,1H),7.00(d, J=16.3Hz,1H),6.94(d,J=8.7Hz,2H),4.17(t,J=4.6Hz,2H),3.89(t,J=4.6Hz,2H),3.79–3.72(m,6H),3.63–3.60(m,2H). 13 C NMR (101MHz, CDCl3) δ159.5,146.5,144.4,133.0,129.3,128.5,126.6,124.3,124.3,115.1,72.6,71.0,70.8,70.5,69.8,67.6,61.9.

[0062] Example 3: Synthesis of Intermediate Compound 12

[0063] Add intermediate 11 (1.68 g, 4.5 mmol), imidazole (613 mg, 9 mmol) and 50 mL of dichloromethane to a round-bottom flask, stir to dissolve, add tert-butyldimethylsilyl chloride (1.02 g, 6.75 mmol) in batches, react at room temperature for 10 hours, add 50 mL of ammonium chloride solution to dilute after the reaction, separate the organic phase, concentrate and column chromatography to obtain intermediate compound 12 (colorless oil, 2.1 g, yield 96%). ESI-MS: [M+NH4] + ,505.66.

[0064] Example 4: Synthesis of Intermediate Compound 13

[0065] In a round-bottom flask, intermediate 12 (1.95 g, 4 mmol), zinc powder (2.62 g, 40 mmol), 10 mL (40 mmol) of ammonium chloride aqueous solution and 50 mL of methanol were added and stirred for 4 hours. After the reaction, the insoluble matter was removed by filtration. The filtrate was concentrated to remove most of the solvent, diluted with 100 mL of water, extracted with 50 mL of ethyl acetate three times, the organic phases were combined, washed once with saturated brine and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate compound 13 (colorless oil, 1.71 g, yield 93%). ESI-MS: [M+NH4] + ,475.59.

[0066] Example 5: Synthesis of Intermediate Compound 14

[0067] In a round-bottom flask, intermediate 13 (1.37 g, 3 mmol), triethylamine (455 mg, 4.5 mmol) and 50 mL of dichloromethane were added, and di-tert-butyl dicarbonate (982 mg, 4.5 mmol) was added after stirring to dissolve. The mixture was reacted at room temperature for 10 hours. After the reaction was completed, 75 mL of dilute hydrochloric acid (1 M) was added to dilute the mixture. The organic phase was separated, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain intermediate compound 14 (white solid, 1.51 g, yield 90%). 1 H NMR (400MHz, CDCl3) δ7.48–7.40(m,4H),7.20(d,J=8.5Hz,2H),7.04(d,J=16.3Hz,1H),6.95(d,J=16.3Hz,1H),6.91(d,J=8.8Hz,2H),4.15(t ,J=5.4Hz,2H),3.87(t,J=5.4Hz,2H),3.77(t,J=5.4Hz,2H),3.75–3.66(m,4H),3.57(t,J=5.4Hz,2H),1.46(s,9H),0.89(s,9H),0.07(s,6H).

[0068] Example 6: Synthesis of Intermediate Compound 5

[0069] To an anhydrous dimethylformamide solution (15 mL) containing intermediate 14 (1.39 g, 2.5 mmol) was added sodium hydride (60% purity, 120 mg, 3 mmol) in batches under an ice-water bath. After stirring for 15 minutes, iodomethane (233 μL, 3.75 mmol) was added and the mixture was returned to room temperature for 5 hours. After the reaction was completed, 100 mL of ammonium chloride solution was added for dilution, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatography was performed to obtain intermediate compound 5 (white solid, 1.24 g, yield 87%). 1 H NMR (400MHz, CDCl3) δ7.43(d,J=7.4Hz,4H),7.20(d,J=8.2Hz,2H),7.06–6.87(m,4H),4.15(t,J=5.0Hz,2H),3.87(t,J=5.0H z,2H),3.77(t,J=5.5Hz,2H),3.75–3.67(m,4H),3.57(t,J=5.5Hz,2H),3.27(s,3H),1.46(s,9H),0.89(s,9H),0.07(s,6H). 13 C NMR (101MHz, CDCl3) δ158.6,154.9,142.9,134.9,130.4,128.1,127.8,126.4,126.1, 125.6,115.0,80.5,72.9,71.0,70.9,69.9,67.6,62.9,37.4,28.5,26.1,18.5,-5.1.

[0070] Example 7: Synthesis of Intermediate Compound 6

[0071] Intermediate 5 (1 g, 1.8 mmol) and 25 mL of tetrahydrofuran were added to a round-bottom flask, and 5 mL of 1 M tetrabutylammonium fluoride solution was added after stirring to dissolve. The mixture was reacted at room temperature for 5 hours. After the reaction, 100 mL of saturated brine was added to dilute the mixture, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain intermediate compound 6 (white solid, 810 mg, yield 98%). 1H NMR(400MHz, CDCl3) δ7.43(d,J=8.4Hz,4H),7.20(d,J=8.2Hz,2H),7.05–6.88(m,4H),4.16(t,J=4.8Hz,2H) ,3.88(t,J=4.8Hz,2H),3.79–3.68(m,6H),3.63(d,J=4.8Hz,2H),3.26(s,3H),2.11(br.s,1H),1.46(s,9H). 13 CNMR (101MHz, CDCl3) δ158.5,154.8,142.9,134.8,130.5,128.1,127.8,126. 4,126.1,125.6,115.0,80.5,72.6,71.0,70.5,69.9,67.5,61.9,37.4,28.5.

