CN101723850B - 18F labeled aromatic amino acid and its preparation method and tumor imaging application - Google Patents

Abstract

The invention discloses a new type of radioactive ¹⁸ F-labeled aromatic amino acid, which is used for tumor positron emission tomography (PET) imaging research, and is characterized in that: one end has an F-substituted alkoxybenzoyl structure; the other end has an α-amino acid Structure, the substituent R1 is located at the α position of the carboxyl group, R1 is phenyl, benzyl, 3-indolyl methyl, R2 is methoxy, and n is 1-5. R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. The compound improves fat solubility, and different amino acid structures are introduced into the structure, and F in the structure is ¹⁹ F and ¹⁸ F.

R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. Compared with the prior art, the ¹⁸ F-labeled amino acid derivatives provided by the present invention not only have better biodistribution discrimination, but also have the potential to be used as tumor imaging agents (especially brain tumor imaging agents), and have the advantages of simple preparation. , The characteristics of high marking rate.

Description

18F labeled aromatic amino acid and its preparation method and tumor imaging application

technical field

The invention relates to a novel ¹⁸ F labeled aromatic amino acid, its preparation method and its application as a positron emission tomography (PET) molecular probe for tumors (especially brain tumors).

Background technique

Positron emission tomography (Positron emission tomography) PET imaging is currently the only technology that uses anatomical morphology to perform functional, metabolic and receptor imaging. It has high sensitivity and specificity, and can quantitatively and dynamically detect Observing the physiological and biochemical changes of drugs or metabolites in the human body from the molecular level has become the best means for diagnosing and guiding the treatment of tumors, cardiovascular diseases and neuropsychiatric diseases. 

¹⁸ F has a long half-life (t _1/2 = 109.8min), decays through β ⁺ and EC, β ⁺ energy is 649kev, has a lower radiation dose and a shorter range to tissues, and is the most commonly used positron nuclide, suitable for For complex organic synthesis of positron emission drugs and clinical applications of PET.

In recent years, due to the relatively easy acquisition of ¹⁸ F nuclides and the continuous maturity of labeling methods and the possibility of automatic production, a large number of compounds have been synthesized and their imaging effects as ¹⁸ F-labeled tracers have been studied. The study of various ¹⁸ F radiolabels has become a hot spot in PET drug research.

After the natural amino acid Tyrosine is radiolabeled, it is transported to the brain to participate in the synthesis of proteins in the brain, so it can be used as an imaging agent, such as ¹⁸ F-Tyrosine. However, it was also discovered that some labeled amino acid derivatives, although not involved in protein synthesis in the brain, can also be used as imaging agents as long as they can be transported by the transport system of tumor tissues and pass through the brain barrier. Certain amino acid derivatives labeled with radionuclides can also be used as brain tumor imaging agents. Recently, Tomio et al. synthesized FMT with [ ¹⁸ F]AcOF as the electrophile by electrophilic substitution method, and studied the in vivo function of FMT. According to the distribution and a series of experiments, the conclusion is that FMT is a promising brain tumor imaging agent similar to IMT (3-[ ¹²³ I]-Iodo-α-Methyltyrosine). Wester et al. explored a simple nucleophilic substitution method and successfully synthesized another ¹⁸ F-labeled tyrosine derivative—O-(2-[ ¹⁸ F]fluoroethyl)-L-tyrosine (FET), a higher yield and a more satisfactory in vivo distribution results were obtained. Hideo Tsukada et al. (Hideo Tsukada, Kengo Sato, Dai Fukumoto, Takeharu Kakiuchi, Eur J Nucl Med Mol Imaging, 2006, 33, 1017—1024) to D- or L-configuration O- ¹⁸ F-fluoromethyl tyrosine (FMT), O- ¹⁸ F-fluoroethyltyrosine (FET) and O- ¹⁸ F-fluoropropyl tyrosine (FPT) were evaluated biologically. Byung Seok Moon et al. (Byung Seok Moon, Tae Sup Lee, Kyo Chul Lee, et al, Bioorganic & Medicinal Chemistry Letters, 2007, 17, 200-204) introduced methoxy or hydrogen and ¹⁸ F propyl or ¹⁸ to the benzene ring of FET The F ethyl group changes the fat solubility of FET, and the obtained amino acid derivatives have achieved certain medicinal effects.

