Compositions, methods, and systems for the synthesis and use of imaging agents

• US 9,682,927 B2
• Filed: 06/01/2016
• Issued: 06/20/2017
• Est. Priority Date: 05/11/2010
• Status: Active Grant

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Inventors: Purohit, Ajay, Benites, Pedro, Cheesman, Edward H., Cesati, Richard R., Looby, Richard J., Radeke, Heike S.
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): PERREIRA, MELISSA JEAN
• Application Number:
  US15/170,848
• Publication Number:
  US 20160362362A1
• Time in Patent Office: 384 Days
• Field of Search: None
• CPC Class Codes: A61K 51/00 Preparations containing radioactive substances for use in therapy or testing in vivo
• CPC Class Codes: A61K 51/04 Organic compounds
• CPC Class Codes: A61K 51/0406 Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 59/001 Acyclic or carbocyclic compounds
• CPC Class Codes: C07C 213/02 by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
• CPC Class Codes: C07C 217/58 with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
• CPC Class Codes: C07C 255/54 containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 277/00 Preparation of guanidine or its derivatives, i.e. compounds containing the group , the singly-bound nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 277/08 of substituted guanidines
• CPC Class Codes: C07C 279/08 being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 279/10 being further substituted by doubly-bound oxygen atoms
• CPC Class Codes: C07C 279/24 Y being a hetero atom
• CPC Class Codes: C07C 303/28 by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
• CPC Class Codes: C07C 303/30 by reactions not involving the formation of esterified sulfo groups
• CPC Class Codes: C07C 309/04 containing only one sulfo group
• CPC Class Codes: C07C 309/30 of six-membered aromatic rings substituted by alkyl groups
• CPC Class Codes: C07C 309/65 of a saturated carbon skeleton
• CPC Class Codes: C07C 309/66 : Methanesulfonates
• CPC Class Codes: C07C 309/73 : to carbon atoms of non-condensed six-membered aromatic rings
• CPC Class Codes: C07C 53/06 : Salts thereof
• CPC Class Codes: C07C 53/10 : Salts thereof
• CPC Class Codes: C07C 53/18 : containing fluorine
• CPC Class Codes: C07C 63/08 : Salts thereof
• CPC Class Codes: C07D 307/58 : One oxygen atom, e.g. butenolide

Abstract

The present invention generally relates to novel synthetic methods, systems, kits, salts, and precursors useful in medical imaging. In some embodiments, the present invention provides compositions comprising an imaging agent precursor, which may be formed using the synthetic methods described herein. An imaging agent may be converted to an imaging agent using the methods described herein. In some cases, the imaging agent is enriched in ¹⁸F. In some cases, an imaging agent including salt forms (e.g., ascorbate salt) may be used to image an area of interest in a subject, including, but not limited to, the heart, cardiovascular system, cardiac vessels, brain, and other organs.

Claims

1. A method, comprising:

reacting a compound comprising formula (II);

5. The method of claim 1, wherein the compound of formula (II) comprises a compound of formula:

6. The method of claim 5, wherein at least one R² is t-butyloxycarbonyl.

7. The method of claim 1, wherein the compound of formula (II) comprises the formula:

11. The method of claim 1, wherein the acid is hydrochloric acid, formic acid, sulfuric acid, benzoic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, phosphoric acid, or methanesulfonic acid.

16. The method of claim 1, wherein the suitable conditions comprise a solution pH equal to or less than 3.

2. A method, comprising:

reacting a compound comprising formula (IV);

3. The method of claim 2, wherein the compound of formula (IV) comprises a compound of formula (III):

4. The method of claim 3, wherein X^⊖

is halide, phosphate, sulfate, trifluoroacetate, tolunesulfonate, acetate, formate, citrate, ascorbate, mesylate (methanesulfonate), or benzoate.

8. The method of claim 2, wherein the compound of formula (IV) comprises the formula:

9. The method of claim 2, wherein m is 3.

10. The method of claim 2, wherein R¹ is:

(a) C₁-C₆ alkyl, haloalkyl, or aryl;

(b) methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, or hexyl;

(c) haloalkyl;

(d) CF₃;

(e) phenyl, optionally substituted;

or

(f) 4-CH₃C₆H₄, 2,4,6-(CH₃)₃C₆H₂, or C₆H₄X, wherein X is halide.

13. The method of claim 2, wherein the suitable conditions comprise reacting at or above room temperature.

14. The method of claim 2, wherein the suitable conditions comprise reacting at a temperature of about 110°

C. for a period of 20 minutes or less.

15. The method of claim 2, wherein the suitable conditions comprise a solution pH of between about 10 and about 13.

17. The method of claim 2, wherein the compound comprising formula (V) is isolated using column chromatography.

20. The method of claim 2, wherein the suitable conditions further comprise exposing a compound comprising formula (IV) to a source of fluoride in the presence of an ammonium salt or a bicarbonate salt.

21. The method of claim 20, wherein the molar ratio of ammonium salt or bicarbonate salt to the compound of formula (IV) is less than or equal to about 5:

1.

22. The method of claim 21, wherein the bicarbonate salt is a tetraalkylammonium bicarbonate.

23. The method of claim 21, wherein the ammonium salt or the bicarbonate salt comprises the formula:

R₄NHCO₃,

wherein R₄ is alkyl.

24. The method of claim 2, wherein the compound comprising formula (V) comprises a compound of formula:

25. The method of claim 2, wherein the compound comprising formula (V) comprises a compound of formula:

26. The method of claim 25, wherein X^⊖

is ascorbate.

27. The method of claim 25, wherein X^⊖

is formate.

12. A method, comprising:

reacting a compound comprising formula (IV);

18. The method of claim 12, wherein the step of reacting comprises exposing a compound comprising formula (IV) to a source of fluoride.

19. The method of claim 18, wherein the source of fluoride is isotopically enriched with ¹⁸F.

28. The method of claim 12, wherein the compound comprising formula (V) comprises a compound of formula: