BENZENE RING-CONTAINING GLUCOSE DERIVATIVE AND USE THEREOF

Abstract

Disclosed herein is a benzene ring-containing glucose derivative of formula (I):

##STR00001##

, where R.sub.1 is each independently

##STR00002##

and R.sub.2 is hydrogen. This application also provides a radioactive drug, including a complex formed by the benzene ring-containing glucose derivative and a radionuclide. Use of the benzene ring-containing glucose derivative in the tumor treatment and diagnosis is further provided.

Claims

1. A benzene ring-containing glucose derivative of formula (I): ##STR00025## wherein one or two R.sub.1 are located on a benzene ring in formula (I); the one or two R.sub.1 are each independently ##STR00026## when there is one R.sub.1, R.sub.1 is on 3-position or 4-position of the benzene ring in formula (I); when there are two R.sub.1, the two R.sub.1 are on 3-position and 4-position of the benzene ring, respectively; R.sub.3 is hydrogen; m is 0 or 1; and ##STR00027## represents chemical bonding between R.sub.1 and the benzene ring in formula (I); R.sub.2 is hydrogen; n is 0,1 or 2; and when m=0 and n=1, R.sub.1 is not on the 4-position of the benzene ring.

2. The benzene ring-containing glucose derivative of claim 1, wherein the sum of m and n is 2.

3. The benzene ring-containing glucose derivative of claim 1, wherein there is one R.sub.1, and the one R.sub.1 is on the 3-position of the benzene ring.

4. A radioactive drug, comprising: a complex formed by the benzene ring-containing glucose derivative of claim 1 and a radionuclide; wherein the radionuclide is .sup.99mTc, and the complex is represented by formula (II): ##STR00028## wherein R.sub.1, R.sub.2, R.sub.3, m, n and ##STR00029## are as defined in claim 1.

5. A tumor diagnosis method, comprising: administering the radioactive drug of claim 4 to a subject in need thereof; and performing imaging by single photon emission computed tomography (SPECT).

Description

DETAILED DESCRIPTION OF EMBODIMENTS

[0032] A benzene ring-containing glucose derivative and a use thereof are provided herein. In an embodiment, a radioactive drug .sup.99mTc-CNBDG is provided, represented by:

##STR00012##

##STR00013##

[0033] where R.sub.1 is on 3-position or 4-position of the benzene ring in the formula of .sup.99mTc-CNBDG; [0034] m is 0 or 1, represents a chemical bonding between R.sub.1 and the benzene ring in the formula of .sup.99mTc-CNBDG; [0035] n is 0, 1 or 2; and [0036] when m=0 and n=1, R.sub.1 is not on the 4-position of the benzene ring.

[0037] The preparation of the .sup.99mTc-CNBDG is performed as follows: [0038] (1) Ligand synthesis [0039] D-glucosamine hydrochloride and NaOH were added to a 25 mL round-bottom flask, to which anhydrous methanol was added. The reaction mixture was stirred at room temperature for complete dissolution, dropwise added with a solution of Compound 1 in methanol, and reacted at room temperature for 24 h. Then the reaction mixture was concentrated by vacuum distillation, and purified by column chromatography (eluent: dichloromethane: methanol=5:1) to obtain the ligand CNBDG, as shown in the following synthesis route: [0040] Compound 1 was shown as: [0041] (2) Preparation of .sup.99mTc-CNBDG [0042] 1 mg of sodium citrate and 1 mg of L-cysteine were dissolved in a proper amount of normal saline, to which 0.06 mg of SnCl.sub.2.Math.2H.sub.2O was added. The reaction mixture was adjusted to pH 6.0, added with 0.5 mg of the ligand CNBDG and 1-2 mL of freshly-eluted Na.sup.99mTcO.sub.4 in sequence, and then reacted at 100° C. for 20 min to obtain a .sup.99mTc-CNBDG complex.

