18F-labelled compound for prostate cancer diagnosis, and use thereof

Abstract

The present invention relates to an 18F-labelled compound, and a use thereof. The compound selectively binds to a prostate-specific membrane antigen (PSMA), and enables the acquisition of clear prostate cancer images in a short time when used in positron emission tomography (PET).

Claims

1. A compound represented by the following formula 1: ##STR00014## wherein, Y is C.sub.1-C.sub.5 alkylene; Z is CH.sub.2(CH.sub.2OCH.sub.2).sub.nCH.sub.2, wherein n is an integer of 0 to 5; R is hydrogen or C.sub.1-C.sub.2 alkyl having a substituent, wherein the substituent is C.sub.6-C.sub.12 aryl or C.sub.4-C.sub.10 heteroaryl containing one or more elements selected from the group consisting of O, S and N; and F is .sup.18F or .sup.19F.

2. The compound according to claim 1, wherein Y is C.sub.1-C.sub.2 alklylene and F is .sup.18F.

3. A compound represented by A the following formula 11: ##STR00015## wherein, Y is C.sub.1-C.sub.5 alkylene; and R is hydrogen or C.sub.1-C.sub.2 alkyl having a substituent, wherein the substituent is C.sub.6-C.sub.12 aryl or C.sub.4-C.sub.10 heteroaryl containing one or more elements selected from the group consisting of O, S and N.

4. The compound according to claim 3, wherein Y is C.sub.1-C.sub.2 alkylene.

5. A pharmaceutical composition for treating or diagnosing prostate cancer comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

6. A radiopharmaceutical for imaging diagnosis of prostate cancer comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

7. The radiopharmaceutical according to claim 6, wherein the imaging diagnosis includes magnetic resonance imaging (MRI) or positron emission tomography (PET).

8. A method for treating or diagnosing prostate cancer in a subject, said method comprising administering to the subject the pharmaceutical composition of claim 5.

9. A method for diagnostically imaging prostate cancer in a subject, said method comprising administering to the subject the radiopharmaceutical of claim 6.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1A and 1B are diagrams illustrating the results of Radio-TLC according to the preparation step of the compound [.sup.18F]1-6.

(2) FIG. 2 is a diagram illustrating the results of HPLC separation according to the preparation step of the compound [.sup.18F] 1-6.

(3) FIG. 3 is a diagram illustrating the results of MicroPET/CT of the prostate cancer mouse.

(4) FIGS. 4A, 4B and 4C are graphs illustrating the intake ratio of muscle, liver and spleen compared to tumor.

(5) FIGS. 5A and 5B are graphs illustrating the organ biodistribution over the time.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(6) The above objects, other objects, features and advantages of the present invention are readily understood through the following preferred examples associated with the accompanying drawings. However, the present invention is not limited to the examples described herein and can be embodied in other forms. Rather, the examples introduced herein are provided so that the disclosure can be made thorough and complete, and to fully transfer the spirit of the present invention to those skilled in the art.

(7) Hereinafter, a compound represented by formula 1 of the present invention is described in detail.

(8) The present invention includes a compound represented by the following formula 1.

(9) ##STR00003##

(10) In formula 1,

(11) Y is C.sub.1-C.sub.5 alkylene;

(12) Z is CH.sub.2(CH.sub.2OCH.sub.2).sub.nCH.sub.2, wherein n is an integer of 0 to 5;

(13) R is hydrogen or C.sub.1-C.sub.2 alkyl having an substituent, wherein the substituent is C.sub.6-C.sub.12 aryl or C.sub.4-C.sub.10 heteroaryl containing one or more elements selected from the group consisting of O, S and N; and

(14) F can be .sup.18F or .sup.19F.

(15) More specifically, Y is C.sub.1-C.sub.2 alkylene;

(16) Z is CH.sub.2(CH.sub.2OCH.sub.2).sub.nCH.sub.2, wherein n is an integer of 0 to 5;

(17) R is hydrogen or C.sub.1-C.sub.2 alkyl having an substituent, wherein the substituent is C.sub.6-C.sub.12 aryl or C.sub.4-C.sub.10 heteroaryl containing one or more elements selected from the group consisting of O, S and N; and

(18) F can be .sup.18F.

(19) Ligands of formula 1 of the present invention can be additionally bound to PSMA proteins via lipophilic bonds because they can be structurally bound to aromatic aryl groups. In addition, the triazole group in the side chain to which .sup.18F is bound can increase the polarity of the compound to reduce non-specific bindings in vivo.

(20) Such a compound labeled with fluorine-18 of the present invention can have excellent binding capacity to PSMA proteins and excellent pharmacokinetic properties simultaneously.

(21) The present invention provide a pharmaceutical composition for treating or diagnosing prostate cancer comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

(22) The present invention also provides a use of a diagnostic radiopharmaceutical to a subject in need of therapeutic monitoring or imaging diagnosis of prostate cancer. Such a radiopharmaceutical for imaging diagnosis can include a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Herein, the imaging diagnosis can include magnetic resonance imaging (MRI) or positron emission tomography (PET), and preferably can be performed using positron emission tomography (PET).

(23) In the compound described above, radioligands are ingested in the prostate cancer tissues expressing PSMA and can be removed in other organs, so that PET images can be obtained clearly in a short time.

(24) Hereinafter, a compound represented by formula 11 of the present invention is described in detail.

(25) The present invention includes a compound represented by the following formula 11.

(26) ##STR00004##

(27) In formula 11,

(28) Y is C.sub.1-C.sub.5 alkylene; and

(29) R is hydrogen or C.sub.1-C.sub.2 alkyl having a substituent, wherein the substituent is C.sub.6-C.sub.12 aryl or C.sub.4-C.sub.10 heteroaryl containing one or more elements selected from the group consisting of O, S and N.

(30) More specifically, Y is C.sub.1-C.sub.2 alkylene; and

(31) R is hydrogen or C.sub.1-C.sub.2 alkyl having a substituent, wherein the substituent is C.sub.6-C.sub.12 aryl or C.sub.4-C.sub.10 heteroaryl containing one or more elements selected from the group consisting of O, S and N.

Example 1. Preparation of N-Propazyl Amine Derivatives

(32) A schematic reaction process of the present invention is shown in reaction formula 1 below.

(33) ##STR00005##

Example 1-1. Preparation of Compound 3 (Step 1)

(34) 4-Aminopyridine (2, 9.0 g, 96 mmol) was dissolved in dichloromethane (400 mL), to which (Boc).sub.2O (25.0 g, 110 mmol) was added at 0 C. Triethylamine (20.0 mL, 140 mmol) was slowly added thereto, followed by stirring at room temperature for 2 hours. Water was added thereto and the organic compound was extracted using dichloromethane three times. The collected organic solvent was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (7% methanol/dichloromethane). As a result, the compound 3 was obtained as a white solid (18.0 g, 97%).

(35) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.53 (s, 9H), 7.29 (brs, 1H), 7.34 (dd, J=4.8, 1.6 Hz, 2H), 8.44 (dd, J=4.8, 1.6 Hz, 2H);

(36) .sup.13C NMR (100 MHz, CDCl.sub.3) 528.2, 81.6, 112.3, 145.8, 150.4, 152.0; MS (ESI) m/z 193 [MH].sup.

Example 1-2. Preparation of Compound 4 (Step 2)

(37) The compound 3 (18.0 g, 93 mmol) synthesized in step 1 above was dissolved in dimethylformamide (DMF, 400 mL), to which sodium hydride (7.4 g, 900 mmol) was added at 0 C. Propazyl bromide was slowly added thereto, followed by stirring at room temperature for 2 hours. Methanol (50 ml) was added thereto at 0 C., followed by stirring for 30 minutes. Water was added thereto and the organic compound was extracted using ethyl acetate three times. The collected organic solvent was washed with ammonium chloride aqueous solution three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (5% methanol/dichloromethane). As a result, the compound 4 was obtained as a light yellow solid (13.4 g, 62%).

(38) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.53 (s, 9H), 2.31 (t, J=2.6 Hz, 1H), 4.43 (d, J=2.4 Hz, 2H), 7.38 (d, J=5.2 Hz, 2H), 8.54 (m, 2H);

(39) .sup.13C NMR (100 MHz, CDCl.sub.3) 28.1, 38.5, 72.4, 79.1, 82.7, 118.0, 149.2, 150.2, 152.6; MS (ESI) m/z 233 [M+H].sup.+

Example 1-3. Preparation of Compound 5 (Step 3)

(40) Dioxane (75 mL) containing 4N HCl was added to the compound 4 (13.0 g, 56 mmol) synthesized in step 2 above, followed by stirring at room temperature for 6 hours. 2N sodium hydroxide aqueous solution (500 ml) was added thereto and the organic compound was extracted using dichloromethane three times. The collected organic solvent was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (60% ethyl acetate/dichloromethane, NH silica gel). As a result, the compound 5 was obtained as a light yellow solid (6.8 g, 92%).

