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

Patent metadata

Field	Value
Publication number	US-9682927-B2
Application number	US-201615170848-A
Country	US
Kind code	B2
Filing date	Jun 1, 2016
Priority date	May 11, 2010
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

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 18 F. 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.

First claim

The invention claimed is:

1. A method, comprising:
reacting a compound comprising formula (II):

or a salt, free base, or combination thereof, under suitable conditions comprising exposing the compound of formula (II) to an acid to form a compound comprising formula (IV):

or a salt, free base, or combination thereof, wherein:
R 1 is alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, heterocyclyl, or haloalkyl, each optionally substituted;
each R 2 can be the same or different and is hydrogen or a nitrogen-protecting group, provided at least one R 2 is not hydrogen;
R 3 , R 4 , R 5 , and R 6 can be the same or different and are individually hydrogen, C 1 -C 6 alkyl, heteroalkyl, halide, —OR 7 , —SR 7 , —N(R 7 ) 2 , or —C(═O)R 8 , each optionally substituted;
each R 7 can be the same or different and is hydrogen, alkyl, heteroalkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted;
each R 8 can be the same or different and is hydrogen, alkyl, heteroalkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl, heteroaryl, —OH, alkoxy, —NH 2 , alkylamino, —SH, or alkylthiol, each optionally substituted;
m is an integer between 1 and 12, inclusive; and
n is an integer between 1 and 4, inclusive.

2. A method, comprising:
reacting a compound comprising formula (IV):

or a salt, free base, or combination thereof, under suitable conditions suitable to form a compound comprising formula (V):

or a salt, free base, or combination thereof, wherein:
R 1 is alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, or haloalkyl, each optionally substituted;
R 3 , R 4 , R 5 , and R 6 can be the same or different and are individually hydrogen, C 1 -C 6 alkyl, heteroalkyl, halide, —OR 7 , —SR 7 , —N(R 7 ) 2 , or —C(═O)R 8 , each optionally substituted;
each R 7 can be the same or different and is hydrogen, alkyl, heteroalkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted;
each R 8 can be the same or different and is hydrogen, alkyl, heteroalkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl, heteroaryl, —OH, alkoxy, —NH 2 , alkylamino, —SH, or alkylthiol, each optionally substituted;
m is an integer between 1 and 12, inclusive; and
n is an integer between 1 and 4, inclusive,
wherein the step of reacting comprises exposing a compound comprising formula (IV) to a source of fluoride, wherein the source of fluoride is isotopically enriched with 18 F.

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

wherein X ⊖ is a counter anion.

4. The method of claim 3 , wherein X ⊖ is halide, phosphate, sulfate, trifluoroacetate, tolunesulfonate, acetate, formate, citrate, ascorbate, mesylate (methanesulfonate), or benzoate.

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

or a salt, free base, or combination thereof.

6. The method of claim 5 , wherein at least one R 2 is t-butyloxycarbonyl.

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

or a salt, free base, or combination thereof.

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

or a salt, free base, or combination thereof.

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

10. The method of claim 2 , wherein R 1 is:
(a) C 1 -C 6 alkyl, haloalkyl, or aryl;
(b) methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, or hexyl;
(c) haloalkyl;
(d) CF 3 ;
(e) phenyl, optionally substituted; or
(f) 4-CH 3 C 6 H 4 , 2,4,6-(CH 3 ) 3 C 6 H 2 , or C 6 H 4 X, wherein X is halide.

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.

12. A method, comprising:
reacting a compound comprising formula (IV):

or a salt, free base, or combination thereof, under suitable conditions to form a compound comprising formula (V):

or a salt, free base, or combination thereof, wherein:
R 1 is alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, or haloalkyl, each optionally substituted;
R 3 , R 4 , R 5 , and R 6 can be the same or different and are individually hydrogen, C 1 -C 6 alkyl, heteroalkyl, halide, —OR 7 , —SR 7 , —N(R 7 ) 2 , or —C(═O)R 8 , each optionally substituted;
each R 7 can be the same or different and is hydrogen, alkyl, heteroalkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted;
each R 8 can be the same or different and is hydrogen, alkyl, heteroalkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl, heteroaryl, —OH, alkoxy, —NH 2 , alkylamino, —SH, or alkylthiol, each optionally substituted;
m is an integer between 1 and 12, inclusive; and
n is an integer between 1 and 4, inclusive,
wherein the compound comprising formula (IV) is provided as a solution in a solvent.

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.

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

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

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 18 F.

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.

Assignees

• Lantheus Medical Imaging Inc

Inventors

• Purohit Ajay
• Benites Pedro
• Cheesman Edward H
• Cesati Richard R
• Looby Richard J
• Radeke Heike S

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07C309/66

  Methanesulfonates · CPC title

• C07C279/10

  being further substituted by doubly-bound oxygen atoms · CPC title

• C07C309/65

  of a saturated carbon skeleton · CPC title