18F-labelled folates
The present invention is directed towards new 18 F-folate radiopharmaceuticals, wherein the fluorine-18 is covalently linked to the aminobenzoyl moiety, which connects the condensed pyrimidine heterocycle to the amino acid portion within folate structures, as well as their precursors and their non-radioactive references, a method of their preparation, as well as their use in diagnosis of a cell or population of cells expressing a folate-receptor and monitoring of cancer and inflammatory and autoimmune diseases and therapy thereof.
1. A folate compound of formula I
wherein
A is an amino acid,
X 1 to X 5 are each N,
Z is an electron-withdrawing group,
R 1 , R 2 are independently of each other H, Hal, O, —OR″, —NHR″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl,
R″ is H or C1-C6 alkyl,
R 3 , R 4 are independently of each other H, formyl, iminomethyl, nitroso, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, or halosubstituted C1-C12 alkanoyl,
m is 0, 1, 2 or 3,
n is 1,
p is 0, 1 or 2,
q has a value of 1 to 7, and
r is 0 or 1.
2. A compound of claim 1 , wherein
m is 1, 2 or 3.
3. The compound of claim 1 , wherein the aminobenzoyl moiety of the compound of formula I is substituted with fluorine-18 in the 2′-position or the 6′-position.
4. The compound of claim 1 , wherein the aminobenzoyl moiety of the compound of formula I is substituted with at least one electron-withdrawing group Z in the 2′-position or the 6′-position.
5. The compound of claim 1 , wherein the electron-withdrawing group Z is selected from the group consisting of —NO 2 , —CN, —N + (CH 3 ) 3 , —SO 3 R′, —COOR′, —COR′, —Cl, —Br, —F, iodonium salts —I + (R′) 2 , dialkyl/-aryl silanes —SiOH(R′) 2 , and silanols —SiH(R′) 2 , wherein R′ is independently a straight-chain or branched C (1-12) alkyl group or an optionally substituted carbocyclic and heterocyclic group comprising five-, six- or ten-membered ring systems.
6. The compound of claim 1 , wherein the aminobenzoyl moiety of the compound of formula I is substituted in the 2′- or the 6′-position with fluorine-18 and in the 6′- or the 2′-position with an electron-withdrawing group selected from the group consisting of —NO 2 , —CN, —N + (CH 3 ) 3 , —SO 3 R′, —COOR′, —COR′, —Cl, —Br, —F, iodonium salts —I + (R′) 2 , dialkyl/-aryl silanes —SiOH(R′) 2 , and silanols —SiH(R′) 2 , wherein R′ is independently a straight-chain or branched C (1-12) alkyl group or an optionally substituted carbocyclic and heterocyclic group comprising five-, six- or ten-membered ring systems.
7. The compound according to claim 1 , wherein A is an amino acid selected from the group consisting of glutamic acid, aspartic acid, glutamine, aspartine, lysine, arginine, cysteine, and homopolymers thereof.
8. The compound of claim 1 having formula II,
wherein
X 1 to X 5 are each N,
X 6 , X 7 are independently of each other C, N or O,
Z is a electron-withdrawing group selected from the group consisting of —NO 2 , —CN, —N + (CH 3 ) 3 , —SO 3 R′, —COOR′, —COR′, —Cl, —Br, —F, iodonium salts —I + (R′) 2 , dialkyl/-aryl silanes —SiOH(R′) 2 , and silanols —SiH(R′) 2 ,
R′ is independently a straight-chain or branched C (1-12) alkyl group or an optionally substituted carbocyclic and heterocyclic group comprising five-, six- or ten-membered ring systems,
R 1 , R 2 are independently of each other H, Hal, O, —OR″, —NHR″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl,
R″ is H or C1-C6 alkyl,
R 3 , R 4 are independently of each other H, formyl, iminomethyl, nitroso, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, or halosubstituted C1-C12 alkanoyl,
R 5 , R 6 are independently of each other H or straight chain or branched C 1 -C 12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, or —C≡C—,
m is 0, 1, 2 or 3,
n is 1,
r is 0 or 1,
p is 0, 1 or 2, and
q has a value of 1 to 7.
