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Use of buffers for radionuclide complexation

A technology of radionuclide and buffer, applied in the field of contrast agent composition, can solve problems such as damage and degradation of carrier chelate

Inactive Publication Date: 2012-02-01
GUERBET SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this microwave step also leads to constraints for the user and presents a risk of damage and / or degradation of the carrier chelate, pharmacological biocarriers are in fact often sensitive to this treatment, especially peptides , organic pharmacophores, vitamins and proteins

Method used

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  • Use of buffers for radionuclide complexation
  • Use of buffers for radionuclide complexation
  • Use of buffers for radionuclide complexation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0216] - illustrates the use of NOTA and PCTA chelates as well as folate and peptide biocarriers for the preparation of supported chelates (chelates + biocarriers) (emphasized that one skilled in the art can thus use many other biocarriers, many other linkers, and many other chelates to prepare similar compounds).

[0217] Example 1: Comparing complexation of buffers

[0218] These buffers were prepared at pH 4. They are obtained by mixing 0.1M weak acid with 0.1M weak base.

[0219] To illustrate (similar protocol used other chelates) the steps for NOTA and PCTA chelates are detailed:

[0220] 50mg of NOTA or PCTA (0.16mmol) was dissolved in 5ml of 0.1M buffer. Add 0.5ml of 0.5M 69 GaCl 3 (1.5eq) solution. The reaction medium is stirred at room temperature. Samples were taken periodically for 15 minutes and analyzed by LC / MS.

[0221] In the table below, "fully complexed" means that the chelate has successfully complexed gallium.

[0222] Positive results were obtai...

Embodiment 2

[0229] Embodiment 2: the synthesis of didenitrogen-NOTA:

[0230]

[0231] step 1:

[0232]K at 0.6g 2 CO 3 Dissolve 0.5 g of Intermediate 2 in 20 ml of CH in the presence of 3 CN. Will be in 20ml CH 3 A suspension of the brominated derivative (int.1) in CN was added. The reaction medium is maintained at reflux for 18 hours under argon and under vigorous magnetic stirring. After returning to ambient temperature, the reaction medium is filtered. The insoluble material was taken up in 20 ml of water, followed by filtration. The filtrate was evaporated under pressure. The resulting residue was absorbed in Et 2 O, and then filtered. 1.2 g of product are obtained. [M+H]+=423.16.

[0233] Step 2:

[0234] 0.6 g of the intermediate obtained in the previous step was suspended in 2.4 ml of ethanol. Dissolution was complete after adding 6 ml of 1M NaOH. The reaction medium is stirred at 70° C. for 1 hour and 30 minutes (1H30). After returning to ambient temperature,...

Embodiment 3

[0250] Example 3: Synthesis of folate-NOTA:

[0251] a) a compound of the formula:

[0252]

[0253] 20g (91.7mmol) of Boc 2 O dissolved in 40 ml of CH 2 Cl 2 middle. Add 22g (366.6mmol) dropwise in 200ml of CH 2 Cl 2 diaminoethane solution in . The reaction vials were mixed for 2 hours at room temperature. First, the product is purified by extraction with water. in Na 2 SO 4 The organic layer was dried and filtered. Then, with CH 2 Cl 2 It was purified by flash chromatography on silica gel with a gradient of methanol / methanol. 4 g of a yellow oil are obtained. m / z = 161 (ES+).

[0254] b) a compound of the formula:

[0255]

[0256] Dissolve 10.27g (24mmol) of Fmoc-Glu-OtBu in 300ml of CH 2 Cl 2 middle. 2.8 g of NHS and 4.98 g of DCC were introduced. After 45 minutes, the reaction mixture was filtered and CH dissolved in 50 ml was added dropwise 2 Cl 2 A solution of 3.869 g of the product obtained in a) in . After 2 hours at room temperature, th...

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Abstract

The present invention relates to a method for complexation of a chelate with a radionuclide, advantageously gallium, the complexation being carried out advantageously at ambient temperature without heating, by adding the radionuclide to the chelate in a buffer solution, the buffer of this solution comprising between two and five functions for coordination with the radionuclide, each coordination function being independently chosen from a carboxylic acid function and a hydroxyl function, on the condition that the buffer comprises at least one carboxylic acid function and at most two carboxylic acid functions. It also relates to the injectable solution obtained.

Description

technical field [0001] The present invention relates to improved compositions of contrast media and to methods for preparing such compositions. The present invention relates in particular to products for PET (Positron Emission Tomography) imaging, and in particular to products containing radionuclides, preferably Gallium 68, for PET imaging. Background technique [0002] Document WO 2007 / 042504 in the name of the applicant details the advantages of PET imaging especially with gallium-68 (Ga68), which is very advantageous because it does not require the use of very bulky and Expensive cyclotrons. Coupling of Ga68 produced by a small dedicated generator to an as yet unlabeled "supported chelate" (indiscriminately referred to in this application as a "cold kit"), a coordination reaction (complexation of the radionuclide by means of a cold box) provided Ga68-"radiolabeled supported chelate" (indiscriminately referred to in this application as "complexed supported chelate"), wh...

Claims

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Application Information

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IPC IPC(8): A61K51/00A61K103/34A61P43/00C07F5/00
CPCC07B59/00C07D255/02C07D239/84C07D403/12A61P43/00A61K51/00C07F5/00
Inventor M·波特C·梅金娜
Owner GUERBET SA
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