(41) .sup.1H NMR (400 MHz, CDCl.sub.3) 2.27 (t, J=2.6 Hz, 1H), 3.97 (dd, J=6.0, 2.4 Hz, 2H), 4.66 (brs, 1H), 6.53 (dd, J=4.8, 1.6 Hz, 2H), 8.26 (dd, J=4.4, 1.6 Hz, 2H);

(42) .sup.13C NMR (100 MHz, CDCl.sub.3) 32.4, 72.0, 79.4, 108.1, 150.1, 152.3; MS (ESI) m/z 133 [M+H].sup.+

Example 2. Preparation of Compound 8 (N-propazyl, N-(pyridine-4-yl methyl)amine)

(43) 4-Pyridinecarboxyaldehyde (7, 0.5 mL, 4.7 mmol) was dissolved in dichloromethane (10 mL), to which propazyl amine (0.31 mL, 5.6 mmol) was added. Sodium triacetoxyborohydride (1.5 g, 7.05 mmol) was slowly added thereto, followed by stirring at room temperature for 2 hours. Water was added thereto and the organic compound was extracted using dichloromethane three times. The collected organic solvent was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (2% methanol/dichloromethane). As a result, the compound 8 was obtained as a bright red liquid (315 mg, 46%).

(44) .sup.1H NMR (400 MHz, CDCl.sub.3) 2.28 (t, J=2.4 Hz, 1H), 3.45 (d, J=2.4 Hz, 2H), 3.93 (s, 2H), 4.24 (brs, 1H), 7.32 (dd, J=5.2, 0.8 Hz, 2H), 8.57 (dd, J=5.2, 0.8 Hz, 2H);

(45) .sup.13C NMR (100 MHz, CDCl.sub.3) 37.4, 50.8, 72.1, 81.3, 123.3, 148.8, 149.4; MS (ESI) m/z 147 [M+H].sup.+

(46) A schematic reaction process of the present invention is shown in reaction formula 2 below.

(47) ##STR00006##

Example 3. Preparation of N-Propazyl Amine-Urea-GUL Compound

(48) A schematic reaction process of the present invention is shown in reaction formula 3 below.

(49) ##STR00007##

Example 3-1. Preparation of Compound 10-1

(50) Triphosgene (107 mg, 0.36 mmol) was dissolved in acetonitrile (5.0 mL), to which glutamate-urea-lysine (9, 500 mg, 1.03 mmol) dissolved in acetonitrile (10 mL) was slowly added at 0 C. Triethylamine (0.50 mL, 3.61 mmol) was added thereto, followed by stirring for 30 minutes. Propazyl amine (0.072 mL, 1.13 mmol) was added thereto at 0 C. 15 minutes later, the mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Water was added thereto and the organic compound was extracted using ethyl acetate three times. The collected organic solvent was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (2% methanol/dichloromethane). As a result, the compound 10-1 was obtained as a white solid (492 mg, 84%).

(51) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.25-1.30 (m, 2H), 1.44 (s, 18H), 1.48 (s, 9H), 1.51-1.60 (m, 3H), 1.67-1.76 (m, 1H), 1.80-1.90 (m, 1H), 2.05-2.13 (m, 1H), 2.18 (t, J=2.6 Hz, 1H), 2.29-2.40 (m, 2H), 3.06-3.12 (m, 1H), 3.30-3.36 (m, 1H), 3.95-4.06 (m, 2H), 4.08-4.14 (m, 1H), 4.36 (sext, J=4.4 Hz, 1H), 5.64 (d, J=7.6 Hz, 1H), 5.69 (t, J=5.2 Hz, 1H), 5.89 (t, J=5.4 Hz, 1H), 6.11 (d, J=8.4 Hz, 1H);

(52) .sup.13C NMR (100 MHz, CDCl.sub.3) 23.4, 27.7, 27.8, 27.9, 28.0, 29.6, 29.7, 31.7, 32.1, 39.4, 53.3, 54.2, 70.5, 80.7, 81.4, 81.5, 83.1, 158.0, 158.2, 172.0, 172.3, 174.6; MS (ESI) m/z 569 [M+H].sup.+

Example 3-2. Preparation of Compound 10-2

(53) The compound 10-2 was obtained by the same manner as described in Example 3-1 as a light yellow solid (270 mg, 66%) except that triphosgene (64 mg, 0.211 mmol) dissolved in acetonitrile (3.0 mL), glutamate-urea-lysine (9, 300 mg, 0.62 mmol) dissolved in acetonitrile (6 mL), triethylamine (0.302 mL, 2.17 mmol) and the compound 8 (100 mg, 0.68 mmol) synthesized in Example 2 were used.

(54) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.22-1.30 (m, 2H), 1.43 (s, 9H), 1.45 (s, 18H), 1.48-1.54 (m, 2H), 1.59-1.64 (m, 1H), 1.71-1.77 (m, 1H), 1.79-1.88 (m, 2H), 2.03-2.09 (m, 1H), 2.27-2.32 (m, 1H), 2.35 (t, J=2.2 Hz, 1H), 3.24 (sept, J=6.2 Hz, 2H), 4.07 (t, J=2.4 Hz, 2H), 4.27-4.35 (m, 2H), 4.60 (dd, J=20.4, 17.2 Hz, 2H), 4.92 (s, 1H), 5.24 (d, J=7.6 Hz, 1H), 5.44 (d, J=8.0 Hz, 1H), 7.24 (d, J=5.2 Hz, 2H), 8.60 (d, J=4.8 Hz, 2H);

(55) .sup.13C NMR (100 MHz, CDCl.sub.3) 22.3, 27.9, 28.0, 28.1, 28.4, 29.4, 31.6, 32.4, 36.8, 40.7, 49.6, 53.0, 53.3, 73.4, 78.8, 80.5, 81.7, 82.0, 122.3, 147.0, 150.2, 157.0, 157.7, 172.3, 172.4, 172.5; MS (ESI) m/z 660 [M+H].sup.+

Example 3-3. Preparation of Compound 10-3

(56) The compound 5 (200 mg, 1.51 mmol) synthesized in Example 1-3 was dissolved in acetonitrile (5.0 mL), to which 4-nitrophenyl chloroformate (305 mg, 1.51 mmol) dissolved in acetonitrile (5.0 mL) was slowly added at 0 C. Triethyl amine (0.50 mL, 3.61 mmol) was added thereto, followed by stirring for 30 minutes. Glutamate-urea-lysine (9, 886 mg, 1.82 mmol) dissolved in acetonitrile (10 mL) was slowly added thereto at 0 C. and then diisopropylamine (0.324 mL, 1.82 mmol) was also added thereto. 15 minutes later, the mixture was stirred at 100 C. for 12 hours. After cooling the mixture to room temperature, water was added thereto and the organic compound was extracted using ethyl acetate three times. The collected organic solvent was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (5% methanol/dichloromethane). As a result, the compound 10-3 was obtained as a colorless liquid (836 mg, 86%).

(57) .sup.1H NM (400 MHz, CDCl.sub.3) 1.27-1.37 (m, 2H), 1.43 (s, 9H), 1.45 (s, 18H), 1.50-1.55 (m, 2H), 1.59-1.65 (m, 1H), 1.72-1.88 (m, 2H), 2.01-2.10 (m, 1H), 2.27-2.34 (m, 1H), 2.35 (t, J=2.4 Hz, 1H), 2.16 (q, J=6.7 Hz, 2H), 4.25-4.34 (m, 2H), 4.50 (ddd, J=25.2, 18.0, 2.4 Hz, 2H), 5.21 (t, J=5.8 Hz, 1H), 5.48 (s, 1H), 5.50 (s, 1H), 7.32 (dd, J=4.8, 1.6 Hz, 2H), 8.59 (d, J=6.4 Hz, 2H);

(58) .sup.13C NMR (100 MHz, CDCl.sub.3) 22.4, 27.9, 28.0, 28.1, 28.3, 29.4, 31.6, 32.4, 38.2, 40.7, 52.9, 53.3, 72.9, 79.3, 80.5, 81.6, 82.0, 119.5, 149.6, 151.2, 155.3, 157.1, 172.3, 172.4, 172.5; MS (ESI) m/z 646 [M+H].sup.+

(59) A schematic reaction process of the present invention is shown in reaction formula 4 below.