9. The compound of claim 8 , wherein the fluorine-18 is at the 2′- or 6′-position.
10. The compound of claim 1 having formulae III or IV,
wherein
X 1 to X 5 are each N,
X 6 , X 7 are independently of each other C, N or O,
Z is a electron-withdrawing group selected from the group consisting of —NO 2 , —CN, —N + (CH 3 ) 3 , —SO 3 R′, —COOR′, —COR′, —Cl, —Br, —F, iodonium salts —I + (R′) 2 , dialkyl/-aryl silanes —SiOH(R′) 2 , and silanols —SiH(R′) 2 ,
R′ is independently a straight-chain or branched C (1-12) alkyl group or an optionally substituted carbocyclic and heterocyclic group comprising five-, six- or ten-membered ring systems,
R 1 , R 2 are independently of each other H, Hal, O, —OR″, —NHR″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl,
R″ is H or C1-C6 alkyl,
R 3 , R 4 are independently of each other H, formyl, iminomethyl, nitroso, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, or halosubstituted C1-C12 alkanoyl,
R 5 , R 6 are independently of each other H or straight chain or branched C 1 -C 12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, or —C≡C—,
m is 0, 1, 2, or 3,
r is 0 or 1,
p is 0, 1 or 2, and
q has a value of 1 to 7.
11. The compound of claim 10 , wherein m is 0.
12. The compound of claim 1 having formulae V or VI,
wherein
X 1 to X 5 are each N,
X 6 , X 7 are independently of each other C, N or O,
R 1 , R 2 are independently of each other H, Hal, O, —OR″, —NHR″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl,
R″ is H or C1-C6 alkyl,
R 3 , R 4 are independently of each other H, formyl, iminomethyl, nitroso, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, or halosubstituted C1-C12 alkanoyl,
R 5 , R 6 are independently of each other H or straight chain or branched C 1 -C 12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, or —C≡C—,
r is 0 or 1,
p is 0, 1 or 2, and
q has a value of 1 to 7.
13. The compound of claim 10 , wherein m is 1 or 2.
14. The compound of claim 10 , wherein Z is located at the 2′- and/or 6′-position.
15. The compound of claim 1 having formulae VII, VIII, IX, X or XI,
wherein
X 1 to X 5 are each N,
X 6 , X 7 are independently of each other C, N or O,
Z is a electron-withdrawing group selected from the group consisting of —NO 2 , —CN, —N + (CH 3 ) 3 , —SO 3 R′, —COOR′, —COR′, —Cl, —Br, —F, iodonium salts —I + (R′) 2 , dialkyl/-aryl silanes —SiOH(R′) 2 , and silanols —SiH(R′) 2 ,
R′ is independently a straight-chain or branched C (1-12) alkyl group or an optionally substituted carbocyclic and heterocyclic group comprising five-, six- or ten-membered ring systems,
R 1 , R 2 are independently of each other H, Hal, O, —OR″, —NHR″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl,
R″ is H or C1-C6 alkyl,
R 3 , R 4 are independently of each other H, formyl, iminomethyl, nitroso, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, or halosubstituted C1-C12 alkanoyl,
R 5 , R 6 are independently of each other H or straight chain or branched C 1 -C 12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, or —C≡C—,
n is 1,
r is 0 or 1,
p is 0, 1 or 2, and
q has a value of 1 to 7.