Positron emission tomography (PET) imaging research in China is relatively late, and domestic Shanghai Applied Physics has been engaged in PET research (Wang Mingwei, Yin Duanjun, Zheng Mingqiang, etc., Nuclear Chemistry and Radiation Chemistry, 2005, 27, 248-252). [ ¹⁸ F]FETs were synthesized by different methods. Most of the major hospitals have done clinical research on PET imaging. For example, Tang Ganghua from Southern Medical University et al.

The preparation and purification of the compound of formula (A) as a non-radioactive reference compound and the compound of formula (B) as a labeling precursor are relatively complicated. F18-labeled 4-O-(2-fluoroalkyl)benzamides have not been reported so far. the

Based on the above considerations, the inventors synthesized and labeled F-generation aromatic amino acids. Preliminary studies have shown that this type of compound is simple to label, easy to operate, high in labeling rate, and low in cost. The aromatic amino acids of the markers have good biological properties and are expected to be used in clinical practice. Potential positron tomography PET imaging agent. the

Contents of the invention

First, the primary purpose of the present invention is to provide a class of ¹⁸ F-labeled aromatic amino acids that can be used as novel positron emission tomography (PET) imaging agents.

The structural formula of the [ ¹⁸ F]fluorine-labeled aromatic amino acid of the present invention is shown in the following formula (A).

R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. the

R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. the

It is characterized in that: one end has an alkoxybenzoyl structure; the other end has an α-amino acid structure, and a substituent R1 is located at the α position of the carboxyl group, R1 is phenyl, benzyl, 3-indolemethyl, and R2 is methyl Oxygen, n is 1-5. R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. The structures at both ends are directly linked by amide bonds. the

Its preparation is mainly divided into two parts: the synthesis of the labeled precursor compound and the ¹⁸ F labeling and post-treatment of the precursor compound.

Specific steps are as follows:

1. Labeling precursor compound (synthesis of formula B)

R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. the

R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. the

The synthetic route is shown in the following formula:

R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. the

R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. the

1) Synthesis of hydroxyalkoxybenzoyl aromatic amino acid

Amino acid methyl ester hydrochloride 1.5mmol, dissolved in 20mL of anhydrous dichloromethane, add 3mmol of triethylamine, 1mmol of hydroxyalkoxybenzoic acid, 1mmol of HOBT, 1.5mmol of DCC, react in ice bath for half an hour, stir at room temperature React for 12 hours. After the reaction, column chromatography separation and purification. A white solid was obtained in 40%-60% yield. the

R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. the

R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. the

2) Synthesis of aromatic amino acid p-toluenesulfonate. the

1 mmol of hydroxyalkoxybenzoyl amino acid, 1.5 mmol of p-toluenesulfonyl chloride, 1.5 mmol of triethylamine, and 0.2 mmol of lutidine amine were dissolved in anhydrous dichloromethane, reacted in ice bath for half an hour, and stirred at room temperature for two Hour. After the solvent was spin-dried, a white solid was obtained through separation and purification by column chromatography. The reaction yield was 70-90%.

R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. the

R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. the

2. Labeling and post-processing of precursor compounds. the

At 80°C--140°C, 2-5 mg of precursors were reacted with ¹⁸ F under the catalytic conditions of K ₂₂₂ for 20 minutes, and the reaction solution was passed through Silica Sep-Pak (Plus) column, C18Sep-Pak (Plus), Al ₂ O ₃ Sep-Pak (Plus) or HPLC purification to obtain ¹⁸ F labeled product ester. ^{The 18} F-labeled product ester is hydrolyzed under alkaline conditions to obtain the ¹⁸ F-labeled product acid. After the prepared solution is aseptically filtered, the target aromatic amino acid ¹⁸ F labeled product is obtained.

R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. the

R1 is phenyl, benzyl, 3-indolylmethyl, R2 is methoxy, and n is 1-5. the

Second, the application of the above-mentioned ¹⁸ F-labeled aromatic amino acid of the present invention as a positron emission tomography (PET) imaging agent.

1) The precursor compound used for ¹⁸ F labeling in the present invention has simple labeling, convenient operation method, high labeling rate and low cost.

2) The ¹⁸ F-labeled compound of the present invention has good biological activity. In particular, there is a huge potential for development in brain tumors.

The prepared ¹⁸ F labeled aromatic amino acid provided by the invention is simple to prepare and is more suitable for clinical application of radiopharmaceuticals. The radiochemical purity of the prepared ¹⁸ F labeled compound is greater than 99%.