(60) ##STR00008##

Example 4. Deprotecting Group of Compound 10

(61) A schematic reaction process of the present invention is shown in reaction formula 5 below.

(62) ##STR00009##

Example 4-1. Preparation of Compound 11-1

(63) The compound 10-1 (450 mg, 0.79 mmol) synthesized in Example 3-1 was dissolved in 60% trifluoroacetic acid/dichloromethane (2 mL), followed by stirring at room temperature for 4 hours. The reactant was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC). As a result, the compound 11-1 was obtained as a white solid (280 mg, 88%).

(64) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.24-1.29 (m, 2H), 1.32-1.39 (m, 2H), 1.46-1.55 (m, 1H), 1.60-1.67 (m, 1H), 1.68-1.77 (m, 1H), 1.84-1.92 (m, 1H), 2.24 (td, J=7.8, 2.6 Hz, 2H), 2.96 (q, J=6.4 Hz, 2H), 3.01 (t, J=2.6 Hz, 1H), 3.77 (dd, J=5.6, 2.4, 2H), 4.05 (sext, J=7.6 Hz, 2H), 5.98 (t, J=5.6 Hz, 1H), 6.13 (t, J=5.6, 1H), 6.31 (d, J=8.4 Hz, 2H), 12.43 (brs, 3H);

(65) .sup.13C NMR (100 MHz, D.sub.2O) 521.4, 25.6, 27.8, 28.5, 29.3, 29.9, 38.7, 52.0, 52.6, 70.5, 80.4, 118.2, 158.3, 159.2, 175.6, 176.4; MS (ESI) m/z 399 [MH].sup.

Example 4-2. Preparation of Compound 11-2

(66) The compound 10-2 (460 mg, 0.70 mmol) synthesized in Example 3-2 was dissolved in 60% trifluoroacetic acid/dichloromethane (2 mL), followed by stirring at room temperature for 4 hours. The reactant was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC). As a result, the compound 11-2 was obtained as a white solid (289 mg, 84%).

(67) .sup.1H NMR (400 MHz, D.sub.2O) 1.10-1.18 (m, 2H), 1.29-1.36 (m, 2H), 1.44-1.52 (m, 1H), 1.56-1.63 (m, 1H), 1.71-1.80 (m, 1H), 1.91-1.99 (m, 1H), 2.28 (t, J=7.4 Hz, 2H), 2.56 (t, J=2.4 Hz, 1H), 3.03 (td, J=6.6, 2.0 Hz, 2H), 3.89 (dd, J=8.6, 5.0 Hz, 1H), 3.98 (dd, J=8.6, 5.0 Hz, 1H), 4.06 (d, J=2.4 Hz, 2H), 4.72 (s, 2H), 7.78 (d, J=5.6 Hz, 2H), 8.55 (d, J=4.8 Hz, 2H);

(68) .sup.13C NMR (100 MHz, D.sub.2O) 22.3, 27.3, 28.7, 30.6, 31.3, 37.7, 40.2, 50.9, 53.9, 54.3, 74.0, 78.6, 124.8, 140.9, 158.7, 158.8, 159.2, 160.3, 178.0, 178.6; MS (ESI) m/z 492 [M+H].sup.+

Example 4-3. Preparation of Compound 11-3

(69) The compound 10-3 (650 mg, 1.01 mmol) synthesized in Example 3-3 was dissolved in 60% trifluoroacetic acid/dichloromethane (3 mL), followed by stirring at room temperature for 4 hours. The reactant was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC). As a result, the compound 11-3 was obtained as a white solid (390 mg, 81%).

(70) .sup.1H NMR (400 MHz, D.sub.2O) 1.21-1.26 (m, 2H), 1.38-1.43 (m, 2H), 1.46-1.53 (m, 1H), 1.58-1.67 (m, 1H), 1.69-1.74 (m, 1H), 1.84-1.93 (m, 1H), 2.22 (t, J=7.6 Hz, 2H), 2.61 (t, J=0.8 Hz, 1H), 3.12 (t, J=6.6 Hz, 2H), 3.92 (q, J=6.5 Hz, 2H), 4.45 (s, 2H), 7.44 (d, J=6.4 Hz, 2H), 8.27 (d, J=4.0 Hz, 2H);

(71) .sup.13C NMR (100 MHz, D.sub.2O) 22.4, 27.1, 27.7, 30.5, 31.2, 37.9, 40.6, 53.6, 54.1, 74.8, 76.5, 114.5, 140.7, 156.1, 156.2, 159.0, 177.7, 177.9, 178.4; MS (ESI) m/z 478 [M+H].sup.+

Example 5. Preparation of Fluorine-Triazole-Urea-GUL Compound Through Click Chemistry

(72) A schematic reaction process of the present invention is shown in reaction formula 6 below.

(73) ##STR00010##

Example 5-1. Preparation of Compound 1-1

(74) 2-Fluoroethyl toluenesulfonate (FCH.sub.2CH.sub.2OTs, 82 mg, 0.38 mmol) was dissolved in dimethylformamide (0.2 mL), to which sodium azide (73 mg, 1.13 mmol) was added, followed by stirring at 60 C. for 12 hours to synthesize fluoroethylazide (12-1). The reaction solution was filtered and washed with ethanol (0.3 mL). An aqueous solution (0.5 mL) in which the compound 11-1 (30 mg, 0.075 mmol) synthesized in Example 4-1 was dissolved was added to the filtrate. CuSO.sub.4.5H.sub.2O aqueous solution (0.5M, 0.046 mL, 0.023 mmol) and sodium ascorbate aqueous solution (0.5M, 0.076 mL, 0.038 mmol) were added thereto stepwise, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered and washed with water. Then, the filtrate was separated by HPLC. As a result, the compound 1-1 was obtained as a white solid (7 mg, 19%).

(75) .sup.1H NMR (400 MHz, D.sub.2O) 1.17-1.28 (m, 2H), 1.30-1.37 (m, 2H), 1.50-1.59 (m, 1H), 1.64-1.72 (m, 1H), 1.77-1.87 (m, 1H), 1.98-2.05 (m, 1H), 2.36 (t, J=7.4 Hz, 2H), 2.96 (t, J=6.4 Hz, 2H), 4.03 (dd, J=8.4, 4.8 Hz, 1H), 4.11 (dd, J=8.8, 5.6 Hz, 1H), 4.24 (s, 2H), 4.56-4.57 (m, 1H), 4.65-4.68 (m, 2H), 4.75 (t, J=4.6 Hz, 1H), 7.79 (s, 1H);

(76) .sup.13C NMR (100 MHz, D.sub.2O) 22.0, 26.1, 28.5, 29.9, 30.4, 34.9, 39.4, 50.7 (d, J=19 Hz), 52.5, 53.1, 81.9 (d, J=168 Hz), 124.0, 146.2, 159.5, 160.2, 176.2, 177.1, 177.2; MS (ESI) m/z 488 [MH].sup.

Example 5-2. Preparation of Compound 1-2

(77) 2-Fluoroethyl toluenesulfonate (FCH.sub.2CH.sub.2OTs, 89 mg, 0.41 mmol) was dissolved in dimethylformamide (0.2 mL), to which sodium azide (79 mg, 1.22 mmol) was added, followed by stirring at 60 C. for 12 hours to synthesize fluoroethylazide (12-1). The reaction solution was filtered and washed with ethanol (0.3 mL). An aqueous solution (0.5 mL) in which the compound 11-2 (40 mg, 0.081 mmol) synthesized in Example 4-2 was dissolved was added to the filtrate. CuSO.sub.4.5H.sub.2O aqueous solution (0.5M, 0.049 mL, 0.024 mmol) and sodium ascorbate aqueous solution (0.5M, 0.081 mL, 0.041 mmol) were added thereto stepwise, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered and washed with water. Then, the filtrate was separated by HPLC. As a result, the compound 1-2 was obtained as a white solid (33 mg, 70%).