[0043] The prepared .sup.99mTc-CNBDG complex had a radiochemical purity of greater than 90%, excellent in vivo and in vitro stability, high uptake and good retention in tumor sites of tumor-bearing mice, and a good target/non-target ratio. Compared with the .sup.99mTc-CNPEDG and .sup.99mTc-(CN5DG).sub.6.sup.+ in the prior art, .sup.99mTc-CNBDG had a higher tumor/muscle ratio and a higher tumor/blood ratio, improving the target/non-target ratio of the imaging agent, and facilitating the promotion and application of .sup.99mTc-CNBDG as a new tumor-imaging agent.

[0044] Described below are only illustrative examples, and are not intended to limit this application. Unless otherwise specified, the operations described in the following examples shall be carried out under conventional conditions or as recommended by the manufacture.

[0045] Unless otherwise specified, the instruments used herein are all commercially-available. Unless otherwise specified, the methods used herein are conventional methods in the art, and the raw materials used herein are all commercially-available.

Example 1

[0046] Provided herein was a .sup.99mTc-labeled benzene ring-containing glucose derivative (.sup.99mTc-4-CNPeDG), represented by:

##STR00017##

.sup.99mTc-4-CNPeDG was prepared as follows.

1. Synthesis of 4-CNPeDG

[0047] ##STR00018##

[0048] 0.269 g of D-glucosamine hydrochloride and 0.055 g of sodium hydroxide were added to a 25 mL round-bottom flask, to which 20 mL of anhydrous methanol was added. The reaction mixture was stirred at room temperature for complete dissolution, added with 10 mL of a methanol solution containing 0.337 g of 4-(2-isocyanoethyl)-benzoic acid-2,3,5,6-tetrafluorophenylester, and reacted at room temperature for 24 h. The reaction mixture was concentrated by vacuum distillation, purified by silica gel column chromatography (eluent: dichloromethane: methanol=5:1) and dried to obtain 0.13 g of a pale yellow solid as 4-CNPeDG (37% yield).

[0049] .sup.1H NMR (400 MHz, methanol-d4): δ7.83(dd, J=15.8,8.5 Hz,2H), 7.37(dd, J=22.4,8.2 Hz, 2H), 5.25(t,J=3.0 Hz, 1H), 4.07(dt,J=10.7,3.1 Hz,1H), 3.97-3.80(m,3H), 3.80-3.67(m,2H), 3.46(dt,J=21.3,8.3 Hz,2H), 3.03 (t,J=6.6 Hz,2H).

[0050] HRMS(m/z): found 335.1252 (calc. 335.1248 for C.sub.16H.sub.19N.sub.2O.sub.6[M—H].sup.-).

[0051] IR(KBr)/cm.sup.-1: 2146.86 (—N═C).

2. Synthesis of .SUP.99m.Tc-4-CNPeDG

[0052] 1 mg of sodium citrate and 1 mg of L-cysteine were dissolved in a proper amount of normal saline, to which 0.06 mg of SnCl.sub.2.Math.2H.sub.2O was added. The reaction mixture was adjusted to pH 6.0, added with 0.5 mg of 4-CNPeDG and 1-2 mL of freshly-eluted Na.sup.99mTcO.sub.4 in sequence, and then reacted at 100° C. for 20 min to obtain the .sup.99mTc-4-CNPeDG.

Example 2

[0053] Provided herein was a .sup.99mTc-labeled benzene ring-containing glucose derivative (.sup.99mTc-4-CNMBDG), represented by:

##STR00019##

.sup.99mTc-4-CNMBDG was prepared as follows.

1. Synthesis of 4-CNMBDG

[0054] ##STR00020##

[0055] 0.220 g of D-glucosamine hydrochloride and 0.045 g of sodium hydroxide were added to a 25 mL round-bottom flask, to which 10 mL of anhydrous methanol was added. The reaction mixture was stirred at room temperature for complete dissolution, added with 10 mL of a methanol solution containing 0.290 g of 2,3,5,6-tetrafluorophenyl 4-isocyanomethyl phenylacetate, and reacted at room temperature for 24 h. The reaction mixture was concentrated by vacuum distillation, purified by silica gel column chromatography (eluent: dichloromethane: methanol=5:1) and dried to obtain 0.15 g of a pale yellow solid as 4-CNMBDG (50% yield).

[0056] .sup.1H-NMR (400 MHz, D.sub.2O): δ7.42(d,J=8.2 Hz,2H),7.37(d,J=8.2 Hz,2H),5.18(d,J=3.7 Hz,1 H),3.98-3.82(m,3 H),3.81-3.74(m,2H),3.74-3.63(m,3 H),3.60-3.37(m,2 H).

[0057] HRMS(m/z): found 337.1398 (calc. 337.1394 for C.sub.16H.sub.21N.sub.2O.sub.6[M+H].sup.+).

[0058] IR(KBr)/cm.sup.-1: 2152.65(—N≡C).

2. Synthesis of .SUP.99m.Tc-4-CNMBDG

[0059] 1 mg of sodium citrate and 1 mg of L-cysteine were dissolved in an appropriate amount of normal saline, to which 0.06 mg of SnCl.sub.2.Math.2H.sub.2O was added. The reaction mixture was adjusted to pH 6.0, added with 0.5 mg of 4-CNMBDG and 1-2 mL of freshly-eluted Na.sup.99mTcO.sub.4 in sequence, and reacted at 100° C. for 20 min to obtain the .sup.99mTc-4-CNMBDG.

Example 3

[0060] Provided herein was a .sup.99mTc-labeled benzene ring-containing glucose derivative (.sup.99mTc-3-CNBzDG), represented by:

##STR00021##

.sup.99mTc-3-CNBzDG was prepared as follows.

1. Synthesis of 3-CNBzDG

[0061] 0.326 g of D-glucosamine hydrochloride and 0.066 g of sodium hydroxide were added to a 25 mL round-bottom flask, to which 10 mL of anhydrous methanol was added. The reaction mixture was stirred at room temperature for complete dissolution, added with 10 mL of a methanol solution containing 0.499 g of 2,3,5,6-tetrafluorophenyl 3-isocyano benzoate, and reacted at room temperature for 24 h. The reaction mixture was concentrated by vacuum distillation, purified by silica gel column chromatography (eluent: dichloromethane: methanol=5:1), and dried to obtain 0.128 g of a pale yellow solid as 3-CNBzDG (29% yield).

[0062] .sup.1H-NMR (400 MHz, D.sub.2O): δ7.97-7.79(m,2 H),7.66(dd,J=17.2,8.0 Hz,1 H),7.56(dtd,J27.2,7.8,2.2 Hz,1 H),5.34(d,J=3.2H z,1 H),4.13(dd,J=10.7,3.4 Hz,1 H),4.03-3.89(m,2 H),3.89-3.74(m,1 H),3.62-3.44(m,2 H).

[0063] HRMS(m/z): found 307.0939 (calc.307.0935 for C.sub.14H.sub.15N.sub.2O.sub.6[M—H].sup.-).

[0064] IR(KBr)/cm.sup.-1: 2127.58(—N≡C).

2. Synthesis of .SUP.99m.Tc-3-CNBzDG

[0065] 1 mg of sodium citrate and 1 mg of L-cysteine were dissolved in a proper amount of normal saline, to which 0.06 mg of SnCl.sub.2.Math.2H.sub.2O was added. The reaction mixture was adjusted to pH 6.0, added with 0.5 mg of 3-CNBzDG and 1-2 mL of freshly-eluted Na.sup.99mTcO.sub.4 in sequence, and then reacted at 100° C. for 20 min to obtain the .sup.99mTc-3-CNBzDG.

Example 4

[0066] Provided herein was a .sup.99mTc-labeled benzene ring-containing glucose derivative (.sup.99mTc-3-CNPEDG), represented by:

##STR00022##

.sup.99mTc-3-CNPEDG was prepared as follows.

1. Synthesis of 3-CNPEDG

[0067] 0.220 g of D-glucosamine hydrochloride and 0.044 g of sodium hydroxide were added to a 25 mL round-bottom flask, to which 15 mL of anhydrous methanol was added. The reaction mixture was stirred at room temperature for complete dissolution, added with 10 mL of a methanol solution containing 0.312 g of 2,3,5,6-tetrafluorophenyl 3-isocyanomethyl benzoate to obtain a reaction solution, and reacted at room temperature for 24 h. The reaction mixture was concentrated by vacuum distillation, purified by silica gel column chromatography (eluent: dichloromethane: methanol=5:1) and dried to obtain 0.119 g of pale yellow solid as 3-CNPEDG (37% yield).

