Method for synthesizing iodo- or astatoarenes using diaryliodonium salts
The present invention concerns a method of synthesizing a iodo- or astatoarene comprising the reaction of a diaryliodonium compound with a iodide or astatide salt, respectively. The invention also relates to said iodo- or astatoarene and diaryliodonium compound as such. The invention also concerns a method of synthesizing a iodo- or astatolabelled biomolecule and/or vector using said iodo- or astatoarene.
1. A method of synthesizing an astatoarene comprising reacting a diaryliodonium compound with an astatide salt, wherein the diaryliodonium compound is of formula (II):
wherein:
Ar 1 and Ar 2 , independently of each other, are chosen from: (C 6 -C 10 )aryl and heteroaryl groups, said aryl and heteroaryl groups being substituted with one or several substituents selected from: (C 1 -C 6 )alkyl, (C 2 -C 6 )alkynyl, optionally substituted heteroaryl, halogen, NO 2 , CN, N 3 , CF 3 , —ORa, —COORb, —C(O)R 8 , —N═C═O, —N═C═S, —N(Ra)COORb, —(C 1 -C 6 )alkylene-N(Ra)—C(O)—Rb, —(C 1 -C 6 )alkylene-N(Ra)—C(O)—(C 1 -C 6 )alkylene-Rb, —(C 1 -C 6 )alkylene-N(Ra)—C(O)—(C 1 -C 6 )alkylene-C(O)O—Rb and maleimidyl, said (C 1 -C 6 )alkyl group being optionally substituted with one or several substituents selected from N 3 , OH, OCH 3 , CF 3 , —O—CH 2 —O—(C 1 -C 6 )alkyl, O—(C 1 -C 6 )alkenyl and —O—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl;
Ra is H or (C 1 -C 6 ) alkyl;
Rb is selected from the group consisting of: H, (C 1 -C 6 ) alkyl, and functional groups able to bind a vector and/or a biomolecule; and
Y is a monovalent anion.
2. The method according to claim 1 , wherein in the diaryliodonium compound of formula (II):
Ar 1 and Ar 2 , independently of each other, are chosen from: (C 6 -C 10 )aryl and heteroaryl groups, said aryl and heteroaryl groups being substituted with one or several substituents selected from: (C 1 -C 6 )alkyl, (C 2 -C 6 )alkynyl, optionally substituted heteroaryl, halogen, NO 2 , CN, N 3 , CF 3 , —ORa, —COORb, —C(O)Ra, —N═C═O, —N═C═S, —N(Ra)COORb, —(C 1 -C 6 )alkylene-N(Ra)—C(O)—Rb, —(C 1 -C 6 )alkylene-N(Ra)—C(O)—(C 1 -C 6 )alkylene-Rb, —(C 1 -C 6 )alkylene-N(Ra)—C(O)—(C 1 -C 6 )alkylene-C(O)O—Rb and maleimidyl, said (C 1 -C 6 )alkyl group being optionally substituted with one or several substituents selected from N 3 , OH, OCH 3 , CF 3 , —O—CH 2 —O—(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkenyl and —O—(C 1 -C 6 ) alkylene-(C 6 -C 10 )aryl;
Ra being H or (C 1 -C 6 )alkyl;
Rb being selected from the group consisting of: H, (C 1 -C 6 )alkyl, succinimidyl, N-hydroxysuccinimidyl, sulfosuccinimidyl, maleimidyl, biotinyl, cyclooctynyl, norbornenyl, cyclopropenyl, bicyclononynyl, and trans-cyclooctenyl; and
Y is a monovalent anion.
3. The method according to claim 1 , wherein the diaryliodonium compound is of formula (II-1):
wherein:
R 1 is selected from the group consisting of: (C 1 -C 6 )alkyl, (C 2 -C 6 )alkynyl, optionally substituted heteroaryl, halogen, NO 2 , CN, N 3 , CF 3 , —ORa, —COORb, —C(O)Ra, —N═C═O, —N═C═S, —N(Ra)COORb, —(C 1 -C 6 )alkylene-N(Ra)—C(O)—Rb, —(C 1 -C 6 )alkylene-N(Ra)—C(O)—(C 1 -C 6 )alkylene-Rb, —(C 1 -C 6 )alkylene-N(Ra)—C(O)—(C 1 -C 6 )alkylene-C(O)O—Rb, and maleimidyl, said (C 1 -C 6 )alkyl group being optionally substituted with one or several substituents selected from N 3 , OH, OCH 3 , CF 3 and —O—CH 2 —CH═CH 2 ;
Ra and Rb being defined as in claim 1 .
4. The method according to claim 1 , wherein the astatoarene is of formula (I):
Ar—X (I)
wherein:
X is At; and
Ar is Ar 1 or Ar 2 .
5. The method of claim 1 , wherein the astatide salt is of formula (III):
A + X − (III)
wherein:
X is as defined in claim 4 ; and
A is a monovalent cation selected among Na, K, Cs, tetraalkylammonium and tetraalkylphosphonium.
6. The method of claim 4 , wherein X is radioactive.
7. The method according to claim 6 , wherein X is 211 At.
8. The method of claim 1 , wherein the reaction is carried out in a solvent selected from the group consisting of: acetonitrile, an alcohol, dimethylformamide, water, and mixtures thereof.
9. The method of claim 1 , further comprising
a purification step wherein the astatoarene is extracted by a solvent in which:
an astatide salt and the diaryliodonium salt of formula (II) are insoluble, and
said astatoarene is soluble.
10. The method of claim 1 , further comprising a step of reducing astatine prior to the step of reacting.
11. A method of synthesizing an astatolabeled biomolecule and/or vector comprising the steps of:
(i) synthesizing an astatoarene according to the method of claim 1 ;
(ii) reacting said astatoarene with a biomolecule and/or a vector carrying a functional group reactive with said astatoarene.
12. The method according to claim 11 , wherein the astatoarene is of formula (I):
Ar—X (I)
where X is radioactive.
13. The method of claim 1 , wherein Y is chosen from: CF 3 COO, TsO, MsO, NsO, TfO, NO 3 , Br, Cl, SO 4 and BF 4 .
14. The method of claim 8 , wherein the alcohol is methanol.