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New synthetic method of PET imaging agent L-5-<18>FETP

A reaction, hydroxytryptophan technology, applied in the field of medical imaging agents, can solve problems such as inability to use clinically, inability to effectively distinguish tumor lesions from normal tissues, and short half-life

Inactive Publication Date: 2010-02-17
PEKING UNION MEDICAL COLLEGE HOSPITAL CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the half-lives of positron radionuclides used in medicine are extremely short (such as 11 C, 20min; 15 O, 2min; 13 N, 10min; 18 F, 110min), need cyclotron production
2-[ 18 F]-fluoride ion substituted deoxyglucose ([ 18 F]FDG) is currently the most commonly used glucose metabolism imaging agent for PET, but it still has many shortcomings such as the inability to effectively distinguish tumor lesions from normal tissues in brain tissue and pelvic cavity.
[0007] However, the inventors found that the method reported in the above literature has defects such as low yield of final product and cannot be used clinically.

Method used

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  • New synthetic method of PET imaging agent L-5-&lt;18&gt;FETP
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  • New synthetic method of PET imaging agent L-5-&lt;18&gt;FETP

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1: Non-radioactive labeling

[0109] Cold test standard O-(2-[ 19 F]-fluoroethyl)-L-5-hydroxytryptophan (L-5- 19 FETP) preparation

[0110] Step 1: Preparation of 1,2-ethylene glycol p-toluenesulfonate

[0111]

[0112] Add 6.2g (0.1mol) of ethylene glycol and 32mL of anhydrous pyridine into a 100mL three-necked round-bottomed flask, and cool to below 0°C in an ice-salt bath. Add 38.2g (0.2mol) of p-toluenesulfonyl chloride in batches under stirring. During the whole reaction process, continuously suck out the ice water in the ice-salt bath and put in new ice cubes to ensure that the reaction temperature remains below 0°C. When the portionwise addition of p-toluenesulfonyl chloride was complete, the reaction was continued (temperature less than 5°C) for 6 hours with constant stirring. After the reaction, the reaction mixture was poured into ice water, and a white solid was precipitated, filtered, washed with water, and dried to obtain 20.2 g o...

Embodiment 2

[0140] Embodiment 2: Optimization of thermal reaction test conditions

[0141]In order to make the reaction complete under the existing conditions, obtain higher radiochemical yields, and have better reproducibility, the present invention respectively adjusts the reaction conditions such as: the preparation of the stock solution, the temperature of the reaction, the speed of ventilation, the reaction The acidity and alkalinity of the solution, the reaction time and the concentration of the reaction solution were investigated.

[0142] 1: Preparation of stock solution

[0143] stock solution (acetonitrile / H 2 O / K 2 CO 3 / K 2.2.2 ), the stock solution is used to [ 18 F]F - It is eluted from the QMA resin column, then evaporated to remove water, and undergoes a nucleophilic reaction with the reaction precursor. According to literature reports, the proportion of water in the stock solution is within a relatively large range. In the fluorine nucleophilic substitution re...

Embodiment 3

[0164] Example 3: Radiolabeling

[0165] Thermal experiment target product O-(2-[ 18 F]-fluoroethyl)-L-5-hydroxytryptophan (L-5- 18 FETP) preparation of

[0166] 1：[ 18 F] Modification of FDG Computer Controlled Chemical Synthesis Unit (CPCU)

[0167] The original laboratory [ 18 F] FDG computer-controlled chemical synthesis module (CPCU) is produced by Simens / CTI for [ 18 F] FDG double-tube method is used for synthesis, the automatic synthesis program is limited and cannot be changed, and there are only 6 sample bottles for use in the device, so it is limited to be used for the synthesis of other and [ 18 F] Imaging agents with different FDG synthesis methods or steps. Used in the present invention to synthesize L-5- 18 The two methods of FETP (single-tube method and double-tube method) are relatively [ 18 F]FDG is more complicated, so it must be modified according to the needs, that is, add a syringe and a pipeline as a sample bottle, and add a small sol...

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Abstract

The invention relates to a new synthetic method of a PET imaging agent L-5-<18>FETP. The method comprises the following steps: (a) carrying out a reaction between 5-hydroxytryptophan and C<1-3>alkylolto obtain a product; carrying out a reaction between the product and di-tert-butyl (i.e. (BOC)2O) to obtain N-BOC-L-5-hydroxytryptophan; (b) fluorizating 1,2-glycol tosylate in the presence of the ions such as potassium carbonate, Kryptate2.2.2 and <18>F<-> to obtain 2-<18F>-fluoroethanol p-toluene sulphonic acid ester (i.e. <18>FCH2CH2OTs); (c) carrying out a reaction between the 2-<18F>-fluoroethanol p-toluene sulphonic acid ester and the alkali metal salt of the N-BOC-L-5-hydroxytryptophan (such as sodium salt) to obtain O-(2-<18F>fluoroethyl)-N-BOC-L-5-hydroxytryptophan; (d) hydrolyzing the O-(2-<18F>fluoroethyl)-N-BOC-L-5-hydroxytryptophan under acidic conditions to remove an amino group and a carboxy protective group and obtain a final product of O-(2-<18F>fluoroethyl)-N-BOC-L-5-hydroxy tryptophan; and (e) purifying the product. The method greatly improves the radiochemical yield, obtains a sufficient quantity of a target product and realizes the clinical application of the target product.

Description

technical field [0001] The invention relates to the field of medical imaging agents. More specifically, it concerns a PET imaging agent L-5- 18 A new synthetic method of FETP, and the L-5- 18 FETP. Background technique [0002] Cancer is one of the leading causes of human death. To prolong the lives of patients with malignant tumors, early detection, early diagnosis and early treatment of cancer must be achieved. Currently the most advanced medical device for cancer diagnosis is positron emission tomography (PET). PET can quantitatively measure the radioactive concentration of positron-emitting nuclides in local tissues. At present, the half-lives of positron radionuclides used in medicine are extremely short (such as 11 C, 20min; 15 O, 2min; 13 N, 10min; 18 F, 110min), need cyclotron production. 2-[ 18 F]-fluoride ion substituted deoxyglucose ([ 18 F]FDG) is currently the most commonly used glucose metabolism imaging agent for PET, but it still has many shortcom...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/20A61K51/04A61K101/02
CPCY02P20/55
Inventor 王世真李瑞芬李方
Owner PEKING UNION MEDICAL COLLEGE HOSPITAL CHINESE ACAD OF MEDICAL SCI
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