[0068] .sup.1H NMR (400 MHz, methanol-d4): δ7.96-7.78(m, 2 H), 7.66-7.44(m, 2 H), 5.26(d, J=3.2 Hz, 1 H), 4.84(s, 2 H), 4.08(dd, J=10 .7, 3 .4Hz, 1 H), 3.99-3.79(m, 3 H), 3.74(dd, J=11.9, 5.5 Hz, 1 H), 3.41(dt, J=30.3, 8.5 Hz, 1 H).

[0069] HRMS(m/z): found 323.1241(calc. 323.1237 for C.sub.15H.sub.19N.sub.2O.sub.6[M+H].sup.+).

[0070] IR(KBr)/cm.sup.-1: 2156.51(—N≡C).

2. Synthesis of .SUP.99m.Tc-3-CNPEDG

[0071] 1 mg of sodium citrate and 1 mg of L-cysteine were dissolved in an appropriate amount of normal saline, to which 0.06 mg of SnCl.sub.2.Math.2H.sub.2O was added. The reaction mixture was adjusted to pH 6.0, added with 0.5 mg of 3-CNPEDG and 1-2 mL of freshly-eluted Na.sup.99mTcO.sub.4 in sequence, and reacted at 100° C. for 20 min to obtain the .sup.99mTc-3-CNPEDG.

Comparative Example 1

[0072] Provided herein was .sup.99mTc-CNPEDG, which was prepared according to the method provided in Chinese Patent Application Publication No. 111138504A, represented by:

##STR00023##

Comparative Example 2

[0073] Provided herein was .sup.99mTc-(CN5DG).sub.6.sup.+, which was prepared according to the method provided in Chinese Patent Application Publication No. 107245087A, represented by:

##STR00024##

Experimental Example

1. Chromatographic Identification of Radioactive Compounds Provided in Examples 1-4

(1.1) Thin-layer Chromatography (TLC)

[0074] Radiochemical yield and radiochemical purity of the labeled substance were tested by using TLC method, where the developing system used herein was a polyamide film-ammonium acetate (1 M)/methanol system (a volume ratio of ammonium acetate to methanol was 2:1). Under such developing system, the R.sub.f (retention factor) value of each radioactive component was shown in Table 1.

TABLE-US-00001 R.sub.ƒ of radioactive components under a polyamide film-ammonium acetate (1 M)/methanol developing system .sup.99mTcO.sub.4.sup.- .sup.99mTcO.sub.2.Math.nH.sub.20 .sup.99mTc-CNBDG R.sub.ƒ value 0-0.1 0-0.1 0.7-1.0

[0075] The chromatographic identification results demonstrated that the radiochemical yield and purity of the .sup.99mTc-CNBDG complex were both greater than 90%. The .sup.99mTc-CNBDG complex was used in subsequent experiments without further purification.

(1.2) High Performance Liquid Chromatography (HPLC)

[0076] The radiochemical purity of the labeled substances was identified by HPLC, where the HPLC parameters were listed as follows: SHIMADZU HPLC system (CL-20AVP); C18 column (Kromasil, 5 .Math.m, 250×4.6 mm); Gabi radioactivity detector (Elysia-raytest GmbH Company); elution gradient: shown in Table 2; flow rate: 1 mL/min; phase A: pure water containing 0.1% trifluoroacetic acid (TFA); and phase B: acetonitrile containing 0.1% trifluoroacetic acid.

TABLE-US-00002 Gradient elution program t/min A/% B/% 0 90 10 2 90 10 10 10 90 18 10 90 25 90 10

[0077] The retention time of the radioactive compounds provided in Examples 1-4 was determined by HPLC: .sup.99mTc-4-CNPeDG: 10.7 min; .sup.99mTc-4-CNMBDG: 10.6 min; .sup.99mTc-3-CNBzDG: 10.4 min; and .sup.99mTc-3-CNPEDG: 10.6 min.

2. Determination of Lipid-Water Partition Coefficient

[0078] A 2 mL centrifuge tube was added with 100 .Math.L (10.Math.Ci) of a labeling solution, then added with 950 .Math.L of n-octanol and 850 .Math.L of phosphate buffer solution (PBS, 0.025 M, pH=7.4). The 2 mL centrifuge tube was subjected to vortex for 3 min (2,500 rpm) and standing until the reaction solution was layered, and then centrifuged at 9,000 rpm for 5 min. Three samples (each for 100 .Math.L) were collected from each of the two phases, and placed in γ-counter for the determination of radioactive counting. The lipid-water partition coefficient (P) was calculated by Organic phase radioactive counting/ water phase radioactive counting, and was usually expressed as Log P. The log P values of the radioactive compounds provided in Examples 1-4 were shown in Table 3. All Log P values were negative, indicating that the samples were all water-soluble substances.

TABLE-US-00003 Lipid-water partition coefficient of .sup.99mTc-CNBDG complexes .sup.99mTc-4-CNPeDG .sup.99MTc-4-CNMBDG .sup.99mTc-3-CNBzDG .sup.99mTc-3-CNPEDG Log P -3.593 ± 0.012 -3.097 ± 0.036 -3.743 ± 0.038 -3.389 ± 0.166

3. Stability Determination

(3.1) In Vitro Stability

[0079] The radioactive complexes provided in Examples 1-4 were respectively placed in normal saline (room temperature) and mouse serum (37° C.) for 4 h, and then analyzed by HPLC for the radiochemical purity. The results indicated that whether kept in normal saline (room temperature) or mouse serum (37° C.) for 4 h, the radioactive samples provided in Examples 1-4 all had a radiochemical purity above 90%, suggesting good in vitro stability.

In Vivo Stability

[0080] Solutions (0.1-0.2 mL, 74 MBq) containing the radioactive samples of Examples 1-4 were respectively injected into the mice via the tail vein. One hour later, the mice were sacrificed by decapitation, and the urine and blood were harvested, and measured for radiochemical purity by HPLC. The results showed that the radiochemical purity of .sup.99mTc-CNBDG complex in urine and blood was still greater than 90% at 1 h post administration, suggesting good in vivo stability.

4. Biodistribution in Tumor-Bearing Mice

[0081] The mice bearing S180 tumors were injected intravenously via the tail vein respectively with the solutions (0.1 mL, 370 kBq) containing the radioactive drugs of Examples 1-4. The mice bearing S180 tumors were sacrificed by decapitation at different time points (30 min, 120 min) after the injection (5 mice for each time point). After dissection, the heart, liver, lung, kidney, spleen, bone, muscle, small intestine, blood and tumors were harvested, and measured for radioactivity with the γ-counter. The biodistribution individual organs or tissues was expressed as the percentage of the injected dose per gram of organ or tissue (% ID/g). The biodistribution results of the labeled substances in tumor-bearing mice were shown in Tables 4-7.

TABLE-US-00004 Biodistribution of .sup.99mTc-4-CNPeDG in mice bearing S180 tumor (n=5, mean ± SD, % ID/g) 30 min 120 min Heart 1.15 ± 0.04 0.15 ± 0.02 Liver 0.95 ± 0.03 0.38 ± 0.08 Lung 2.80 ± 0.13 0.23 ± 0.03 Kidney 7.32 ± 0.90 2.98 ± 0.74 Spleen 0.70 ± 0.02 0.17 ± 0.03 Bone 1.10 ± 0.07 0.18 ± 0.03 Muscle 0.68 ± 0.05 0.10 ± 0.02 Small intestine 1.38 ± 0.20 0.31 ± 0.07 Tumor 2.80 ± 0.04 0.95 ± 0.21 Blood 2.42 ± 0.16 0.10 ± 0.04 Thyroid (%ID/g) 0.02 ± 0.00 0.003 ± 0.001 Tumor/muscle ratio 4.16 ± 0.35 9.69 ± 1.81 Tumor/blood ratio 1.16 ± 0.09 10.17 ± 1.95

