Method of labeling complex metal chelates with radioactive metal isotopes

• US 3,936,440 A
• Filed: 05/22/1974
• Issued: 02/03/1976
• Est. Priority Date: 05/22/1974
• Status: Expired due to Term

• Current Assignee: Drexel University
• Original Assignee: Drexel University
• Inventors: Nath, Amar
• Primary Examiner(s): Brown, Johnnie R.
• Assistant Examiner(s): Owens, Cary B.
• Application Number:
  US05/472,305
• Time in Patent Office: 622 Days
• Field of Search: 260/211.7, 424/1
• US Class Current: 536/26.41
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds

Abstract

A method is provided for labeling a complex metal chelate with a radioactive metal isotope via isotopic exchange between the metal atom of the complex metal chelate and the radioactive metal isotope. The complex metal chelate, in a suitable redox state, is mixed in solution with a radioactive metal isotope, freeze-dried, exposed to an electron-accepting gas and thereafter subjected to thermal treatment, whereby isotopic exchange occurs and the complex metal chelate is labeled with the radioactive metal isotope. Furthermore, an additional step comprising exposure to an atmosphere of high relative humidity is provided to increase the yield of isotopic exchange.

Claims

1. A method of labeling a complex metal chelate compound with a radioactive metal isotope, comprising the steps of;

a. providing a radioactive metal isotope dopant and a complex metal chelate compound in solution;

then

b. removing solvent from said solution of radioactive metal dopant and complex metal chelate compound, whereby a solid mixture of said radioactive metal isotope dopant and complex metal chelate compound is formed;

then

c. exposing said mixture to an electron-accepting gas; and

then

d. subjecting said mixture in the presence of said electron-accepting gas to thermal treatment, whereby isotopic exchange between said radioactive metal isotope dopant and said complex metal chelate compound occurs and said complex metal chelate compound labeled with said radioactive metal isotope is produced.

2. The method of claim 1, wherein said complex metal chelate compound is provided in a reduced redox state and wherein said method further includes the additional step of converting the reduced complex metal chelate compound labeled with said radioactive isotope to a higher redox state.

3. The method of claim 1, furthermore including the additional step after thermal treatment, said of exposing said mixture to an atmosphere of high relative humidity, whereby the yield of said isotopic exchange is increased.

4. The method of claim 3, wherein said mixture is exposed to said atmosphere of high relative humidity at a temperature of about 35°

C for a period of about 24 hours.

5. The method of claim 3, wherein said high relative humidity is about 95%.

6. The method of claim 1, wherein said electron-accepting gas is selected from the group consisting of oxygen, nitrous oxide, carbon dioxide and sulfur hexafluoride.

7. The method of claim 1, wherein said thermal treatment consists essentially of heating said mixture to a temperature of between 100°

-300°

C for a period of between 24-96 hours.

8. The method of claim 7, wherein said temperature is 150°

C and said period is 24 hours.

9. The method of claim 1, wherein said complex metal chelate compound is selected from the group consisting of cobaltocene, cyanocobalamin, aquocabalamin, porphyrins, and phthalocyanines.

10. The method of claim 1, wherein said radioactive metal isotope dopant is a radioactive cobalt isotope dopant.

11. The method of claim 10, wherein said radioactive isotope of cobalt is selected from the group consisting of ⁵⁷ Co.sup.⁺² and ⁶⁰ Co.sup.⁺².

12. The method of claim 10, wherein said reduced complex cobalt chelate compound is formed by exposure of said complex cobalt chelate compound to hydrogen in the presence of PtO₂ catalyst in aqueous solution.

13. The method of claim 10, including the additional step of purifying said reduced complex cobalt chelate compound labeled with said radioactive isotope of cobalt.

14. The method of claim 13, wherein said purifying step comprises the steps of:

a. providing a solution of said labeled reduced cobalt chelate compound in water;

b. adding a trace amount of cobalt chloride hexahydrate to said solution;

c. passing the solution of step (b), above, through a column containing a suitable Co.sup.⁺² ion exchange resin; and

d. withdrawing the effluent from said column, said effluent containing a purified derivative of said labeled cobalt chelate compound which is substantially free of Cobalt (+2) ions.

15. A method of synthesis of Vitamin B₁₂ containing a radioactive isotope of cobalt, comprising the steps of:

a. providing an aqueous solution containing reduced Vitamin B₁₂ and a radioactive cobalt isotope dopant, said reduced Vitamin B₁₂ having cobalt in the Co (II) redox state and said radioactive cobalt isotope dopant existing in the Co (+2) redox state in said solution;

then

b. freeze-drying said aqueous solution, whereby a solid mixture of said reduced Vitamin B₁₂ and said radioactive cobalt isotope dopant is formed;

then

c. exposing said solid mixture to oxygen gas;

then

d. subjecting said solid mixture in the presence of said oxygen gas to thermal treatment, whereby isotopic exchange occurs between cobalt in said reduced Vitamin B₁₂ and said radioactive cobalt isotope dopant and reduced Vitamin B₁₂ labeled with said radioactive isotope of cobalt is produced; and

then

e. converting said reduced Vitamin B₁₂ labeled with said radioactive isotope of cobalt to a higher redox state, whereby Vitamin B₁₂ containing said radioactive isotope of cobalt is produced.

16. The method of claim 15, wherein said radioactive isotope of cobalt is selected from the group consisting of ⁵⁷ Co.sup.⁺² and ⁶⁰ Co.sup.⁺².

17. The method of claim 15, including the additional step after said thermal treatment, of exposing said solid mixture to an atmosphere of about 95% relative humidity at a temperature of about 35°

C for at least 24 hours, whereby the yield of said isotopic exchange is increased.

18. The method of claim 15, wherein said reduced Vitamin B₁₂ is prepared from Vitamin B₁₂ by the steps of:

a. providing a reducing solution containing water and PtO₂ catalyst;

b. bubbling hydrogen gas through said reduced solution for at least 15 minutes;

then

c. adding said Vitamin B₁₂ to said reducing solution, whereby said Cobalt (III) in said Vitamin B₁₂ is reduced to the Cobalt (II) state and said reduced Vitamin B₁₂ is formed.

19. The method of claim 15, wherein said solid mixture is exposed to said oxygen at a pressure between about 40 to 200 mm Hg.

20. The method of claim 15, wherein said thermal treatment consists essentially of heating said solid mixture to a temperature of about 100°

-300°

C for a period of between 24-96 hours.

21. The method of claim 20, wherein said temperature is 150°

C and said period is 24 hours.

22. The method of claim 15, furthermore including the additional step of purifying Vitamin B₁₂ containing said radioactive isotope of cobalt by the steps of;

a. dissolving said Vitamin B₁₂ containing said radioactive isotope of cobalt in water, whereby a solution is formed;

then

b. adding 1-2 mg of cobalt chloride hexahydrate to said solution;

then

c. slowly passing said solution through an ionic exchange column, said column containing a suitable Co.sup.⁺² ion exchange resin;

then

d. withdrawing said effluent from said column, said effluent containing purified aquocobalamin containing said radioactive cobalt isotope; and

then

e. converting said purified aquocobalamin to said Vitamin B₁₂ containing said radioactive isotope of cobalt.

23. The method of claim 22, wherein said purified aquocobalamin is converted to said Vitamin B₁₂ containing said radioactive isotope of cobalt by the steps of;

a. adding potassium cyanide to said effluent containing said purified aquocobalamin, whereby dicyanocobalamin is formed; and

then

b. adjusting the pH of said effluent containing said dicyanocobalamin to about pH 4.0, whereby Vitamin B₁₂ containing said radioactive isotope of cobalt is formed.