16. The compound of claim 1 having formula XV,
wherein
Z is a electron-withdrawing group selected from the group consisting of —NO 2 , —CN, —N + (CH 3 ) 3 , —SO 3 R′, —COOR′, —COR′, —Cl, —Br, —F, iodonium salts —I + (R′) 2 , dialkyl/-aryl silanes —SiOH(R′) 2 , and silanols —SiH(R′) 2 ,
R′ is independently a straight-chain or branched C (1-12) alkyl group or an optionally substituted carbocyclic and heterocyclic group containing a five-, six- or ten-membered ring system,
R 5 , R 6 are independently of each other H or straight chain or branched C 1 -C 12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, or —C≡C—,
Y 1 , Y 2 are independently of each other H, or a straight chain or branched C 1 -C 6 alkyl,
R 4 is H, nitroso, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 alkanoyl, or halosubstituted C 1 -C 12 alkanoyl,
m is 0, 1, 2 or 3, and
n is 1.
17. The compound of claim 1 having formula XVI,
wherein
Z is a electron-withdrawing group selected from the group consisting of —NO 2 , —CN, —N + (CH 3 ) 3 , —SO 3 R′, —COOR′, —COR′, —Cl, —Br, —F, iodonium salts —I + (R′) 2 , dialkyl/-aryl silanes —SiOH(R′) 2 , and silanols —SiH(R′) 2 ,
R′ is independently a straight-chain or branched C (1-12) alkyl group or an optionally substituted carbocyclic and heterocyclic group comprising five-, six- or ten-membered ring systems,
R 3 , R 4 are independently of each other H, formyl, iminomethyl, nitroso, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, or halosubstituted C1-C12 alkanoyl,
R 5 , R 6 are independently of each other H or straight chain or branched C 1 -C 12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, or —C≡C—,
Y 1 , Y 2 are independently of each other H, a or straight chain or branched C 1 -C 6 alkyl,
m is 0, 1, 2 or 3, and
n is 1.
18. The compound of claim 1 having formula XVII,
wherein
Z is an electron-withdrawing group selected from the group consisting of —NO 2 , —CN, —N + (CH 3 ) 3 , —SO 3 R′, —COOR′, —COR′, —Cl, —Br, —F, iodonium salts —I + (R′) 2 , dialkyl/-aryl silanes —SiOH(R′) 2 , and silanols —SiH(R′) 2 ,
R′ is independently a straight-chain or branched C (1-12) alkyl group or an optionally substituted carbocyclic and heterocyclic group comprising five-, six- or ten-membered ring systems
R 5 , R 6 are independently of each other H or straight chain or branched C 1 -C 12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, or —C≡C—,
m is 0, 1, 2 or 3, and
n is 1.
19. The compound of claim 1 having formula XVIII,
wherein,
Z is an electron-withdrawing group selected from the group consisting of —NO 2 , —CN, —N + (CH 3 ) 3 , —SO 3 R′, —COOR′, —COR′, —Cl, —Br, —F, iodonium salts —I + (R′) 2 , dialkyl/-aryl silanes —SiOH(R′) 2 , and silanols —SiH(R′) 2 ,
R′ is independently a straight-chain or branched C (1-12) alkyl group or an optionally substituted carbocyclic and heterocyclic group comprising five-, six- or ten-membered ring systems,
R 3 is H, methyl- or formyl-,
R 5 , R 6 are independently of each other H or straight chain or branched C 1 -C 12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, or —C≡C—,
m is 0, 1, 2 or 3, and
n is 1.
20. A method of production of a compound according to claim 1 , comprising direct radiolabeling with [ 18 F]fluoride of the aminobenzoyl moiety of the compound of formula I.
21. A method of production of a compound according to claim 20 , comprising providing a compound that is with the exception of n being 0 is a compound of formula I and reacting said compound with [ 18 F] fluoride to give a compound of formula I wherein n=1.
22. The compound of claim 1 , wherein R 1 is H, Hal, —OR″, —NHR″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl.
23. The compound of claim 8 , wherein R 1 is H, Hal, —OR″, —NHR″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl.
24. The compound of claim 10 , wherein R 1 is H, Hal, —OR″, —NHR″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, and (C1-C12 alkylamino)carbonyl.
25. The compound of claim 12 , wherein R 1 is H, Hal, —OR″, —NHR″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl.
26. The compound of claim 15 , wherein R 1 is H, Hal, —OR″, —NHR″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl.