.SUP.99m.Tc-labeled isonitrile-containing glucose derivative and preparation method and use thereof

Abstract

A .sup.99mTc-labeled isonitrile-containing glucose derivative having the general formula [.sup.99mTc-(CNDG).sub.6].sup.+, preparation method and use thereof is disclosed herein. The derivative is centered on .sup.99mTc.sup.+, and the carbon atom of the isonitrile in CNDG coordinates with .sup.99mTc(I) to form a hexacoordinated complex [.sup.99mTc-(CNDG).sub.6].sup.+. The [.sup.99mTc-(CNDG).sub.6].sup.+ derivative was obtained by the synthesis of the ligand CNDG and the preparation of the lyophilized CNDG kit. The derivative of this disclosure has good stability, simple preparation, high uptake and good retention at a tumor site, and high tumor/non-target ratio, and it is a novel .sup.99mTc-labeled isonitrile-containing glucose derivative with excellent performance for tumor imaging. The derivative of this disclosure is advantageous for popularization and application.

Claims

1. A .sup.99mTc-labeled isonitrile-containing glucose derivative having a structural formula (I) of [.sup.99mTc-(CNDG).sub.6].sup.+, wherein structural formula (I) is shown as follows: ##STR00005## wherein, in the structural formula, a .sup.99mTc.sup.+ core is taken as the central nucleus (I), the carbon atom of isonitrile in the CNDG coordinates with .sup.99mTc(I) to form a hexacoordinated complex [.sup.99mTc-(CNDG).sub.6].sup.+, and n is an integer greater than two (2).

2. A method of preparing a .sup.99mTc-labeled isonitrile-containing glucose derivative (“CNDG”) having a structural formula (I) of [.sup.99mTc-(CNDG).sub.6].sup.+, wherein formula (I) is as follows: ##STR00006## wherein, in the structural formula (I), a .sup.99mTc.sup.+ core is a central nucleus, the carbon atom of isonitrile in the CNDG coordinates with .sup.99mTc(I) to form a hexacoordinated complex [.sup.99mTc-(CNDG).sub.6].sup.+, and n is an integer greater than two (2), the method comprising: (a) synthesizing a CNDG ligand by a method comprising: weighing an appropriate amount of glucosamine hydrochloride; adding anhydrous methanol to dissolve glucosamine hydrochloride to produce a methanol solution; adding an appropriate amount of NaOH; allowing a reaction between NaOH and glucosamine hydrochloride to proceed at room temperature for about 30 minutes; placing the reaction in an ice water bath; adding a methanol solution comprising a compound of structural formula (II) dropwise to the reaction in the ice water bath for three hours after addition is completed to produce the CNDG ligand, the compound of the structural formula (II) as follows: ##STR00007## wherein n is an integer greater than two (2); and removing the solvent from the CNDG ligand upon completion of the reaction; (b) producing a solution of CNDG ligand, SnCl.sub.2.2H.sub.2O and sodium citrate dissolved in redistilled water, wherein a pH of the solution is adjusted to a pH from 5 to 6 after dissolution, wherein an appropriate volume of the solution is dispensed into a receptacle; (c) lyophilizing the solution in the receptacle to produce a lyophilized CNDG kit; (d) adding freshly washed Na.sup.99mTcO.sub.4 to the lyophilized CNDG kit; and (e) heating the solution containing the CNDG kit contents and Na.sup.99mTcO.sub.4 to produce the [.sup.99mTc-(CNDG).sub.6].sup.+.

Description

DETAILED DESCRIPTION

(1) This disclosure will be described in detail below by way of Examples: .sup.99mTc-labeled isonitrile-containing glucose derivatives having the structural formula of [.sup.99mTc-(CNDG).sub.6].sup.+, which are prepared by the following steps:

(2) a: synthesis of the ligand CNDG:

(3) An appropriate amount of glucosamine hydrochloride was weighed in a 25 mL round bottom flask. Anhydrous methanol was added for dissolving. Then, an appropriate amount of NaOH was added, and the reaction was performed at room temperature while stirring for 30 minutes. Then, the reaction flask was placed in an ice-water bath. An appropriate amount of a methanol solution of compound (II) was slowly dropwise added while stirring. The reaction continued in ice-water bath for 3 hours after dropwise addition was completed. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residues were purified by column chromatography (dichloromethane-methanol) to obtain the ligand CNDG.

(4) The specific synthetic route was as follows:

(5) ##STR00004##

(6) b: preparation of the complex [.sup.99mTc-(CNDG).sub.6].sup.+, the specific preparation steps were as follows:

(7) 1. Synthesis of CN2DG

(8) Ninety-one mg (0.423 mmol) of glucosamine hydrochloride was weighed in a 25 mL round bottom flask. Three ml of anhydrous methanol was added for dissolving, then 17 mg (0.423 mmol) of NaOH was added. The reaction was performed at room temperature while stirring for 30 minutes. Then, the reaction flask was placed in an ice-water bath. One ml of a methanol solution containing 114 mg (0.466 mmol) of the compound II (n=2) was slowly dropwise added while stirring. The reaction continued in an ice-water bath for 3 hours after dropwise addition was completed. After the reaction was completed, the solvent methanol was distilled off under reduced pressure, and the residual solid was separated and purified with a silica gel column (dichloromethane:methanol=5:1) and dried to obtain the product CN2DG, 83 mg, 75% yield. .sup.1H-NMR (400 MHz, D.sub.2O): δ (ppm) 3.65-3.89 (m, 7H), 3.34-3.44 (m, 2H), 2.65 (t, 2H). HRMS Calculated for, C.sub.10H.sub.16N.sub.2O.sub.6Na [M+Na].sup.+283.0911, found 283.0906. IR (KBr)/cm.sup.−1: 3303.24 (—OH), 2933.85, 2149.76 (—NC), 1647.28 (—C═O), 1560.48, 1303.03, 586.39.

(9) 2. Synthesis of CN3DG

(10) One hundred seventeen mg (0.544 mmol) of glucosamine hydrochloride was weighed in a 25 mL round bottom flask. Three ml of anhydrous methanol was added for dissolving, then 22 mg (0.544 mmol) of NaOH was added. The reaction was performed at room temperature while stirring for 30 minutes. Then, the reaction flask was placed in an ice-water bath. One ml of a methanol solution containing 156 mg (0.598 mmol) of the compound II (n=3) was slowly dropwise added while stirring. The reaction continued in an ice-water bath for 3 hours after dropwise addition was completed. After the reaction was completed, the solvent methanol was distilled off under reduced pressure, and the residual solid was separated and purified with a silica gel column (dichloromethane:methanol=5:1) and dried to obtain the product CN3DG, 85 mg, 57% yield. .sup.1H-NMR (400 MHz, D.sub.2O): δ (ppm) 3.65-3.85 (m, 5H), 3.42-3.49 (m, 4H), 2.37-2.42 (m, 2H), 2.19 (t, 2H). HRMS Calculated for C.sub.11H.sub.18N.sub.2O.sub.6Na [M+Na].sup.+, 297.1057, found, 297.1052. IR (KBr)/cm.sup.−1: 3299.38 (—OH), 2932.89, 2149.76 (—NC), 1647.28 (—C═O), 1558.55, 1303.03, 588.31.

(11) 3. Synthesis of CN4DG

(12) One hundred twenty-nine mg (0.600 mmol) of glucosamine hydrochloride was weighed in a 25 mL round bottom flask. Three ml of anhydrous methanol was added for dissolving, then 24 mg (0.600 mmol) of NaOH was added. The reaction was performed at room temperature while stirring for 30 minutes. Then, the reaction flask was placed in an ice-water bath, 1 ml of a methanol solution containing 182 mg (0.660 mmol) of the compound II (n=4) was slowly dropwise added while stirring. The reaction continued in the ice-water bath for 3 hours after dropwise addition was completed. After the reaction was completed, the solvent methanol was distilled off under reduced pressure, and the residual solid was separated and purified with a silica gel column (dichloromethane:methanol=5:1) and dried to obtain the product CN4DG, 108 mg, 63% yield. .sup.1H-NMR (400 MHz, D.sub.2O): δ (ppm) 3.65-3.89 (m, 5H), 3.38-3.44 (m, 4H), 2.28 (t, 2H), 1.60-1.75 (m, 4H). HRMS Calculated for C.sub.12H.sub.21N.sub.2O.sub.6 [M+H].sup.+, 289.1394, found 289.1396. IR (KBr)/cm.sup.−1: 3295.52 (—OH), 2943.50, 2150.72 (—NC), 1645.35 (—C═O), 1542.15, 1093.69, 1033.89, 599.89.

(13) 4. Synthesis of CN5DG

(14) One hundred forty-seven mg (0.684 mmol) of glucosamine hydrochloride was weighed in a 25 mL round bottom flask. Three ml of anhydrous methanol was added for dissolving, then 27 mg (0.684 mmol) of NaOH was added. The reaction was performed at room temperature while stirring for 30 minutes. Then, the reaction flask was placed in an ice-water bath, 1 ml of a methanol solution containing 217 mg (0.752 mmol) of the compound II (n=5) was slowly dropwise added while stirring. The reaction continued in the ice-water bath for 3 hours after dropwise addition was completed. After the reaction was completed, the solvent methanol was distilled off under reduced pressure, and the residual solid was separated and purified with a silica gel column (dichloromethane:methanol=5:1) and dried to obtain the product CN5DG 161 mg, yield 78%. .sup.1H-NMR (400 MHz, D.sub.2O): δ (ppm) 3.74-3.82 (m, 3H), 3.63-3.70 (m, 2H), 3.34-3.40 (m, 4H), 2.24 (q, 2H), 1.53-1.59 (m, 4H), 1.33-1.38 (m, 2H). HRMS Calculated for C.sub.13H.sub.22N.sub.2O.sub.6Na [M+Na].sup.+, 325.1374, found 325.1370. IR (KBr)/cm.sup.−1: 3294.56 (—OH), 2941.57, 2148.79 (—NC), 1645.35 (—C═O), 1538.30, 1093.69, 1032.93, 590.85.

