Synthesis of 18F-labeled tracers in hydrous organic solvents

• US 9,023,316 B2
• Filed: 04/08/2011
• Issued: 05/05/2015
• Est. Priority Date: 04/08/2010
• Status: Active Grant

• Current Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Original Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Inventors: Gangadharmath, Umesh, Walsh, Joseph, Kolb, Hartmuth
• Primary Examiner(s): BLAND, LAYLA D
• Application Number:
  US13/634,708
• Publication Number:
  US 20130005956A1
• Time in Patent Office: 1,488 Days
• Field of Search: None
• US Class Current: 424/1.89
• CPC Class Codes: A61K 51/04 Organic compounds
• CPC Class Codes: A61K 51/0448 tropane or nortropane groups, e.g. cocaine
• CPC Class Codes: A61K 51/0453 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 51/0455 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 51/0459 having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
• CPC Class Codes: A61K 51/047 Benzodiazepines
• CPC Class Codes: A61K 51/0491 Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
• CPC Class Codes: B01D 15/363 Anion-exchange

Abstract

A method for synthesizing an ¹⁸F-labeled probe. The method includes a step of eluting an amount of ¹⁸F with a first solvent which includes a predetermined amount of water and at least one organic solvent. In this step, the ¹⁸F elutes as an ¹⁸F solution. The method also includes a step of using the ¹⁸F solution to perform ¹⁸F-labeling in the presence of at least one labeling reagent and at least one phase transfer catalyst so as to generate the ¹⁸F-labeled probe. In the method, there is no step of drying the ¹⁸F starting from a time when the eluting step is performed and ending at a time when the ¹⁸F-labeling step is performed.

Claims

1. A method for synthesizing an ¹⁸F-labeled probe the method comprising:

(1) eluting an amount of ¹⁸F with a first solvent comprising a predetermined amount of water and at least one organic polar aprotic solvent, but no organic erotic solvents, the ¹⁸F eluting as an ¹⁸F solution, the predetermined amount of water being in a range of about 0.1 vol % to about 5.0 vol %; and

(2) using the ¹⁸F solution to perform ¹⁸F-labeling in the presence of at least one labeling reagent and at least one phase transfer catalyst so as to generate the ¹⁸F-labeled probe;

wherein the at least one labeling reagent comprises K₂CO₃, KHCO₃, Cs₂CO₃, potassium mesylate, potassium oxylate, or tetrabutylammonium bicarbonate;

wherein the water content of the ¹⁸F solution during ¹⁸F-labeling is in a range of about 0.1 vol % to about 2.0 vol %; and

wherein there is no step of drying the ¹⁸F solution starting from a time when the eluting is performed and ending at a time when the ¹⁸F-labeling is performed.

2. The method of claim 1, wherein the first solvent further comprises the at least one labeling reagent and the at least one phase transfer catalyst.

3. The method of claim 1, wherein the ¹⁸F-labeling step includes combining the ¹⁸F solution with a probe precursor so as to arrive at an ¹⁸F-labeling solution with the total amount of water in a range of about 0.1 vol % to about 2.0 vol %.

4. The method of claim 3, wherein the ¹⁸F-labeling step further includes diluting at least one of the ¹⁸F solution and the probe precursor with an organic solvent so that, when the ¹⁸F solution and the probe precursor are combined, the total amount of water in the ¹⁸F-labeling solution is in the range of about 0.1 vol % to about 2.0 vol %.

5. The method of claim 1, wherein the at least one phase transfer catalyst is Kryptofix K222.

6. The method of claim 1;

wherein the polar aprotic solvent is selected from the group consisting of acetonitrile, tetrahydrofuran (“

THF”

), dimethylformamide (“

DMF”

), N methylpyrrolidone (“

NMP”

), and dioxane.

7. The method of claim 1, wherein the ¹⁸F-labeled probe generated is selected from the group consisting of ¹⁸F FDG, ¹⁸F HX4, ¹⁸F FLT, ¹⁸F MISO, ¹⁸F FAZA, ¹⁸F Fallypride, ¹⁸F FHBG, ¹⁸F FHPG, ¹⁸F-4-fluorobenzaldehyde, ¹⁸F-4-fluoroethylbenzoate, ¹⁸F-4-fluoromethyl benzoate, ¹⁸F-fluoroethylazide, and ¹⁸F-W372.

8. The method of claim 1;

wherein the ¹⁸F-labeled probe generated is ¹⁸F-VM4-037.

9. A method for synthesizing an ¹⁸F-labeled probe the method comprising:

(1) eluting an amount of ¹⁸F with a solution comprising;

(a) a first solvent comprising a predetermined amount of water and at least one organic aprotic solvent, but no organic protic solvents; and

(b) at least one labeling reagent comprising K₂CO₃, KHCO₃, Cs₂CO₃, potassium mesylate, potassium oxylate, or tetrabutylammonium bicarbonate; and

(c) at least one phase transfer catalyst;

the ¹⁸F eluting as an ¹⁸F solution, wherein a total amount of water in the ¹⁸F solution is in a range of about 0.1 vol % to about 5.0 vol %; and

(2) diluting the ¹⁸F solution with the organic solvent so as to provide an ¹⁸F-labeling solution having a total amount of water in the range of about 0.5 vol % to about 1.5 vol %;

(3) using the ¹⁸F solution to perform ¹⁸F-labeling so as to generate the ¹⁸F labeled probe;

wherein there is no step of drying the ¹⁸F solution starting from a time when the eluting is performed and ending at a time when the ¹⁸F-labeling is performed.

16. The method of claim 9, wherein the ¹⁸F-labeled probe is ¹⁸F FDG, ¹⁸F HX4, ¹⁸F FLT, ¹⁸F MISO, ¹⁸F FAZA, ¹⁸F Fallypride, ¹⁸F FHBG, ¹⁸F FHPG, ¹⁸F-4-fluorobenzaldehyde, 18F-4-fluoroethylbenzoate, ¹⁸F-4-fluoromethyl benzoate, ¹⁸F-fluoroethylazide, or ¹⁸F-W372.

10. A method for synthesizing an ¹⁸F-labeled probe the method comprising:

(1) eluting an amount of ¹⁸F with a solution comprising;

(a) a first solvent comprising a predetermined amount of water, no organic protic solvents, and at least one organic aprotic solvent, selected from acetonitrile, tetrahydrofuran (“

THF”

), dimethylformamide (“

DMF”

), N methylpyrrolidone (“

NMP”

), and dioxane; and

(b) at least one labeling reagent comprising K₂CO₃, KHCO₃, Cs₂CO₃, potassium mesylate, potassium oxylate, or tetrabutylammonium bicarbonate; and

(c) at least one phase transfer catalyst;

the ¹⁸F eluting as an ¹⁸F solution, wherein a total amount of water in the ¹⁸F solution is in a range of about 0.1 vol % to about 5.0 vol %;

(2) diluting the ¹⁸F solution with the organic solvent so as to provide an ¹⁸F-labeling solution having a total amount of water in the range of about 0.1 vol % to about 2.0 vol %;

(3) using the ¹⁸F solution to perform ¹⁸F-labeling so as to generate the ¹⁸F labeled probe; and

wherein there is no step of drying the ¹⁸F starting from a time when the eluting is performed and ending at a time when the ¹⁸F-labeling is performed.

11. The method of claim 10, wherein a total amount of water in the ¹⁸F solution is in a range of about 0.5 vol % to about 1.5 vol %.

12. The method of claim 10, wherein the ¹⁸F-labeling further includes diluting at least one of the ¹⁸F solution and the probe precursor with an organic solvent so that, when the ¹⁸F solution and the probe precursor are combined, the ¹⁸F-labeling solution has the total amount of water in the range of about 0.1 vol % to about 2.0 vol %.

13. The method of claim 10, wherein the at least one phase transfer catalyst is Kryptofix K222.

14. The method of claim 10, wherein the ¹⁸F-labeled probe is ¹⁸F FDG, ¹⁸F HX4, ¹⁸F FLT, ¹⁸F MISO, ¹⁸F FAZA, ¹⁸F Fallypride, ¹⁸F FHBG, ¹⁸F FHPG, ¹⁸F-4-fluorobenzaldehyde, 18F-4-fluoroethylbenzoate, ¹⁸F-4-fluoromethyl benzoate, ¹⁸F-fluoroethylazide, or ¹⁸F-W372.

15. The method of claim 10, wherein the ¹⁸F-labeled probe is ¹⁸F-VM4-037.