Method for production of F-18 labeled amyloid beta ligands
This invention relates to methods, which provide access to [F-18]fluoropegylated (aryl/heteroaryl vinyl)-phenyl methyl amine derivatives.
1. A method for producing a compound of Formula I
comprising the steps of:
Step 1: radiolabeling a compound of Formula II with a F-18 fluorinating agent, to obtain a compound of Formula I, if R=H, or to obtain a compound of Formula III, if R=PG,
wherein the radiolabeling is carried out in a mixture of acetonitrile and a co-solvent, wherein the percentage of acetonitrile is at least 50%,
Step 2: if R=PG, cleavage of the protecting group PG to obtain a compound of Formula I, and
Step 3: purification of a compound of Formula I,
wherein:
n=1-6,
selected from the group consisting of: a) CH, and b) N,
R is selected from the group consisting of: a) H, and b) PG,
PG is an amine-protecting group,
LG is a leaving group, wherein LG contains 0-3 fluorine atoms.
2. A method according to claim 1 , wherein PG is selected from the group consisting of:
a) Boc,
b) trityl and
c) 4-methoxytrityl.
3. A method according to claim 1 , wherein LG is selected from the group consisting of:
a) a halogen and
b) a sulfonyloxy,
wherein the halogen is chloro, bromo or iodo.
4. A method according to claim 3 , wherein the sulfonyloxy is selected from the group consisting of:
a) methanesulfonyloxy,
b) p-toluenesulfonyloxy,
c) (4-nitrophenyl)sulfonyloxy, and
d) (4-bromophenyl)sulfonyloxy.
5. A method according to claim 1 , wherein n=3 and X=CH.
6. A method according to claim 1 , wherein n=3, X=CH, R=Boc, and LG=methanesulfonyloxy.
7. A method according to claim 1 , wherein the radiolabeling is carried out in a mixture of acetonitrile and co-solvents, wherein the percentage of acetonitrile is at least 70%.
8. A method according to claim 1 , wherein the radiolabeling is carried out in a mixture of acetonitrile and co-solvents, wherein the percentage of acetonitrile is at least 90%.
9. A method according to claim 1 , wherein 1.5-75 μmol of a compound of Formula II are used in Step 1.
10. A method according claim 1 , wherein the method is performed as a fully automated process.
11. A method according to claim 1 , wherein Step 3 comprises a purification by HPLC.
12. A method according to claim 11 , wherein the purification by HPLC in Step 3 employs a solvent which is a mixture of ethanol and an aqueous buffer.
13. A method according to claim 12 , wherein the aqueous buffer comprises ascorbic acid or a salt thereof.
14. A method according to claim 1 , wherein 10-30 μmol of a compound of Formula II are used in Step 1.
15. A method according to claim 1 , wherein 12-25 μmol of a compound of Formula II are used in Step 1.