[0072] Example 8: Synthesis of Labeled Precursor Compound 7

[0073] Intermediate 6 (595 mg, 1.3 mmol), triethylamine (223 mg, 2.2 mmol) and 25 mL of dichloromethane were added to a round-bottom flask, and methanesulfonic anhydride (350 mg, 2 mmol) was added after stirring to dissolve. The mixture was reacted at room temperature for 12 hours. The reaction solution was washed with sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatography was performed to obtain the labeled precursor compound 7 (light yellow solid, 635 mg, yield 92%). 1 H NMR(400MHz, CDCl3)δ7.47–7.40(m,4H),7.20(d,J=8.3Hz,2H),7.04–6.87(m,4H),4.40–4.35(m,2H),4.17–4 .11(m,2H),3.88–3.83(m,2H),3.80–3.75(m,2H),3.75–3.68(m,4H),3.26(s,3H),3.05(s,3H),1.46(s,9H). 13 C NMR (126MHz, CDCl3) δ158.5,154.9,142.9,134.8,130.5,128.0,127.8,126.5,126.2,1 25.6,114.9,80.5,70.9,70.8,69.9,69.4,69.2,67.6,37.8,37.4,28.5.ESI-MS:[M+H] + ,536.57;[M+NH4] + ,553.58.

[0074] The total yield of the labeled precursor in the reaction route was 44%, which was higher than the actual yield of the literature route, and the purity of the compound was 99.4%.

[0075] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A 18 The method for synthesizing a F-fluorobitaban labeled precursor is characterized in that: The following synthesis route was used 18 F-fluorobitaban labeled precursor; The specific steps of the route include: Step (1): 4-nitrophenylacetic acid and p-hydroxybenzaldehyde undergo a condensation reaction under the action of piperidine to generate 4-nitro-4'-hydroxystilbene; Step (2): 4-nitro-4'-hydroxystilbene and 2-[2-(2-chloroethoxy)ethoxy]ethanol undergo a substitution reaction at the phenolic hydroxyl group in the presence of potassium iodide and a base to generate 2-[2-(2-{4-[2-(4-methylaminophenyl)-vinyl]-phenoxy}-ethoxy)-ethoxy]ethanol; Step (3): reacting 2-[2-(2-{4-[2-(4-methylaminophenyl)-vinyl]-phenoxy}-ethoxy)-ethoxy]ethanol with tert-butyldimethylsilyl chloride to obtain an intermediate compound 12; Step (4): reducing the nitro group of the intermediate compound 12 to an amino group under the action of a reducing agent to generate an intermediate compound 13; Step (5): using di-tert-butyl dicarbonate and an organic base to protect the amino group of the intermediate compound 13 to obtain the intermediate compound 14; Step (6): Using sodium hydride as a base, iodomethane is used to N-methylate the intermediate compound 14 to obtain the intermediate compound 5; Step (7): Under the action of tetrabutylammonium fluoride, the tert-butyldimethylsilyl group of the intermediate compound 5 is removed to obtain the intermediate compound 6; Step (8): The side chain hydroxyl group of the intermediate compound 6 is mesylated to obtain the labeled precursor 7.

2. The method according to claim 1 18 The method for synthesizing a F-fluorobitaban labeled precursor is characterized in that: The molar ratio of 4-nitrophenylacetic acid, p-hydroxybenzaldehyde and piperidine is 1-1.5:1:1-2; Or, the condensation reaction temperature is 140°C-145°C.

3. The method according to claim 1 18 The method for synthesizing a F-fluorobitaban labeled precursor is characterized in that: In step (2), the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, pyridine, triethylamine, diisopropylethylamine, etc.; the reaction solvent is selected from at least one of dimethylformamide, dimethylacetamide, acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, xylene, and chlorobenzene; Alternatively, the temperature of the substitution reaction is 60-150°C.

4. The method according to claim 1 18 The method for synthesizing a F-fluorobitaban labeled precursor is characterized in that: In step (3), the reaction solvent is selected from at least one of dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide, and acetonitrile; Alternatively, the reaction temperature is 0°C to room temperature.

5. The method according to claim 1 18 The method for synthesizing a F-fluorobitaban labeled precursor is characterized in that: In step (4), the reducing agent is selected from zinc powder / ammonium chloride or palladium carbon / hydrogen; Or, the reaction solvent is selected from at least one of dichloromethane, tetrahydrofuran, ethyl acetate, methanol and ethanol; Alternatively, the reaction temperature is room temperature.

6. The method for synthesizing the 18F-flubitaban labeled precursor according to claim 1, characterized in that: In step (5), the organic base is selected from at least one of triethylamine, pyridine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, and N-methylmorpholine; Or, the reaction solvent is selected from at least one of dichloromethane, tetrahydrofuran, 1,4-dioxane, and acetonitrile; Alternatively, the reaction temperature is 0°C to room temperature.

7. The method for synthesizing a 18F-flubitaban labeled precursor according to claim 1, characterized in that: In step (6), the reaction solvent is selected from at least one of dimethylformamide, dimethylacetamide, tetrahydrofuran, and 2-methyltetrahydrofuran; Alternatively, the reaction temperature is 0°C to room temperature.

8. The method according to claim 1 18 The method for synthesizing a F-fluorobitaban labeled precursor is characterized in that: In step (7), the reaction solvent is selected from at least one of dichloromethane, tetrahydrofuran, ethyl acetate, methanol and ethanol; Alternatively, the reaction temperature is room temperature.

9. The method according to claim 1 18 The method for synthesizing a F-fluorobitaban labeled precursor is characterized in that: In step (8), the mesylation agent is selected from methanesulfonyl chloride or methanesulfonic anhydride; Or, the reaction solvent is selected from at least one of dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, and acetone; Alternatively, the reaction temperature is 0°C to room temperature.

10. The method synthesized according to any one of claims 1 to 9 18 F-Fluorobitaban labeled precursor.

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