Catalytic radiofluorination

Patent metadata

Field	Value
Publication number	US-10058625-B2
Application number	US-201514695176-A
Country	US
Kind code	B2
Filing date	Apr 24, 2015
Priority date	Feb 24, 2004
Publication date	Aug 28, 2018
Grant date	Aug 28, 2018

Abstract

One aspect of the present invention relates to a method of preparing radiofluorinated substituted alkyl, cycloalkyl, aryl, and alkenyl compounds. In a preferred embodiment, potassium fluoride-18 is used. Another aspect of the invention relates to piperazine compounds containing fluorine-18 that are useful as imaging agents. In certain embodiments, the piperazine compounds contain a quaternary amine. Another aspect of the invention relates to arylphosphonium compounds containing fluorine-18 that are useful as imaging agents. In certain embodiments, the phosphonium compound is a tetraaryl phosphonium salt. Another aspect of the present invention relates to a method of obtaining a positron emission image of a mammal, comprising the steps of administering to a mammal a compound of the invention, and acquiring a positron emission spectrum of the mammal.

First claim

We claim:

1. A method according to Scheme 3:

wherein
A is aryl, heteroaryl, aralkyl, alkenyl or has the formula a or b:

and, when A is aryl or heteroaryl, A does not contain an activating group or electron-withdrawing group to enhance the reactivity of X; wherein
R 1 represents independently for each occurrence alkyl, cycloalkyl, aryl, or heteroaryl;
R 2 represents alkylene, cycloalkylene, arylene, or heteroarylene, and, when R 2 is arylene or heteroarylene, R 2 is not further substituted with an activating group or electron-withdrawing group to enhance the reactivity of X;
R 3 represents independently for each occurrence H, alkyl, or halogen;
R 4 represents independently for each occurrence H, alkyl, halogen, hydroxyl, amino, aminoalkyl, or alkoxyl;
R 5 is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, or —CO 2 H; and
Z is halide, nitrate, acetate, benzoate, or sulfonate;
X is sulfonate or nitro;
M is an alkali metal, transition metal, or ammonium;
Y is fluoride or iodide;
A is non-covalently bound to a transition metal cation; and
the method is practiced under substantially anhydrous conditions.

2. The method of claim 1 , wherein Y is a radioactive fluoride or radioactive iodide.

3. The method of claim 1 , wherein Y is fluoride.

4. The method of claim 1 , wherein Y comprises 18 F.

5. The method of claim 1 , wherein Y is iodide.

6. The method of claim 1 , wherein Y comprises 123 I, 124 I, 125 I, or 131 I.

7. The method of claim 1 , wherein A is aryl or heteroaryl.

8. The method of claim 1 , wherein A is alkenyl.

9. The method of claim 1 , wherein A has the formula a:

wherein
R 1 represents independently for each occurrence aryl or heteroaryl; and
R 2 represents arylene or heteroarylene.

10. The method of claim 1 , wherein A has the formula b:

wherein
R 2 represents arylene or heteroarylene.

11. The method of claim 1 , wherein M is an alkali metal.

12. The method of claim 1 , wherein M is potassium, sodium, or lithium.

13. The method of claim 1 , wherein M is ammonium.

14. The method of claim 1 , wherein said transition metal complex comprises a transition metal cation selected from the group consisting of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold and mercury.

15. The method of claim 1 , wherein said transition metal cation is chromium.

16. The method of claim 1 , wherein A-Y is [F-18]-(4-fluorophenyl)triphenylphosphonium nitrate.

17. The method of claim 1 , wherein A-X is 4-(nitrophenyl)triphenylphosphonium nitrate.

18. The method of claim 1 , wherein MY is ammonium [F-18]-fluoride.

19. The method of claim 1 , further comprising adding a crown ether.

20. The method of claim 1 , wherein A-X is 4-(nitrophenyl)triphenylphosphonium nitrate, A-Y is [F-18]-(4-fluorophenyl)triphenylphosphonium nitrate, and MY is ammonium [F-18]-fluoride.

Assignees

• Massachusetts Gen Hospital

Inventors

• Elmaleh David R
• Fischman Alan J
• Shoup Timothy M

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K51/0459 Primary

  having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine · CPC title

• A61K51/0489

  Phosphates or phosphonates, e.g. bone-seeking phosphonates; (phospholipids: A61K51/0408; nucleotides or nucleic acids: A61K51/0491) · CPC title

• C07F9/5442

  Aromatic phosphonium compounds (P-C aromatic linkage) · CPC title

• A61K51/04

  Organic compounds · CPC title