R1 is benzyl, and R2 is the test result of the labeled compound when methoxy:

Table 1: Biodistribution data of ¹⁸ F-labeled aromatic amino acids in the S180 tumor-bearing mouse model (%ID/g±SD, n=5)

From the data listed in Table 1, it can be seen that compared with the existing domestic methods, the present invention has better cellular uptake, retention and metabolism than [ ¹⁸ F]FET. When R1 is benzyl and R2 is methoxy, the ¹⁸ F-labeled compound A is injected into the tumor mouse model within 120 minutes, and the tumor/non-tumor ratio is as high as 2.95. The clearance rate of the marker in the blood is also fast, and the blood clearance rate of the marker is above 65% after 120 minutes.

Compared with ¹⁸ F-FDG, which is most widely used in clinical PET tumor imaging, the ¹⁸ F-labeled compound of the present invention has some advantages in distinguishing tumors from normal brain tissues. There are tests to prove:

In vivo distribution experiment of ¹⁸ F-FDG in tumor-bearing mice was carried out in the same way, and the tumor/brain ratio of ¹⁸ F-FDG obtained after sorting out the data is shown in Table 2:

Table 2 Tumor/brain ratio of ¹⁸ F-FDG in S180 tumor-bearing mice

Comparing Table 1, it can be seen that the ¹⁸ F-labeled compound of the present invention has better tumor/normal brain tissue discrimination than ¹⁸ F-FDG. This makes it possible for the ¹⁸ F-labeled compound of the present invention to obtain higher quality images than ¹⁸ F-FDG for brain tumor imaging.

Compared with the current PET tumor imaging agent ¹⁸ F-FET with great application potential, the ¹⁸ F-labeled compound of the present invention also has obvious advantages in distinguishing tumors from normal tissues. There are tests to prove:

The biodistribution experiment of ¹⁸ F-FET in tumor-bearing mice was carried out according to the same implementation method, and the tumor/normal tissue ratio of ¹⁸ F-FDG obtained after sorting out the data is shown in Table 3:

Table 3 Tumor/normal tissue (T/N) ratio of ¹⁸ F-FET in S180 tumor-bearing mice

Comparing Table 1, it can be seen that the tumor/brain ratio of the ¹⁸ F-labeled compound of the present invention in each time period is similar to that of ¹⁸ F-FET in the corresponding phase. ¹⁸ F-FET at 60-120min, the tumor/brain ratio is stable at the level of 30-60min or even increased. Considering the systemic distribution rate, the size of the normal injection dose and the loss characteristics of radiopharmaceuticals according to the law of radioactive exponential decay, the best The imaging time should be 30-60min after injection, and within this interval, the T/N ratio of the ¹⁸ F-labeled aromatic amino acid compound of the present invention has a similar effect, which makes ^{the 18} F-labeled compound of the present invention perform tumor imaging, especially the brain Images of the same quality may be obtained when imaging tumors.

According to the research on the in vivo distribution experiment of S180 tumor-bearing mice, we further conducted the study on the in vivo distribution of glioma tumor-bearing mice, and the results were similar to the biodistribution trend of S180 tumor-bearing mice. The results are shown in Table 4.

Table 4: Tumor/brain uptake ratio of ¹⁸ F-labeled aryloxy acids in glioma tumor-bearing mice

Comparing Table 1, it can be seen that the radiation uptake trends of glioma animal models and S180 tumor-bearing mice are the same. The ratio of tumor/normal tissues and organs showed an increasing trend. The tumor/brain ratio reaches 3.34, which is slightly larger than the tumor/brain uptake ratio of ¹⁸ F-FET. In subsequent PET imaging, the imaging effect of the tumor may be more clear. The clearance rate of the marked drug in the blood reached more than 60% within 120 minutes.

In summary, compared with the prior art, ^{the 18} F-labeled aromatic amino acid provided by the present invention not only has a good degree of biodistribution discrimination, but also has the potential to be used as a tumor imaging agent, especially a brain tumor imaging agent, and has the potential to prepare Simple and high marking rate.