(78) .sup.1H NMR (400 MHz, D.sub.2O) 1.21-1.34 (m, 2H), 1.41-1.50 (m, 2H), 1.59-1.68 (m, 1H), 1.71-1.80 (m, 1H), 1.86-1.96 (m, 1H), 2.08-2.16 (m, 1H), 2.45 (t, J=7.2 Hz, 2H), 3.16 (t, J=6.6 Hz, 2H), 4.09 (dd, J=8.4, 5.2 Hz, 1H), 4.21 (dd, J=8.8, 5.6 Hz, 1H), 4.63-4.70 (m, 6H), 4.84 (s, 2H), 7.72 (d, J=6.0 Hz, 2H), 7.93 (s, 1H), 8.60 (dd, J=6.8, 1.2 Hz, 2H);

(79) .sup.13C NMR (100 MHz, D.sub.2O) 22.1, 26.0, 28.5, 29.9, 30.4, 40.0, 42.6, 50.5, 50.6 (d, J=19 Hz), 81.9 (d, J=168 Hz), 124.6, 124.7, 140.6, 143.5, 159.0, 159.2, 160.6, 176.1, 177.0, 177.1; MS (ESI) m/z 581 [M+H].sup.+

Example 5-3. Preparation of Compound 1-3

(80) 2-Fluoroethyl toluenesulfonate (FCH.sub.2CH.sub.2OTs, 91 mg, 0.42 mmol) was dissolved in DMF (0.2 mL), to which NaN (82 mg, 1.26 mmol) was added, followed by stirring at 60 C. for 12 hours to synthesize fluoroethylazide (12-1). The reaction solution was filtered and washed with ethanol (0.3 mL). An aqueous solution (0.5 mL) in which the compound 11-3 (40 mg, 0.084 mmol) synthesized in Example 4-3 was dissolved was added to the filtrate. CuSO.sub.4.5H.sub.2O aqueous solution (0.5M, 0.050 mL, 0.025 mmol) and sodium ascorbate aqueous solution (0.5M, 0.084 mL, 0.042 mmol) were added thereto stepwise, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered and washed with water. Then, the filtrate was separated by HPLC. As a result, the compound 1-3 was obtained as a white solid (27 mg, 57%).

(81) .sup.1H NMR (400 MHz, D.sub.2O) 1.15-1.24 (m, 2H), 1.36-1.43 (m, 2H), 1.49-1.58 (m, 1H), 1.63-1.72 (m, 1H), 1.75-1.84 (m, 1H), 1.96-2.05 (m, 1H), 2.34 (t, J=7.4 Hz, 2H), 3.15 (t, J=6.6 Hz, 2H), 4.01 (dd, J=8.8, 5.2 Hz, 1H), 4.10 (dd, J=9.0, 5.0 Hz, 1H), 4.55-4.61 (m, 3H), 4.73 (t, J=4.4 Hz, 1H), 5.05 (s, 2H), 7.47 (d, J=7.6 Hz, 2H), 7.92 (s, 1H), 8.27 (d, J=7.6 Hz, 2H);

(82) .sup.13C NMR (100 MHz, D.sub.2O) 22.2, 26.1, 27.5, 29.9, 30.4, 40.4, 43.2, 50.7 (d, J=19 Hz), 52.4, 53.0, 81.9 (d, J=168 Hz), 114.4, 124.7, 140.7, 142.3, 156.4, 156.8, 159.2, 176.1, 176.9, 177.1; MS (ESI) m/z 567 [M+H].sup.+

Example 5-4. Preparation of Compound 1-4

(83) A solution prepared by dissolving the compound 11-1 (40 mg, 0.10 mmol) synthesized in Example 4-1 in water (0.5 mL) was added to ethanol (0.5 mL) in which 1-azido-2-(2-fluoroethoxy)ethane (12-2, 16 mg, 0.12 mmol) was dissolved. CuSO.sub.4.5H.sub.2O aqueous solution (0.5M, 0.060 mL, 0.030 mmol) and sodium ascorbate aqueous solution (0.5M, 0.100 mL, 0.050 mmol) were added thereto stepwise, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered and washed with water. Then, the filtrate was separated by HPLC. As a result, the compound 1-4 was obtained as a white solid (20 mg, 38%).

(84) .sup.1H NMR (400 MHz, D.sub.2O) 1.14-1.22 (m, 2H), 1.24-1.32 (m, 2H), 1.45-1.54 (m, 1H), 1.59-1.66 (m, 1H), 1.72-1.82 (m, 1H), 1.93-2.02 (m, 1H), 2.31 (t, J=7.2 Hz, 2H), 2.91 (t, J=6.8 Hz, 2H), 3.51 (td, J=4.0, 0.8 Hz, 1H), 3.58 (td, J=4.0, 0.8 Hz, 1H), 3.81 (t, J=4.8 Hz, 2H), 3.98 (dd, J=8.8, 4.8 Hz, 1H), 4.06 (dd, J=9.2, 5.2 Hz, 1H), 4.20 (s, 2H), 4.28 (td, J=4.0, 0.8 Hz, 1H), 4.39 (td, J=4.0, 0.8 Hz, 1H), 4.45 (t, J=4.68 Hz, 2H), 7.78 (s, 1H);

(85) .sup.13C NMR (100 MHz, D.sub.2O) 22.0, 26.0, 28.4, 29.9, 30.4, 34.7, 39.4, 50.3, 52.4, 53.0, 68.6, 69.7 (d, J=18 Hz), 83.1 (d, J=162 Hz), 124.3, 145.8, 159.2, 160.1, 176.1, 177.0, 177.1; MS (ESI) m/z 534 [M+H].sup.+

Example 5-5. Preparation of Compound 1-5

(86) A solution prepared by dissolving the compound 11-2 (40 mg, 0.081 mmol) synthesized in Example 4-2 in water (0.5 mL) was added to ethanol (0.5 mL) in which 1-azido-2-(2-fluoroethoxy)ethane (12-2, 13 mg, 0.097 mmol) was dissolved. CuSO.sub.4.5H.sub.2O aqueous solution (0.5M, 0.049 mL, 0.024 mmol) and sodium ascorbate aqueous solution (0.5M, 0.081 mL, 0.041 mmol) were added thereto stepwise, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered and washed with water. Then, the filtrate was separated by HPLC. As a result, the compound 1-5 was obtained as a white solid (37 mg, 72%).

(87) .sup.1H NMR (400 MHz, D.sub.2O) 1.16-1.23 (m, 2H), 1.33-1.40 (m, 2H), 1.52-1.60 (m, 1H), 1.63-1.70 (m, 1H), 1.81-1.88 (m, 1H), 2.00-2.07 (m, 1H), 2.38 (t, J=7.4 Hz, 2H), 3.07 (t, J=6.8 Hz, 2H), 3.57 (t, J=4.0 Hz, 1H), 3.65 (t, J=4.0 Hz, 1H), 3.83 (t, J=5.0 Hz, 2H), 4.02 (dd, J=8.4, 5.2 Hz, 1H), 4.14 (dd, J=9.0, 5.0 Hz, 1H), 4.34 (t, J=4.0 Hz, 1H), 4.45-4.49 (m, 3H), 4.59 (s, 2H), 4.75 (s, 2H), 7.69 (d, J=6.8 Hz, 2H), 7.86 (s, 1H), 8.55 (d, J=6.8 Hz, 2H);

(88) .sup.13C NMR (100 MHz, D.sub.2O) 22.2, 26.2, 28.6, 29.9, 30.5, 40.1, 42.7, 49.9, 50.6, 52.5, 53.2, 68.7, 69.7 (d, J=19 Hz), 83.2 (d, J=163 Hz), 124.7, 124.9, 140.7, 143.5, 159.1, 159.2, 160.7, 176.1, 177.0, 177.1; MS (ESI) m/z 625 [M+H].sup.+

Example 5-6. Preparation of Compound 1-6

(89) A solution prepared by dissolving the compound 11-3 (40 mg, 0.084 mmol) synthesized in Example 4-3 in water (0.5 mL) was added to ethanol (0.5 mL) in which 1-azido-2-(2-fluoroethoxy)ethane (12-2, 13 mg, 0.10 mmol) was dissolved. CuSO.sub.4.5H.sub.2O aqueous solution (0.5M, 0.050 mL, 0.025 mmol) and sodium ascorbate aqueous solution (0.5M, 0.084 mL, 0.042 mmol) were added thereto stepwise, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered and washed with water. Then, the filtrate was separated by HPLC. As a result, the compound 1-6 was obtained as a white solid (38 mg, 75%).

(90) .sup.1H NMR (400 MHz, D.sub.2O) 1.20-1.28 (m, 2H), 1.40-1.47 (m, 2H), 1.54-1.62 (m, 1H), 1.66-1.74 (m, 1H), 1.77-1.86 (m, 1H), 1.98-2.08 (m, 1H), 2.36 (t, J=7.4 Hz, 2H), 3.17 (t, J=6.8 Hz, 2H), 3.52 (t, J=3.8 Hz, 1H), 3.60 (t, J=4.0 Hz, 1H), 3.83 (t, J=5.0 Hz, 2H), 4.05 (dd, J=8.8, 4.8 Hz, 1H), 4.12 (dd, J=9.2, 5.2 Hz, 1H), 4.28 (t, J=4.0 Hz, 1H), 4.40 (t, J=3.8 Hz, 1H), 4.48 (t, J=5.0 Hz, 2H), 5.06 (s, 2H), 7.48 (d, J=7.6 Hz, 2H), 7.90 (s, 1H), 8.28 (d, J=7.6 Hz, 2H);

(91) .sup.13C NMR (100 MHz, D.sub.2O) 22.3, 26.2, 27.6, 29.9, 30.5, 40.5, 43.3, 50.0, 52.5, 53.1, 68.7, 69.7 (d, J=19 Hz), 83.1 (d, J=163 Hz), 114.4, 124.7, 140.7, 142.1, 156.4, 156.8, 159.2, 176.1, 176.9, 177.1; MS (ESI) m/z 611 [M+H].sup.+

Example 5-7. Preparation of Compound 1-7

(92) A solution prepared by dissolving the compound 11-1 (40 mg, 0.10 mmol) synthesized in Example 4-1 in water (0.5 mL) was added to ethanol (0.5 mL) in which 1-azido-2-(2-(2-fluoroethoxy)ethoxy)ethane (12-3, 21 mg, 0.12 mmol) was dissolved. CuSO.sub.4.5H.sub.2O aqueous solution (0.5M, 0.060 mL, 0.030 mmol) and sodium ascorbate aqueous solution (0.5M, 0.100 mL, 0.050 mmol) were added thereto stepwise, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered and washed with water. Then, the filtrate was separated by HPLC. As a result, the compound 1-3 was obtained as a white solid (50 mg, 77%).

(93) .sup.1H NMR (400 MHz, D.sub.2O) 1.16-1.26 (m, 2H), 1.28-1.36 (m, 2H), 1.49-1.58 (m, 1H), 1.63-1.71 (m, 1H), 1.76-1.85 (m, 1H), 1.97-2.06 (m, 1H), 2.35 (t, J=7.4 Hz, 2H), 2.94 (t, J=6.4 Hz, 2H), 3.49-3.50 (m, 5H), 3.57 (td, J=4.0, 1.2 Hz, 1H), 3.81 (t, J=4.8 Hz, 2H), 4.02 (dd, J=8.8, 4.8 Hz, 1H), 4.10 (dd, J=9.0, 5.4 Hz, 1H), 4.24 (s, 2H), 4.34 (td, J=4.4, 1.2 Hz, 1H), 4.45-4.49 (m, 3H), 7.84 (s, 1H);

(94) .sup.13C NMR (100 MHz, D.sub.2O) 22.0, 26.1, 28.4, 29.9, 30.4, 34.6, 39.4, 50.5, 52.4, 53.0, 68.4, 69.3, 69.4, 69.7 (d, J=19 Hz), 83.1 (d, J=163 Hz), 124.5, 145.5, 159.2, 160.1, 176.2, 177.0, 177.1; MS (ESI) m/z 578 [M+H].sup.+

Example 5-8. Preparation of Compound 1-8

(95) A solution prepared by dissolving the compound 11-2 (40 mg, 0.081 mmol) synthesized in Example 4-2 in water (0.5 mL) was added to ethanol (0.5 mL) in which 1-azido-2-(2-(2-fluoroethoxy)ethoxy)ethane (12-3, 17 mg, 0.097 mmol) was dissolved. CuSO.sub.4.5H.sub.2O aqueous solution (0.5M, 0.049 mL, 0.024 mmol) and sodium ascorbate aqueous solution (0.5M, 0.081 mL, 0.041 mmol) were added thereto stepwise, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered and washed with water. Then, the filtrate was separated by HPLC. As a result, the compound 1-8 was obtained as a white solid (47 mg, 87%).

(96) .sup.1H NMR (400 MHz, D.sub.2O) 1.13-1.25 (m, 2H), 1.36 (quint, J=7.0 Hz, 2H), 1.50-1.60 (m, 1H), 1.63-1.72 (m, 1H), 1.79-1.88 (m, 1H), 2.00-2.09 (m, 1H), 2.38 (t, J=7.2 Hz, 2H), 3.07 (t, J=6.8 Hz, 2H), 3.52 (s, 4H), 3.54 (t, J=4.0 Hz, 1H), 3.62 (t, J=4.0 Hz, 1H), 3.80 (t, J=5.2 Hz, 2H), 4.02 (dd, J=8.6, 5.4 Hz, 1H), 4.14 (dd, J=9.0, 5.0 Hz, 1H), 4.38 (t, J=4.0 Hz, 1H), 4.46-4.51 (m, 3H), 4.58 (s, 2H), 4.75 (s, 2H), 7.70 (d, J=6.4 Hz, 2H), 7.88 (s, 1H), 8.55 (d, J=6.8 Hz, 2H);

(97) .sup.13C NMR (100 MHz, D.sub.2O) 22.2, 26.2, 28.6, 30.0, 30.5, 40.1, 42.7, 50.0, 50.6, 52.5, 53.2, 68.6, 69.4, 69.5, 69.7 (d, J=19 Hz), 83.3 (d, J=162 Hz), 124.7, 124.9, 140.8, 143.5, 159.1, 159.2, 160.7, 176.1, 177.0, 177.1; MS (ESI) m/z 669 [M+H].sup.+

Example 5-9. Preparation of Compound 1-9

(98) A solution prepared by dissolving the compound 11-3 (40 mg, 0.084 mmol) synthesized in Example 4-3 in water (0.5 mL) was added to ethanol (0.5 mL) in which 1-azido-2-(2-(2-fluoroethoxy)ethoxy)ethane (12-3, 18 mg, 0.10 mmol) was dissolved. CuSO.sub.4.5H.sub.2O aqueous solution (0.5M, 0.050 mL, 0.025 mmol) and sodium ascorbate aqueous solution (0.5M, 0.084 mL, 0.042 mmol) were added thereto stepwise, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered and washed with water. Then, the filtrate was separated by HPLC. As a result, the compound 1-9 was obtained as a white solid (30 mg, 55%).

(99) .sup.1H NMR (400 MHz, D.sub.2O) 1.15-1.22 (m, 2H), 1.35-1.40 (m, 2H), 1.47-1.56 (m, 1H), 1.61-1.68 (m, 1H), 1.72-1.81 (m, 1H), 1.93-2.03 (m, 1H), 2.31 (t, J=7.2 Hz, 2H), 3.12 (t, J=6.6 Hz, 2H), 3.43 (s, 4H), 3.46 (t, J=4.0 Hz, 1H), 3.54 (t, J=4.0 Hz, 1H), 3.75 (t, J=4.8 Hz, 2H), 3.99 (dd, J=8.8, 5.2 Hz, 1H), 4.07 (dd, J=9.2, 5.2 Hz, 1H), 4.30 (t, J=4.0 Hz, 1H), 4.41-4.44 (m, 3H), 5.00 (s, 2H), 7.43 (d, J=7.6 Hz, 2H), 7.87 (s, 1H), 8.24 (d, J=7.2 Hz, 2H);

(100) .sup.13C NMR (100 MHz, D.sub.2O) 22.2, 26.1, 27.5, 29.9, 30.4, 40.4, 43.2, 50.0, 52.4, 53.0, 68.6, 69.3, 69.4, 69.7 (d, J=18 Hz), 83.1 (d, J=162 Hz), 114.3, 124.6, 140.6, 142.0, 156.3, 156.8, 159.2, 176.1, 176.9, 177.1; MS (ESI) m/z 655 [M+H].sup.+

Example 6. Synthesis of .SUP.125.I-MIP1095 Compound

(101) A schematic reaction process of the present invention is shown in reaction formula 7 below.