TABLE-US-00005 Biodistribution of .sup.99mTc-4-CNMBDG in mice bearing S180 tumor (n=5, mean ± SD, % ID/g) 30 min 120 min Heart 2.67 ± 0.41 1.31 ± 0.18 Liver 3.00 ± 0.55 2.43 ± 0.49 Lung 5.89 ± 0.59 1.31 ± 0.44 Kidney 10.18 ± 1.28 7.37 ± 1.71 Spleen 2.24 ± 0.38 1.28 ± 0.34 Bone 3.05 ± 0.62 1.27 ± 0.35 Muscle 1.96 ± 0.50 0.86 ± 0.15 Small intestine 4.04 ± 0.87 1.65 ± 0.43 Tumor 6.46 ± 1.86 6.22 ± 1.77 Blood 4.08 ± 0.57 0.64 ± 0.22 Thyroid (%ID/g) 0.07 ± 0.01 0.03 ± 0.01 Tumor/muscle ratio 3.52 ± 1.35 7.14 ± 1.11 Tumor/blood ratio 1.57 ± 0.36 10.06 ± 1.54

TABLE-US-00006 Biodistribution of .sup.99mTc-3-CNBzDG in mice bearing S180 tumor (n=5, mean ± SD, % ID/g) 30 min 120 min Heart 1.44 ± 0.21 0.54 ± 0.07 Liver 1.38 ± 0.24 0.89 ± 0.09 Lung 4.00 ± 0.52 0.76 ± 0.20 Kidney 6.69 ± 0.68 4.49 ± 0.56 Spleen 1.06 ± 0.27 0.43 ± 0.17 Bone 1.44 ± 0.29 0.42 ± 0.03 Muscle 0.77 ± 0.06 0.24 ± 0.05 Small intestine 2.05 ± 0.29 0.70 ± 0.10 Tumor 2.51 ± 0.52 1.47 ± 0.22 Blood 2.53 ± 0.83 0.27 ± 0.02 Thyroid (%ID/g) 0.03 ± 0.01 0.01 ± 0.00 Tumor/muscle ratio 3.28 ± 0.66 6.16 ± 0.71 Tumor/blood ratio 1.04 ± 0.22 5.39 ± 0.79

TABLE-US-00007 In vivo biodistribution of .sup.99mTc-3-CNPEDG in mice bearing S180 tumor (n=5, mean ± SD, %ID/g) 30 min 120 min Heart 1.18 ± 0.12 0.23 ± 0.05 Liver 1.30 ± 0.06 0.68 ± 0.07 Lung 3.10 ± 0.22 0.42 ± 0.09 Kidney 9.69 ± 3.48 4.70 ± 0.81 Spleen 0.86 ± 0.09 0.25 ± 0.06 Bone 1.26 ± 0.23 0.30 ± 0.06 Muscle 0.82 ± 0.24 0.16 ± 0.04 Small intestine 2.19 ± 0.69 0.43 ± 0.11 Tumor 2.72 ± 0.36 1.35 ± 0.20 Blood 2.82 ± 0.30 0.22 ± 0.07 Thyroid (%ID/g) 0.04 ± 0.01 0.01 ± 0.00 Tumor/muscle ratio 3.49 ± 0.71 8.76 ± 1.14 Tumor/blood ratio 0.97 ± 0.07 6.40 ± 1.45

[0082] Referring to Tables 4-7, the results showed that the radioactive drugs provided in Examples 1-4 had good retention in tumors, and were rapidly metabolized in non-target organs. The tumor/muscle and tumor/blood ratios were higher at 120 min postinjection.

[0083] The radioactive drugs provided in Examples 1-4 were compared with the .sup.99mTc-CNPEDG in Comparative Example 1 and .sup.99mTc-(CN5DG).sub.6.sup.+ provided in Comparative Example 2 in terms of the biodistribution in tumor-bearing mice, and the results were shown in Table 8.

TABLE-US-00008 Comparison of Examples 1-4, and Comparative Examples 1-2 in terms of biodistribution in mice bearing S180 tumor (120 min p.i., %ID/g, mean ± SD) .sup.99mTc-4-CNPeDG .sup.99mTc-4-CNMBDG .sup.99mTc-3-CNBzDG Liver 0.38 ± 0.08 2.43 ± 0.49 0.89 ± 0.09 Lung 0.23 ± 0.03 1.31 ± 0.44 0.76 ± 0.20 Kidney 2.98 ± 0.74 7.37 ± 1.71 4.49 ± 0.56 Muscle 0.10 ± 0.02 0.86 ± 0.15 0.24 ± 0.05 Tumor 0.95 ± 0.21 6.22 ± 1.77 1.47 ± 0.22 Blood 0.10 ± 0.04 0.64 ± 0.22 0.27 ± 0.02 Tumor/muscle ratio 9.69 ± 1.81 7.14 ± 1.11 6.16 ± 0.71 Tumor/blood ratio 10.17 ± 1.95 10.06 ± 1.54 5.39 ± 0.79 .sup.99mTc-3-CNPEDG .sup.99mTc-CNPEDG .sup.99mTc-(CN5DG).sub.6.sup.+ Liver 0.68 ± 0.07 2.52 ± 0.26 0.34 ± 0.08 Lung 0.42 ± 0.09 2.39 ± 0.31 0.29 ± 0.06 Kidney 4.70 ± 0.81 7.56 ± 0.94 2.07 ± 0.13 Muscle 0.16 ± 0.04 0.82 ± 0.08 0.18 ± 0.03 Tumor 1.35 ± 0.20 4.25 ± 0.56 0.75 ± 0.07 Blood 0.22 ± 0.07 1.29 ± 0.16 0.16 ± 0.02 Tumor/muscle ratio 8.76 ± 1.14 5.21 ± 0.50 4.16 Tumor/blood ratio 6.40 ± 1.45 3.29 ± 0.12 4.69

[0084] Referring to the results shown in Table 7, the tumor uptake and target/non-target ratio of the radioactive drugs provided in Examples 1-4 were higher than those of 99mTc-(CN5DG).sub.6.sup.+. Although .sup.99mTc-4-CNPeDG, .sup.99mTc-3-CNBzDG, .sup.99mTc-3-CNPEDG had lower tumor uptake than .sup.99mTc-CNPEDG, but they had lower uptake and larger metabolic rate in non-target organs, leading to a better target/non-target ratio. It was worth noting that .sup.99mTc-4-CNMBDG had higher tumor uptake and faster clearance in blood, thereby greatly improving the tumor/blood ratio.

[0085] Additionally, it was found that compared with the p-substituted .sup.99mTc complexes (such as .sup.99mTc-4-CNBzDG and .sup.99mTc-4-CNPEDG), the m-substituted .sup.99mTc complexes (such as .sup.99mTc-3-CNBzDG and .sup.99mTc-3-CNPEDG) had higher tumor/muscle ratio, tumor/blood ratio and tumor/lung ratio (see Table 9).

TABLE-US-00009 Comparison of target/non-target ratios of .sup.99mTc-3-CNPEDG, .sup.99mTc-4-CNPEDG, .sup.99mTc-3-CNBzDG and .sup.99mTc-4-CNBzDG (120 min p.i., mean ± SD) .sup.99mTc-3- CNPEDG .sup.99mTc-4- CNPEDG .sup.99mTc-3- CNBzDG .sup.99mTc-4- CNBzDG R.sub.1 Meta-position Para-position Meta-position Para-position Tumor/muscle ratio 8.76 ± 1.14 5.21 ± 0.50 6.16 ± 0.71 2.34 ± 0.18 Tumor/blood ratio 6.40 ± 1.45 3.29 ± 0.12 5.39 ± 0.79 0.47 ± 0.02 Tumor/lung ratio 3.26 ± 0.37 1.81 ± 0.30 2.01 ± 0.35 0.49 ± 0.02 Note: the difference between .sup.99mTc-4-CNPEDG and .sup.99mTc-3-CNPEDG was only in the R.sub.1 substitution site, and so was the difference between .sup.99mTc-4-CNBzDG and .sup.99mTc-3-CNBzDG.

[0086] Described above are merely preferred embodiments of the application, which are not intended to limit the application. Although the disclosure has been described in detail above, those skilled in the art can still make various variations, modifications and replacements to the embodiments provided herein. It should be understood that any modifications or improvements made by those skilled in the art without departing from the spirit of the application shall fall within the scope of the present application defined by the appended claims.