Method for synthesizing radioactive ligand having
View Patent ↗A phenyl tin compound is synthesized by using a derivative having various functional groups and a bromo- or iodo-benzene ring as a labeling material of a radioactive ligand. On the other hand, a novel hydroxytosyl iodobenzene compound having an electron-donating group is obtained by oxidizing iodobenzene having one or more electron-donating groups and reacting it with tosylic acid. Then, a diphenyliodonium salt which is a labeling precursor is synthesized by reacting the resulting compound with various phenyl tin compounds. Finally, a 18 F-labeled ligand having various functional groups and a [ 18 F] fluorobenzene ring is synthesized by reacting the resulting diphenyliodonium salt with [ 18 F]F − .
1. A method for synthesizing a radioactive ligand having a 18 F-labeled fluorobenzene ring of general formula (7),
comprising the steps of:
(A) reacting a phenylhalide compound of general formula (1)
wherein X is Br or I; R 1 , R 2 , R 3 , R 4 and R 5 may be the same or different and each represent a hydrogen atom, an alkyl group or a heteroatom-containing functional group, provided that all of R 1 , R 2 , R 3 , R 4 and R 5 are not a hydrogen atom or an alkyl group,
with a trialkyltin of general formula (2)
Sn(R 10 ) 3 ( 2 )
wherein R 10 represents an alkyl group
in the presence of a palladium catalyst to obtain a phenyltin compound of general formula
wherein X, R 1 , R 2 , R 3 , R 4 , R 5 and R 10 are as defined above;
(B) oxidizing an iodobenzene compound of general formula (4)
wherein E represents a functional group which donates electron to a π electron system, and n is 1, 2, 3, 4 or 5,
and then reacting the oxidized compound with toluenesulfonic acid monohydrate to obtain a hydroxytosyliodobenzene compound of general formula (5)
wherein Ts represents a toluenesulfonyl group; and E and n are as defined above;
(C) reacting the hydroxytosyliodobenzene compound of general formula (5) with the phenyltin compound of general formula (3) to obtain a diphenyliodonium salt of general formula (6)
wherein R 1 , R 2 , R 3 , R 4 , R 5 , E, n and Ts are as defined above;
and
(D) reacting the diphenyliodonium salt of general formula (6) with [ 18 F]F − to obtain a radioactive ligand having a 18 F-labeled fluorobenzene ring of general formula (7)
wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
2. A method for obtaining a hydroxytosyliodobenzene compound of general formula (5)
wherein Ts represents a toluenesulfonyl group; and E and n are as defined below,
by oxidizing an iodobenzene compound of general formula (4)
wherein E represents a functional group which donates electron to a π electron system, and n is 1, 2, 3, 4 or 5,
and then reacting the oxidized compound with toluenesulfonic acid monohydrate.
3. The method for synthesizing a radioactive ligand as claimed in claim 1 ,
wherein R 2 is —NR 6 (C═O)R 7 , R 6 is a 2,5-dimethoxybenzyl group, R 7 is a methyl group, R 3 is a phenoxy group, and R 1 , R 4 and R 5 are each a hydrogen atom.
4. The method for synthesizing a radioactive ligand as claimed in claim 1 ,
wherein R 1 is —CH 2 CH(NHR)COOR, R 3 and R 4 are —OR or —OCOR, R is a C 1-6 alkyl group, and R 2 and R 5 are each a hydrogen atom.
5. The method for synthesizing a radioactive ligand as claimed in claim 4 ,
wherein R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl group.
6. The method for synthesizing a radioactive ligand as claimed in claim 1 ,
wherein E is selected from the group consisting of —NR 2 , —OR, —NHCOR, —NHSO 2 R, —OCOR, —SR, and —R, wherein R is a hydrogen atom or a C 1-6 alkyl group.
7. The method for synthesizing a radioactive ligand as claimed in claim 2 ,
wherein E is selected from the group consisting of —NR 2 , —OR, —NHCOR, —NHSO 2 R, —OCOR, —SR, and —R, wherein R is a hydrogen atom or a C 1-6 alkyl group.
8. The method for synthesizing a radioactive ligand as claimed in claim 1 ,
wherein when n is 2, 3, 4 or 5, n quantities of E may be the same or different.
9. The method for synthesizing a radioactive ligand as claimed in claim 2 ,
wherein when n is 2, 3, 4 or 5, n quantities of E may be the same or different.
10. The method for synthesizing a radioactive ligand as claimed in claim 1 ,
wherein n=1, and 1 quantity of E is a methoxy group and is substituted at the para-position, relative to I of the benzene ring.
11. The method for synthesizing a radioactive ligand as claimed in claim 2 ,
wherein n=1, and 1 quantity of E is a methoxy group and is substituted at the para-position, relative to I of the benzene ring.
12. The method for synthesizing a radioactive ligand as claimed in claim 8 ,
wherein n=2, and 2 quantities of E are both a methoxy group and are substituted at the meta- and para-positions, relative to I of the benzene ring.
13. The method for synthesizing a radioactive ligand as claimed in claim 9 ,
wherein n=2, and 2 quantities of E are both a methoxy group and are substituted at the meta- and para-positions, relative to I of the benzene ring.
14. The method for synthesizing a radioactive ligand as claimed in claim 1 ,
wherein in step (B) the oxidized compound is a periodine compound, and wherein the iodobenzene compound of general formula (4)
is oxidized by reacting with peracetic acid or sodium borate in acetic acid to form the periodine compound.