(102) ##STR00011##

Example 6-1. Preparation of Compound 13 (Step 1)

(103) Triphosgene (21 mg, 0.071 mmol) was dissolved in dichloromethane (5 mL), to which 4-iodoaniline (45 mg, 0.205 mmol) dissolved in dichloromethane (5 mL) was slowly added at 0 C. Triethylamine (0.57 mL, 0.410 mmol) was added thereto, followed by stirring for 30 minutes. Glutamate-urea-lysine (9, 100 mg, 0.205 mmol) dissolved in dichloromethane (10 mL) was slowly added thereto at 0 C. Triethylamine (0.57 mL, 0.410 mmol) was also added thereto. 15 minutes later, the mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure and purified by column chromatography (2% methanol/dichloromethane). As a result, the compound 13 was obtained as a white liquid (66 mg, 44%).

(104) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.20-1.27 (m, 2H), 1.37 (s, 9H), 1.40 (s, 9H), 1.44 (s, 9H), 1.47-1.57 (m, 2H), 1.71-1.81 (m, 2H), 1.83-1.91 (m, 1H), 2.03-2.11 (m, 1H), 2.37 (sext, J=8.2 Hz, 2H), 3.01-3.07 (m, 1H), 3.51-3.56 (m, 1H), 3.97-4.01 (m, 1H), 4.26-4.32 (m, 1H), 5.75 (d, J=7.2 Hz, 1H), 6.31 (q, J=3.4 Hz, 1H), 6.40 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 7.90 (s, 1H);

(105) .sup.13C NMR (100 MHz, CDCl.sub.3) 24.5, 27.1, 27.8, 27.9, 28.0, 29.6, 31.7, 32.0, 39.1, 53.8, 54.9, 81.0, 81.8, 83.6, 83.7, 120.2, 137.5, 140.2, 155.6, 158.5, 171.8, 172.0, 175.3; MS (ESI) m/z 733 [M+H].sup.+

Example 6-2. Preparation of Compound 14 (Step 2)

(106) The compound 13 (50 mg, 0.068 mmol) synthesized in step 1 above was dissolved in 1,4-dioxane (1.0 mL), to which hexamethylditin (0.043 mL, 0.206 mmol) and bis(triphenylphosphine)palladium(II) dichloride (4.8 mg, 0.005 mmol) were added stepwise, followed by stirring at 110 C. for 1.5 hours. After cooling the mixture to room temperature, potassium fluoride aqueous solution (50 mL) was added thereto and the organic compound was extracted using ethyl acetate three times. The collected organic solvent was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (triethylamine:ethyl acetate:n-hexane, 1:40:59). As a result, the compound 14 was obtained as a white solid (28 mg, 53%).

(107) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.25 (s, 9H), 1.22-1.29 (m, 2H), 1.38 (s, 9H), 1.41 (s, 9H), 1.43 (s, 9H), 1.48-1.59 (m, 2H), 1.72-1.78 (m, 1H), 1.81-1.91 (m, 1H), 2.05-2.13 (m, 2H), 2.34-2.43 (m, 2H), 3.04-3.09 (m, 1H), 3.51-3.55 (m, 1H), 4.04 (pent, J=4.9 Hz, 1H), 4.33 (sext, J=4.5 Hz, 1H), 5.73 (d, J=6.8 Hz 1H), 6.23 (br s, 1H), 6.32 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.73 (s, 1H);

(108) .sup.13C NMR (100 MHz, CDCl.sub.3) 9.5, 24.2, 27.4, 27.8, 27.9, 28.0, 29.7, 31.8, 32.1, 39.1, 53.7, 54.7, 80.9, 81.7, 83.5, 118.4, 133.6, 136.2, 140.4, 155.9, 158.3, 171.9, 172.2, 175.1; MS (ESI) m/z 771 [M+2H]+

Example 7. Preparation of .SUP.18.F-Labelled Compound ([.SUP.18.F]1)

(109) A schematic reaction process of the present invention is shown in reaction formula 8 below.

(110) ##STR00012##

Example 7-1. Preparation of [.SUP.18.F]1-1 Compound

(111) Distilled water (3 mL) was poured down on Chromafix (HCO.sub.3), which passed through [.sup.18F] fluoride aqueous solution (508 mCi), and then ethanol (1 mL) was poured down thereto. Krytofix222-Potassium methanesulfonate (10 mg) was dissolved in ethanol (1 mL), through which Chromafix was passed, and the solvent was removed by blowing nitrogen to the solution at 100 C. 2-Azidoethyl 4-toluenesulfonate 15-1 (1.2 mg) was dissolved in t-butanol (500 L), which was placed in a reaction vessel containing [.sup.18F]fluoride, followed by reaction at 100 C. for 10 minutes (preparation of [.sup.18F]12-1). The reaction mixture was cooled to room temperature. Then, 150 L (137 mCi) of the reaction mixture was placed in another reaction vessel, to which ethanol (150 L), an aqueous solution containing the compound 11-1 (1 mg) dissolved therein (100 L), 0.5M CuSO.sub.4 (5 L) and 0.5M sodium ascorbate (10 L) were added in that order, followed by reaction at room temperature for 10 minutes. Distilled water (2 mL) was added to the reaction mixture, which was filtered and separated by HPLC. As a result, the compound [.sup.18F]1-1 (55.3 mCi) was obtained.

(112) HPLC condition: Column, XTerra MS C18 (250 mm10 mm); Moving phase, 5-30% acetonitrile/water (0.1% TFA), 70 minutes; Flow rate, 4 mL/min.; UV, 230 mm; Retention time, 15-20 minutes.

Example 7-2. Preparation of [.SUP.18.F]1-2 Compound

(113) 150 L (122 mCi) of t-butanol containing [.sup.18F]12-1 prepared in Example 7-1 dissolved therein was placed in another reaction vessel, to which ethanol (150 L), an aqueous solution containing the compound 11-2 (1.5 mg) dissolved therein (100 L), 0.5M CuSO.sub.4 (5 L) and 0.5M sodium ascorbate (10 L) were added in that order, followed by reaction at room temperature for 10 minutes. Distilled water (2 mL) was added to the reaction mixture, which was filtered and separated by HPLC. As a result, the compound [.sup.18F]1-2 (39 mCi) was obtained.

(114) HPLC condition: Column, XTerra MS C18 (250 mm10 mm); Moving phase, 5-30% acetonitrile/water (0.1% TFA) 50 minutes; Flow rate, 4 mL/min.; UV, 230 mm; Retention time, 17-20 minutes.

Example 7-3. Preparation of [.SUP.18.F]1-3 Compound

(115) 200 L (120 mCi) of t-butanol containing [.sup.18F]12-1 prepared in Example 7-1 dissolved therein was placed in another reaction vessel, to which ethanol (150 L), an aqueous solution containing the compound 11-3 (1.5 mg) dissolved therein (100 L), 0.5M CuSO.sub.4 (5 L) and 0.5M sodium ascorbate (10 L) were added in that order, followed by reaction at room temperature for 10 minutes. Distilled water (2 mL) was added to the reaction mixture, which was filtered and separated by HPLC. As a result, the compound [.sup.18F]1-3 (19.9 mCi) was obtained.

(116) HPLC condition: Column, XTerra MS C18 (250 mm10 mm); Moving phase, 5-30% acetonitrile/water (0.1% TFA), 90 minutes; Flow rate, 4 mL/min.; UV, 230 mm; Retention time, 14-16 minutes.

Example 7-4. Preparation of [.SUP.18.F]1-4 Compound

(117) Distilled water (3 mL) was poured down on Chromafix (HCO.sub.3), which passed through [.sup.18F] fluoride aqueous solution (493 mCi), and then ethanol (1 mL) was poured down thereto. Krytofix222-Potassium methanesulfonate (10 mg) was dissolved in ethanol (1 mL), through which Chromafix was passed, and the solvent was removed by blowing nitrogen to the solution at 100 C. 2-(2-Azidoethoxy)ethyl methanesulfonate 15-2 (2.2 mg) was dissolved in t-butanol (500 L), which was placed in a reaction vessel containing [.sup.18F]fluoride, followed by reaction at 10 C. for 10 minutes (preparation of [.sup.18F]12-2). The reaction mixture was cooled to room temperature. Then, 150 L (81.3 mCi) of the reaction mixture was placed in another reaction vessel, to which ethanol (150 L), an aqueous solution containing the compound 11-1 (2 mg) dissolved therein (100 L), 0.5M CuSO.sub.4 (5 L) and 0.5M sodium ascorbate (10 L) were added in that order, followed by reaction at room temperature for 10 minutes. Distilled water (2 mL) was added to the reaction mixture, which was filtered and separated by HPLC. As a result, the compound [.sup.18F]1-4 (16.8 mCi) was obtained.

(118) HPLC condition: Column, XTerra MS C18 (250 mm10 mm); Moving phase, 5-30% acetonitrile/water (0.1% TFA), 70 minutes; Flow rate, 4 mL/min.; UV, 254 mm; Retention time, 26-29 minutes.

Example 7-5. Preparation of [.SUP.18.F]1-5 Compound

(119) 150 L (88.4 mCi) of t-butanol containing [.sup.18F]12-2 prepared in Example 7-4 dissolved therein was placed in another reaction vessel, to which the compound 11-2 (1.5 mg) dissolved in distilled water (100 L), 0.5M CuSO.sub.4 (5 L) and 0.5M sodium ascorbate (10 L) were added in that order, followed by reaction at room temperature for 10 minutes. Distilled water (2 mL) was added to the reaction mixture, which was filtered and separated by HPLC. As a result, the compound [.sup.18F]1-5 (26.5 mCi) was obtained.

(120) HPLC condition: Column, XTerra MS C18 (250 mm10 mm); Moving phase, 5-30% acetonitrile/water (0.1% TFA), 50 minutes; Flow rate, 4 mL/min.; UV, 254 mm; Retention time, 29 minutes.

Example 7-6. Preparation of [.SUP.18.F]1-6 Compound

(121) 100 L (88.0 mCi) of t-butanol containing [.sup.18F]12-2 prepared in Example 7-4 dissolved therein was placed in another reaction vessel, to which the compound 11-3 (2 mg) dissolved in distilled water (100 L), 0.5M CuSO.sub.4 (5 L) and 0.5M sodium ascorbate (10 L) were added in that order, followed by reaction at room temperature for 10 minutes. Distilled water (2 mL) was added to the reaction mixture, which was filtered and separated by HPLC. As a result, the compound [.sup.18F]1-6 (16.1 mCi) was obtained.

(122) FIGS. 1A, 1B and 2 are graphs illustrating the results of Radio-TLC and HPLC separation according to the preparation step of the compound [.sup.18F]1-6.

(123) HPLC condition: Column, XTerra MS C18 (250 mm10 mm); Moving phase, 5-30% acetonitrile/water (0.1% TFA), 50 minutes; Flow rate, 4 mL/min.; UV, 254 mm; Retention time, 27 minutes.

Example 7-7. Preparation of [.SUP.18.F]1-7 Compound

(124) Distilled water (3 mL) was poured down on Chromafix (HCO.sub.3.sup.), which passed through [.sup.18F] fluoride aqueous solution (574 mCi), and then ethanol (1 mL) was poured down thereto. Krytofix222-Potassium methanesulfonate (10 mg) was dissolved in ethanol (1 mL), through which Chromafix was passed, and the solvent was removed by blowing nitrogen to the solution at 100 C. 2-(2-(2-Azidoethoxy)ethoxy)ethyl methanesulfonate 15-3 (2.7 mg) was dissolved in t-butanol (500 L), which was placed in a reaction vessel containing [.sup.18F]fluoride, followed by reaction at 100 C. for 10 minutes (preparation of [.sup.18F]12-3). Upon completion of the reaction, the solvent was removed by gently blowing nitrogen gas to the solution at 100 C., and then the reaction mixture was dissolved in ethanol (300 L). 100 L (87 mCi) of the ethanol solution containing [.sup.18F]12-3 dissolved therein was placed in another reaction vessel, to which distilled water containing the compound 11-1 (2 mg) dissolved therein (100 L), 0.5M CuSO.sub.4 (5 L) and 0.5M sodium ascorbate (10 L) were added in that order, followed by reaction at room temperature for 10 minutes. Distilled water (2 mL) was added to the reaction mixture, which was filtered and separated by HPLC. As a result, the compound [.sup.18F]1-7 (31.2 mCi) was obtained.

(125) HPLC condition: Column, XTerra MS C18 (250 mm10 mm); Moving phase, 5-30% acetonitrile/water (0.1% TFA), 50 minutes; Flow rate, 4 mL/min.; UV, 254 mm; Retention time, 29 minutes.

Example 7-8. Preparation of [.SUP.18.F]1-8 Compound

(126) 100 L (87 mCi) of the ethanol solution (100 L) containing [.sup.18F]12-3 prepared in Example 7-7 dissolved therein was placed in another reaction vessel, to which the compound 11-2 (1.5 mg) dissolved in distilled water (100 L), 0.5M CuSO.sub.4 (5 L) and 0.5M sodium ascorbate (10 L) were added in that order, followed by reaction at room temperature for 10 minutes. Distilled water (2 mL) was added to the reaction mixture, which was filtered and separated by HPLC. As a result, the compound [.sup.18F]1-8 (26.5 mCi) was obtained.

(127) HPLC condition: Column, XTerra MS C18 (250 mm10 mm); Moving phase, 5-30% acetonitrile/water (0.1% TFA), 50 minutes; Flow rate, 4 mL/min.; UV, 254 mm; Retention time, 27 minutes.

Example 7-9. Preparation of [.SUP.18.F]1-9 Compound

(128) 100 L (89 mCi) of the ethanol solution (100 L) containing [.sup.18F]12-3 prepared in Example 7-7 dissolved therein was placed in another reaction vessel, to which the compound 11-3 (2 mg) dissolved in distilled water (100 L), 0.5M CuSO.sub.4 (5 L) and 0.5M sodium ascorbate (10 L) were added in that order, followed by reaction at room temperature for 10 minutes. Distilled water (2 mL) was added to the reaction mixture, which was filtered and separated by HPLC. As a result, the compound [.sup.18F] 1-9 (18.9 mCi) was obtained.

(129) HPLC condition: Column, XTerra MS C18 (250 mm10 mm); Moving phase, 5-30% acetonitrile/water (0.1% TFA), 50 minutes; Flow rate, 4 mL/min.; UV, 254 mm; Retention time, 27.5 minutes.

Comparative Example 1. Preparation of [.SUP.125.I]15 ([.SUP.121.I]MIP-1095) Compound

(130) The compound 14 (0.1 mg) synthesized in Example 6-2 was dissolved in ethanol (250 L), which was added to sodium [.sup.125I]iodide aqueous solution (4.6 mCi, 50 L), followed by stirring. 1N HCl aqueous solution (100 L) and 3% H.sub.2O.sub.2 were added thereto, followed by stirring at room temperature for 10 minutes. 0.1M sodium thiosulfate aqueous solution (200 L) and distilled water (18 mL) were added to the reaction mixture, which was passed through C-18 Sep-Pak, followed by pouring with distilled water (20 mL). Acetonitrile (2.0 mL) was poured into C-18 Sep-Pak, and then the acetonitrile was removed by blowing nitrogen to the solution. Dichloromethane (0.2 mL) and trifluoroacetic acid (0.8 mL) were added thereto, followed by stirring at room temperature for 20 minutes. The reaction solvent was removed by blowing nitrogen to the solution. Distilled water (2 mL) was added to the reaction mixture, which was separated by HPLC. As a result, the compound [.sup.125I]15 (1.1 mCi, 24%) was obtained.

(131) HPLC condition: Column, XTerra MS C18 (250 mm10 mm); Moving phase, 30% acetonitrile/water (0.1% TFA); Flow rate, 5 mL/min; UV, 254 mm; Retention time, 10.4 minutes.

(132) A schematic reaction process of the present invention is shown in reaction formula 9 below.

(133) ##STR00013##

Reference Example 1. Material Preparation

(134) A human prostate cancer cell line (22RV1) used herein was purchased from American Type Culture Collection (ATCC). PC3 PIP (PSMA.sup.+) and PC3 flu (PSMA.sup.), the human prostate cancer cell lines, were provided by Dr. Martin G. Pomper (Johns Hopkins Medical School, Baltimore, Md.). The human prostate cancer cell lines were maintained in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% antibiotic/antifungal agent. In the culture of PC3 PIP (PSMA+) and PC3 flu (PSMA) cell lines, puromycin was additionally added at the concentration of 2 g/mL.

(135) As test animals, 6 weeks old male nude mice (Narabio, Seoul, Korea) were used.

(136) Experimental Example 1. Measurement of Binding Capacity

(137) To confirm the binding capacity of the .sup.18F-labelled compound obtained in Example 7 and the [.sup.125I]15 obtained in Comparative Example 1 of the present invention to prostate cancer cell line, the following experiment was performed.

(138) RPMI1640 supplemented with 1% BSA (bovine serum albumin) was used as a buffer solution.

(139) [.sup.125I]15 (0.1 nM) was added to a vessel containing 22RV1 cells (510.sup.4), to which [.sup.18F]1-1 to [.sup.18F]1-9 compounds were loaded at 9 concentrations (1.0010.sup.4 to 1.0010.sup.12M), followed by stirring at 37 C. for 2 hours. Upon completion of the stirring, the vessel was washed with 2 mL of PBS solution three times, and then the remaining radioactivity and 50% inhibition concentration (nonlinear regression method) were measured using a gamma counter (2480 WIZARD2 Gamma Counter PerkinElmer Co., MA) and GraphPad Prism (GraphPad Software, Inc., CA).

(140) Table 1 is a table showing the measurement results.

(141) As a result, as shown in Table 1, the IC.sub.50 value of [.sup.18F]1-6 (Example 7-6) in which pyridine was directly bound to the urea functional group was the best (5.08), the IC.sub.50 value of [.sup.18F]1-3 (Example 7-3) without pyridine was worse more than 70 times, and the IC.sub.50 value of [.sup.18F]1-9 (Example 7-9) in which methylpyridine was bound was worse more than 40 times. Therefore, it was confirmed that the pyridine of ([.sup.18F]1-6 (Example 7-6) formed a high lipophilic bond with the PSMA protein.

(142) Example 7-4 to Example 7-6 were compared. As a result, it was confirmed that the longer the distance between the triazole group and the .sup.18F isotope, the better the IC.sub.50 value.

(143) Therefore, it was found that the [.sup.1F]1-6 (Example 7-6) having pyridine directly bound to urea and having a triethylene glycol group between the .sup.18F isotope and the triazole group was most strongly bound to the PSMA protein.

(144) The IC.sub.50 value of [.sup.18F]DCFPyL (Comparative Example 1) was 30.71. Therefore, [.sup.18F]1-6 (Example 7-6) of the present invention was confirmed to have about 6 times higher binding capacity.

(145) TABLE-US-00001 TABLE 1 Compound IC.sub.50 (Mean SD, nM) Comparative 30.71 10.18 Example 1 Example 7-1 635.13 262.66 Example 7-2 65.34 39.08 Example 7-3 391.00 227.94 Example 7-4 56.99 33.02 Example 7-5 11.80 Example 7-6 5.08 2.57 Example 7-7 64.62 38.44 Example 7-8 284.10 115.70 Example 7-9 235.63 190.70

Experimental Example 2. Measurement of Cellular Internalization

(146) To confirm the cellular internalization characteristics of the .sup.18F-labelled compound obtained in Example 7 and the [.sup.125I]15 obtained in Comparative Example 1 of the present invention to prostate cancer cell line, the following experiment was performed.

(147) 3.7 MBq (100 Ci) of Example 7-3, Example 7-6, and Comparative Example 1 were added to PC-3 PIP (110.sup.6/1 mL), which was washed twice each with 2 mL of PBS solution after 30, 60, and 120 minutes. Then, the membrane protein and the cytoplasmic protein were separated by using Mem-PER Plus Membrane Protein Extraction Kit and NE-PER Nuclear and Cytoplasmic Extraction Kit (ThermoFisher Scientific). The internalization rate (%) was confirmed by obtaining the radioactivity ratio in the cytoplasmic protein to the total radioactivity.

(148) Table 2 shows the rate of cellular internalization.

(149) As a result, as shown in Table 2, it was confirmed that the three compounds were well internalized in prostate cancer cells without any significant difference and the internalization was almost complete within the first 30 minutes without any change over the time.

(150) TABLE-US-00002 TABLE 2 Time % Internalization ratio Classify (min) (Mean SD) Example 7-3 30 94.24 0.80 60 92.33 1.89 120 85.77 6.12 240 95.47 1.52 Example 7-6 30 93.30 2.11 60 91.89 5.76 120 94.77 2.92 240 96.32 1.08 Comparative 30 91.27 4.03 Example 1 60 86.91 8.13 120 94.31 2.94 240 95.01 2.58

Experimental Example 3. Measurement of MicroPET/CT in Mice Transplanted with Prostate Cancer Cell Lines

(151) To confirm the binding properties of the .sup.18F-labelled compound obtained in Example 7 and the [.sup.125I]15 obtained in Comparative Example 1 of the present invention to prostate-specific cell membrane antibody, the following experiment was performed.

(152) A tumor model was prepared by subcutaneously injecting PSMA.sup.+ PC-3 PIP cells (a human prostate cancer cell line) to the right side of the nude mouse hind leg and subcutaneously injecting PSMA PC-3 flu cells to the left side of the nude mouse hind leg as the control. In addition, each of Example 7-3 and Example 7-6 was intravenously injected with 5.5 to 7.4 MBq (200 L), and PET/CT images were obtained using small animal nanoScan PET/CT (Mediso, Budapest, Hungary) for 60 minutes. The obtained PET/CT image results were quantitatively analyzed using InterView FUSION software (Mediso). Comparative Example 1 was used as the control compound.

(153) FIG. 3 is a diagram illustrating the results of MicroPET/CT of the prostate cancer mouse. FIGS. 4A to 4C are graphs illustrating the intake ratio of muscle, liver and spleen compared to tumor.

(154) As shown in FIG. 3, it was confirmed that Example 7-3, Example 7-6, and Comparative Example 1 were rapidly excreted through the kidneys and bladder, and they selectively bound to PSMA+PC-3 PIP tumors. As shown in FIGS. 4A to 4C, it was confirmed that Example 7-3 showed relatively higher tumor/muscle (tumor to muscle ratio) and tumor/liver (tumor to liver ratio) intake ratios than those of Example 7-6 and Comparative Example 1.

Experimental Example 4. Biodistribution Test with Prostate Cancer Model Mouse

(155) To confirm the biodistribution of the .sup.18F-labelled compound obtained in Example 7 and the [.sup.125I]15 obtained in Comparative Example 1 of the present invention in the prostate cancer model mouse, the following experiment was performed.

(156) A tumor model was prepared by subcutaneously injecting PSMA.sup.+ PC-3 PIP cells (a human prostate cancer cell line) to the right side of the nude mouse (6 weeks old, 20-25 g) hind leg and subcutaneously injecting PSMA.sup. PC-3 flu cells to the left side of the nude mouse hind leg as the control. The compounds of Example 7-3 and Example 7-6 were synthesized, which were injected into the tail vein of the mouse at the dose of 3.7 MBq (100 Ci), respectively. Each organ (blood, muscle, fat, heart, lung, liver, spleen, stomach, intestine, kidney, bone and tumor) was extracted at 30 minutes, 1 hour, 2 hours and 4 hours later and the radioactivity thereof was measured using a gamma counter.

(157) Table 3 and Table 4 show the radioactivity degree of the compounds of Example 7-3 and Example 7-6 in each organ. FIGS. 5A and 5B are graphs illustrating the organ biodistribution over the time.

(158) As a result, as shown in Tables 3 and 4 and FIGS. 5A and 5B, the tumor intake rate (% ID/g) was increased to more than 10%, 30 minutes after the injection of the compounds of Examples 7-3 and 7-6. In addition, the compound of Example 7-3 was confirmed to have higher PSMA-tumor tissue (PC-3 flu) intake rate compared to PSMA.sup.+ tumor (PC-3 PIP) and superior normal tissue intake rate compared to tumor.

(159) TABLE-US-00003 TABLE 3 Time PIP to PIP to PIP to PIP to (h) PIP/flu muscle blood spleen liver 0.5 40.59 9.85 47.39 38.05 35.64 25.01 7.74 6.03 17.35 4.34 1 103.45 9.73 86.15 29.07 98.69 30.64 13.77 5.53 15.92 1.95 2 176.33 65.83 334.14 260.49 487.24 354.87 58.80 53.63 18.47 7.63 4 232.60 71.80 533.90 188.93 766.82 331.65 128.24 95.38 20.93 7.40

(160) TABLE-US-00004 TABLE 4 Time PIP to PIP to PIP to PIP to (h) PIP/flu muscle blood spleen liver 0.5 16.00 5.68 13.00 4.97 14.05 3.61 7.31 3.34 5.64 6.10 1 23.08 14.91 20.11 14.99 30.30 17.05 12.46 16.18 9.93 13.26 2 33.32 14.64 38.11 14.83 36.90 9.52 25.98 8.66 13.71 12.60 4 35.69 11.64 45.39 22.54 42.90 18.49 32.51 10.12 19.77 11.81

(161) The present invention has been described in detail according to the above embodiments. However, the present invention is not limited by the above embodiments and can be variously modified without departing from the scope of the invention.