(15) 5. Synthesis of [.sup.99mTc-(CN2DG).sub.6].sup.+, [.sup.99mTc-(CN3DG).sub.6].sup.+, [.sup.99mTc-(CN4DG).sub.6].sup.+ and [.sup.99mTc-(CN5DG).sub.6].sup.+

(16) Preparation of lyophilized CN2DG kit: CN2DG, SnCl.sub.2.2H.sub.2O and sodium citrate were dissolved in an appropriate amount of redistilled water, and pH of the solution was adjusted to 5 to 6. Then, the resultant solution was dispensed into clean penicillin vials in an amount of 1 mL after full dissolution, each vial containing 1.0 mg of CN2DG, 0.03 mg of SnCl.sub.2.2H.sub.2O and an appropriate amount of sodium citrate. The kit was ready for use after lyophilization.

(17) One to 5 mL of freshly washed Na.sup.99mTcO.sub.4 was added to the lyophilized CN2DG kit, shaken well, and heated in a boiling water bath for 20 minutes after the solid was completely dissolved, resulting in the complex [.sup.99mTc-(CN2DG).sub.6].sup.+.

(18) Preparation of lyophilized CN3DG kit: CN3DG, SnCl.sub.2.2H.sub.2O and sodium citrate were dissolved in an appropriate amount of redistilled water, and pH of the solution was adjusted to 5 to 6. Then, the resultant solution was dispensed into clean penicillin vials in an amount of 1 mL after full dissolution, each vial containing 1.0 mg of CN3DG, 0.03 mg of SnCl.sub.2.2H.sub.2O and an appropriate amount of sodium citrate. The kit was ready for use after lyophilization.

(19) One to 5 mL of freshly washed Na.sup.99mTcO.sub.4 was added to the lyophilized CN3DG kit, shaken well, and heated in a boiling water bath for 20 minutes after the solid was completely dissolved, resulting in the complex [.sup.99mTc-(CN3DG).sub.6].sup.+.

(20) Preparation of lyophilized CN4DG kit: CN4DG, SnCl.sub.2.2H.sub.2O and sodium citrate were dissolved in an appropriate amount of redistilled water, and pH of the solution was adjusted to 5 to 6. Then, the resultant solution was dispensed into clean penicillin vials in an amount of 1 mL after full dissolution, each vial containing 1.0 mg of CN4DG, 0.03 mg of SnCl.sub.2.2H.sub.2O and an appropriate amount of sodium citrate. The kit was ready for use after lyophilization.

(21) One to 5 mL of freshly washed Na.sup.99mTcO.sub.4 was added to the lyophilized CN4DG kit, shaken well, and heated in a boiling water bath for 20 minutes after the solid was completely dissolved, resulting in the complex [.sup.99mTc-(CN4DG).sub.6].sup.+.

(22) Preparation of lyophilized CN5DG kit: CN5DG, SnCl.sub.2.2H.sub.2O and sodium citrate were dissolved in an appropriate amount of redistilled water, and pH of the solution was adjusted to 5 to 6. Then, the resultant solution was dispensed into clean penicillin vials in an amount of 1 mL after full dissolution, each vial containing 1.0 mg of CN5DG, 0.03 mg of SnCl.sub.2.2H.sub.2O and an appropriate amount of sodium citrate. The kit was ready for use after lyophilization.

(23) One to 5 mL of freshly washed Na.sup.99mTcO.sub.4 was added to the lyophilized CN5DG kit, shaken well, and heated in a boiling water bath for 20 minutes after the solid was completely dissolved, resulting in the complex [.sup.99mTc-(CN5DG).sub.6].sup.+.

(24) Use of the .sup.99mTc-labeled isonitrile-containing glucose derivative as described above as a tumor imaging agent in the field of nuclear medicine.

(25) The above-described Examples are merely illustrative of the disclosure, but not intended to limit the scope of the disclosure.

INDUSTRIAL APPLICABILITY

(26) This disclosure provides a .sup.99mTc labeled isonitrile-containing glucose derivative having the general formula of [.sup.99mTc-(CNDG).sub.6].sup.+, preparation method and use thereof. This derivative is centered on .sup.99mTc.sup.+, and the carbon atom of isonitrile in CNDG coordinates with .sup.99mTc(I) to form a hexacoordinated complex [.sup.99mTc-(CNDG).sub.6].sup.+. The derivative provided by this disclosure has good stability, simple preparation, high uptake and good retention at tumor sites, and high tumor/non-target ratio, and it is a novel .sup.99mTc labeled isonitrile-containing glucose derivative with excellent performance for tumor imaging. The derivative provided by this disclosure is advantageous for popularization and application, and has high economic value and good application prospects.