Therefore, the aromatic amino acid of the formula (A) of the present invention can be used as a positron tomography (PET) imaging molecular probe for reporting and diagnosing tumors, and has high sensitivity and good selectivity. the

Description of drawings

Fig. 1 is a biodistribution diagram of Formula A of the present invention in a tumor-bearing mouse model. the

Fig. 2 is a comparison of the tumor/brain ratio between Formula A of the present invention and [ ¹⁸ F]-FET in a tumor-bearing mouse model. Comparison of the tumor/brain ratio of Formula A of the present invention with [ ¹⁸ F]-FET and [ ¹⁸ F]FDG in tumor-bearing mouse models.

Detailed ways

The present invention can be explained more clearly by specific preparation example and embodiment below:

Embodiment 1 Formula C compound 2-(4-(2-hydroxyethoxy) benzamido) methyl phenylpropionate

Amino acid methyl ester hydrochloride (3mmol) was dissolved in 20mL of dichloromethane, redistilled triethylamine (3mmol) was added in one go, stirred for 5min, and 4-(2-hydroxyalkoxy)benzoic acid (2mmol) was added and HOBt (1-hydroxybenzotriazole) (2.2mmol), the reaction mixture was cooled to 0°C, and 5mL of DCC (2.2mmol) in dichloromethane was added dropwise. React overnight at room temperature, TLC shows that after the reaction is over, remove a large amount of white precipitate DCU by suction filtration, the organic phase is washed with water, saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the oil is obtained after spin-off solvent Object. Column chromatography, eluent (ethyl acetate: methanol 10: 1) to obtain a light yellow oil, add a small amount of ethyl acetate and petroleum ether mixed solvent and fully grind to obtain a white solid, the solid after suction filtration A white solid was obtained after recrystallization from a mixed solvent of ethyl acetate, petroleum ether and anhydrous methanol. 

Synthesis of embodiment 2 formula B compound 2-(4-(2-(p-toluenesulfonyl) ethoxy) benzamidophenylpropionate methyl ester.

Dissolve the compound C (1 mmol) prepared above into 20 mL redistilled dichloromethane, add TEA (triethylamine) (1.5 mmol), cool in an ice bath to below 0°C, add DMAP (4-N, N-dichloromethane picoline) (0.2mmol) and p-toluenesulfonyl chloride (1.5mmol) of re-purification treatment, after continuing the low-temperature reaction for 30min, rising to room temperature and reacting overnight, TLC showed that the reaction was complete. After adding saturated aqueous sodium bicarbonate solution and fully stirring, the organic The layer was fully washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography.

Example 3 Synthesis of the compound of formula A, methyl 2-(4-(2-fluoroethoxy)benzamido)phenylpropionate. the

Dissolve 0.63 g of 2mmol tetrabutylammonium fluoride trihydrate into 1mL of re-evaporated dry acetonitrile, heat in a nitrogen atmosphere, and continuously feed nitrogen to evaporate the acetonitrile to dryness, then add 2mL of acetonitrile and repeat the above operation twice, and add 1mmol of the compound 10mL redistilled acetonitrile solution of B, the reaction mixture was refluxed for 6h under nitrogen atmosphere, TLC showed that the reaction was complete, the acetonitrile was spinned off, and ^{the 19F} generation product was obtained by column chromatography with a yield of about 60%.

Example 4 Radiosynthesis of formula (A) 4-(2-fluoroalkoxy)benzamido amino acid methyl ester. the

Take 100 μL of [ ¹⁸ F]F ^- solution and add it to the reaction bottle containing K ₂₂₂ (10-15 mg) and potassium carbonate (3 mg), immerse the reaction bottle in an oil bath at 80°C--140C, add 500 μL of acetonitrile Water was removed azeotropically under nitrogen. Add the precursor solution dissolved in 0.5mL DMF, and seal the reaction for 20min. Cool to room temperature after the reaction. The radiochemical yield is 20%--40%, and the radiochemical purity is >99%.

Raw materials in this preparation method: acetonitrile, N, N-dimethylamide, and Kriyptofix222 were purchased from Fluka Chemical Reagent Company. Triethylamine was purchased from Beijing Chemical Plant. [ ¹⁸ F]F-provided by partner hospital units.

The physical and chemical properties and spectral data of final product of the present invention and main intermediate are as follows:

2-4-(2-Hydroxyethoxy)benzamido-3-phenylpropanoic acid methyl ester

mp: 115-120°C; IR (KBr, cm ^-1 ): v3451, 3200, 1734, 1630, 1610, 1634, 1497, 1257; ¹ HNMR (CDCl ₃ , 500MHz): δ7.72 (d, 2H, J =8.6Hz, Ar-H), 7.32(t, 2H, J=6.8Hz, Ar-H), 7.15(d, 2H, J=6.9Hz, Ar-H), 6.95(2H, J=8.6Hz, Ar-H), 6.51(d, 1H, J=7.1Hz, NH), 5.10(q, 1H, J=5.6Hz, NHCHCH ₂ PhCOOCH ₃ ), 4.15(t, 2H, J=4.1Hz, CH ₂ CH _2OH ), 4.01(t, 2H, J=4.5Hz, _CH2CH2OH ), 3.78(s, 3H, _COOCH3 ), 3.27(dq, _2H , J=5.7Hz, _-CH2Ph ,); ¹³ CNMR (CDCl ₃ , 125MHz) δ: 172.18, 161.49, 135.92, 129.36, 128.93, 128.62, 127.18, 69.36, 61.33, 53.48, 52.41, 37.99, 23.46.

Methyl 2-4-(2-p-toluenesulfonylethoxy)benzamido-3-phenylpropionate: mp: 118-119°C IR (KBr, cm ^-1 ): v3340, 1741, 1626, 1605, 1497, 1357, 1261, 1172, 1220, 1017, 936, 765; ¹ HNMR (CDCl ₃ , 500MHz): δ7.83 (d, 2H, J=8.1Hz, Ar-H), 7.67 (d, 2H , J=8.5Hz, Ar-H), 7.36(d, 1H, J=7.9Hz, Ar-H), 7.31(t, 2H, J=7.1Hz, Ar-H), 7.29(d, 2H, J =5.7Hz, Ar-H), 7.14(d, 2H, J=7.0Hz, Ar-H), 6.80(d, 2H, J=8.6Hz, Ar-H), 6.48(d, 1H, J=7.3 Hz, NH), 5.09(m, 1H, J=5.8Hz, CHCOOCH ₃ ), 4.40(t, 2H, J=4.5Hz, CH ₂ CH ₂ OTs), 4.20(t, 2H, J=4.7Hz, CH ₂ CH ₂ OTs), 3.78 (s, 3H, COOCH ₃ ), 3.27 (dq, 2H, J=5.7Hz, CH ₂ Ph), 3.01 (s, 3H, Ts-CH ₃ ); ¹³ CNMR (CDCl ₃ , 125MHz) δ: 172.17, 166, 11, 150.77, 145.08, 135.92, 129.91, 129.35, 128.88, 128.63, 128.01, 127.19, 126.89, 114.34, 67.83, 65.52, 53.49, _{52.42, 37.9} H ₂₇ NO ₇ S: C, 62.76; H, 5.47; N, 2.82; Found: C, 62.84; H, 5.78; N, 2.95.

2-4-(2-fluoroethoxy)benzamido-3-phenylpropanoic acid methyl ester:

m.p118-120℃; IR (KBr, cm ^-1 ): v3333, 1741, 1626, 1605, 1538, 1504, 1257, 1224, 1176, 1068, 839; ¹ HNMR (CDCl ₃ , 500MHz): δ7.73 (d, 2H, J=8.7Hz, Ar-H), 7.15(d, 2H, J=7.1Hz, Ar-H), 6.96(d, 2H, J=8.7Hz, Ar-H), 6.53(d , 1H, J=7.3Hz, NH), 5.10 (q, 1H, J=5.6Hz, -CHCH ₂ Ph), 4.84-4.75 (d×t, 2H, ² J _HF = 47.3Hz, -CH ₂ CH ₂ F), 4.30-4.24 (d×t, 2H, ³ J _HF = 27.7Hz, CH ₂ CH ₂ F), 3.79 (s, 3H, COOCH ₃ ), 3.27 (dq, 2H, J = 5.8Hz, -CH ₂ Ph); ¹⁹ FNMR (CDCl ₃ , 400MHz): -224.167 (JC _H2CH2F = 27.7Hz), -224.292 (JC _H2CH2F = 47.4Hz); ¹³ CNMR (CDCl ₃ , 125MHz) δ: 172.19, 166.20, 161.23, 135.93 , 129.36, 128.95, 128.63, 127.19, 126.79, 114.43, 82.36, 81.01, 53.49, 52.40, 37.97; MS-EI: m/z=345.14 (found: 345.13); Anal.calcdfor C ₁₉ H ₂₀ FNO ₄ : C66. 08, H5.84, N4.06; found: C65.90, H5.64, N4.07.

2-(4-2-Fluoroethoxybenzamido)-3-phenylpropanoic acid

IR (KBr, cm ^-1 ): v3344, 1746, 1626, 1608, 1532, 1510, 1255, 1222, 1176, 1069, 841; ¹ HNMR (CDCl ₃ , 500MHz): 8.58 (d, 1H, J=8.0Hz , NH), δ7.79(d, 2H, J=8.7Hz, Ar-H), 7.31(d, 2H, J=8.7Hz, Ar-H), 7.26(d, 2H, J=7.4Hz, Ar -H), 7.17(d, 2H, J=7.2Hz, Ar-H), 7.02(d, 2H, J=8.7Hz, Ar-H), 4.81-4.70(d×t, 2H, ² J _HF = 47.8Hz, -CH2CH2F) _, 4.58(q, 1H, J=4.2Hz ^, -CHCH2Ph), 4.33-4.25(d×t, 2H, _3JHF =30.2Hz, _CH2CH2F ), 3.11(dq, 2H, J=4.3Hz, -CH ₂ Ph); ¹³ CNMR (CDCl ₃ , 125MHz) δ: 172.19, 166.20, 161.23, 135.93, 129.36, 128.95, 128.63, 127.19, 126.79, 114.43, 82.36, 81.01, 52.409, , 37.97; MS-EI: m/z=331.12 (found: 331.06)

2-4-(2-p-toluenesulfonylethoxy)benzamido-3-(2-indolyl)-propionic acid methyl ester:

IR (Film, cm ^-1 ): v3416, 1737, 1642, 1607, 1499, 1356, 1254, 1189, 1175, 930; ¹ HNMR (CDCl ₃ , 500MHz): δ8.36 (s, 1H, indole-NH) , 7.82(d, 2H, J=8.2Hz, Ar-H), 7.62(d, 2H, J=8.8Hz, Ar-H), 7.55(d, 1H, J=7.9Hz, Ar-H), 7.37 (d, 1H, J=8.2Hz, Ar-H), 7.35(d, 2H, J=8.0Hz, Ar-H), 7.19(t, 1H, J=7.2Hz, Ar-H), 7.09(s , 1H, J=7.2Hz, Ar-H), 7.01(d, 1H, J=7.0Hz, Ar-H), 6.74(d, 2H, J=8.7Hz, Ar-H), 6.62(d, 1H , J=7.5Hz, amide-NH), 5.14(m, 1H, CHCOOCH ₃ ), 4.38(t, 2H, J=4.5Hz, CH ₂ CH ₂ OTs), 4.16(t, 2H, J=4.6Hz, CH ₂ CH ₂ OTs), 3.73 (s, 3H, CHCOOCH ₃ ), 3.45 (q, 2H, J=2.5Hz, Indole-CH ₂ ), 2.45 (s, 2H, Ts-CH3); ¹³ CNMR (CDCl ₃ ，125MHz)δ：172.50，166.20，160.68，145.11，136.18，132.79，129.91，128.96，127.99，127.68，126.85，122.89，122.27，119.70，118.65，114.24，111.37，110.02，67.87，65.47，53.46，52.43，27.69 , 21.65, 14.21.

2-4-(2-fluoroethoxy)benzamido-3-(2-indolyl)-propionic acid methyl ester:

mp: 86-88°C; IR (KBr, cm ^-1 ): v3416, 1737, 1642, 1607, 1499, 1254, 1189, 1175, 930; ¹ HNMR (CDCl ₃ , 500MHz): δ8.21(s, 1H , Indole-NH), 7.69 (d, 2H, J=8.7Hz, Ar-H), 7.56 (d, 1H, J=7.9Hz, Ar-H), 7.39 (d, 1H, J=8.1Hz, Ar -H), 7.28(s, 1H, Ar-H), 7.21(t, 1H, J=7.2Hz, Ar-H), 7.10(t, 1H, J=7.3Hz, Ar-H), 7.03(d , 1H, J=1.5Hz, Ar-H), 6.92(d, 2H, J=8.7Hz, Ar-H), 6.62(d, 1H, J=7.3Hz, Amide-NH), 5.17(m, 1H , CHCOOCH ₃ ), 4.84-4.74 (d×t, 2H, ² J _HF = 47.3Hz, CH ₂ CH ₂ F), 4.29-4.23 (d×t, 2H, ³ J _HF = 27.7Hz, CH ₂ CH ₂ F), 3.74 (s, 3H, COOCH ₃ ), 3.47 (d, 2H, J=5.3Hz, Indole-CH ₂ ); ¹³ CNMR (CDCl ₃ , 125MHz) δ: 172.52, 166.29, 161.15, 136.15, 129.03, 127.72, 126.78, 122.81, 122.32, 119.76, 118.73, 114.33, 111.28, 110.18, 82.37, 81.01, 67.25, 53.44, 52.42, 49.19, 33.96, 27.72, 25.62, 238.94: 385.38); Anal.calcd for C ₂₁ H ₂₁ FN ₂ O ₄ : C, 65.62; H, 5.51; N, 7.29; Found: C, 65.16; H, 5.24; N, 7.37.

Test Example 1 The biodistribution test of formula A compound of the present invention

The establishment method of the tumor mouse model: the S180 cells in the logarithmic production phase were washed with normal saline, digested, added to the medium solution, and the suspension was prepared. Injected subcutaneously in the left upper limb of KM mice. After 7 days of solid tumor formation, it was used for (A) compound biological evaluation and micro-PET imaging test. the

25 KM mice planted with S180 tumor model were injected with 10 μCi of the compound preparation of formula (A) through the tail vein respectively, and sacrificed for 5 min, 15 min, 30 min, 60 min, and 120 min, and were dissected, and the organs and tissues of interest were collected: heart, liver, spleen , lung, kidney, stomach, small intestine, large intestine, bone, muscle, brain, tumor, blood, etc. Counts from each tissue sample were compared to standard counts after weighing, technique, and decay correction. The result is expressed as %ID/g±SD (the radioactivity per gram of tissue accounts for the percentage of the injected amount), which is the relative absorption value of each organ to the compound of formula (A). The relative absorption value of each organ to the compound of formula (A) is shown in FIG. 1 . It can be seen from the figure that the compound of formula (A) has relatively high initial absorption in liver, kidney and blood. The clearance rate is also fast. The ratio of tumor to non-tumor was up to 2.95 at 120min. the

Test Example 2 The abnormal toxicity check of the formula A compound of the present invention

According to the method described in the Pharmacopoeia of the People's Republic of China in 2005. Inject 0.5mL (37MBq) injection (equivalent to hundreds of times the dosage for adults) into the tail vein of 10 normal Kunming mice (18-20g) and observe for 48 hours. The mice grew normally, and no death or adverse reactions occurred. After dissection, no organ damage was found. Abnormal toxicity checks meet radiopharmaceutical quality requirements.

Claims (4)

1. shown in one type of formula (A) ¹⁸F mark aromatic amino acid is characterized in that: an end has F substituted alkoxy benzoyl-structure; The other end has the a-amino acid structure, and substituent R 1 is positioned on the alpha site of carboxyl group, and R1 is a benzyl, and R2 is a methyl, and n is 1,

。

2. claim 1 is said ¹⁸The preparation method of F mark aromatic amino acid is characterized in that it comprises the following steps: to use 15mg K ₂₂₂And 3mgK ₂CO ₃Acetonitrile solution drip washing ¹⁸F ^-The QMA post of enrichment is behind the acetonitrile azeotropic water removing, with containing K ₂CO ₃, K ₂₂₂, ¹⁸F ^-Mixture and labelled precursor formula (B) compound at N, in the N-dimethylformamide solvent, reaction under heating condition, temperature of reaction is 80 ℃--140 ℃, the reaction times is 20 minutes, separates purification with performance liquid (HPLC), obtains ¹⁸F target-marking product, putting of affinity tag is pure greater than 99%,

R1 is a benzyl, and R2 is a methyl, and n is 1.

3. claim 2 is described ¹⁸F mark aromatic amino acid preparation method is characterized in that: take 15mg K ₂₂₂With 3mg K ₂CO ₃Acetonitrile 1mL and the mixed solution of water 0.5mL obtain radioactivity as elutriant ¹⁸The F ion, and use the anhydrous acetonitrile azeotropic water removing.

4. claim 1 is described ¹⁸The application of F mark aromatic amino acid in the positron emission tomography molecular probe of preparation report tumour.

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