18F-LABELLED FOLATES
The present invention is directed towards a new method of synthesis of 18 F-folate radiopharmaceuticals, wherein fluorine-18 is attached to a pteroate (or folate) or derivative thereof, through direct radiolabeling with 18 [F]fluoride, as well as 18 F-folate radiopharmaceuticals obtained by such method of synthesis and their use in diagnosis and monitoring of cancer therapy and therapy of inflammatory and autoimmune diseases.
1 . A method of synthesis of an 18 F-labeled compound of general formula I
wherein
P is a pteroate, and
S 1 is a spacer,
comprising the steps of (a) providing a precursor of formula II,
wherein Z is a leaving group, and P and S 1 are defined as hereinabove,
and (b) subjecting said precursor to direct radiolabeling with 18 F to obtain a compound of formula I.
2 . A method according to claim 1 , wherein S 1 is a straight-chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2 groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof.
3 . A method according to claim 1 , wherein 18 F in step (b) is activated by phase transfer catalysts such as tetrabutylammonium carbonate or aminopolyethers (e.g. Kryptofix© 2.2.2) in combination with potassium carbonate or oxalate.
4 . A method according to claim 1 , wherein Z is selected from Hal, NO 2 , diazonium salts, sulfonate esters, including mesylate, tosylate, pentafluorobenzoate, triflate, iodonium salts, dialkyl/-aryl silanes, and silanols.
5 . A method according to claim 1 wherein the obtained compound of general formula I has the formula III
wherein
X 1 to X 5 are independently of each other C or N,
R 1 , R 2 are independently of each other 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, wherein 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, halosubstituted C1-C12 alkanoyl,
R 5 is H, CN, Hal, NO 2 , C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, (C1-C12 alkylamino)carbonyl,
S 1 is a straight-chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2 groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof,
p is 0, 1 or 2, and
q has a value of 1 to 7.
6 . A method of synthesis according to claim 1 of a 18 F-labeled compound of general formula III
wherein
X 1 to X 5 are independently of each other C or N,
R 1 , R 2 are independently of each other 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, wherein 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, halosubstituted C1-C12 alkanoyl,
R 5 is H, CN, Hal, NO 2 , C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, (C1-C12 alkylamino)carbonyl,
S 1 is a straight-chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2 groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof,
p is 0, 1 or 2, and
q has a value of 1 to 7,
comprising the steps of (a) providing a precursor of formula IV,
wherein Z is a leaving group, and X 1 to X 5 , R 1 to R 5 , S 1 , p, and q are defined as hereinabove, and (b) subjecting said precursor to direct radiolabeling with 18 F.
7 . A method according to claim 7 , wherein S 1 is straight-chain or branched C1-C8 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof.
8 . A method according to claim 7 , wherein 18 F in step (b) is activated by phase transfer catalysts such as tetrabutylammonium carbonate or aminopolyethers (e.g. Kryptofix© 2.2.2) in combination with potassium carbonate or oxalate.
9 . A method according to claim 6 , wherein Z is selected from Hal, NO 2 , diazonium salts, sulfonate esters, including mesylate, tosylate, pentafluorobenzoate, triflate, iodonium salts, dialkyl/-aryl silanes, and silanols.
10 . A method according to claim 1 , wherein the obtained compound has the formula V
wherein
X 6 , X 7 are independently of each other N or O,
R 6 , R 7 are independently of each other H, straight chain or branched C 1 -C 12 alkyl, which is unsubstituted or substituted by at least one CN, Hal or NO 2 , or a group —S 2 — 18 F, wherein S 2 is straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2 groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof,
with the proviso that at least one of R 6 and R 7 is a group —S 2 — 18 F, and
X 1 to X 5 , R 1 to R 5 , p and q, are as defined in claim 1 .
11 . A method according to claim 10 , wherein S 2 is straight chain or branched C1-C8 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof.
12 . A method according to claim 1 , wherein the obtained compound has the formulae VI or VIa,
wherein
X 1 to X 5 are independently of each other C or N,
X 6 , X 7 are independently of each other C, O or N,
R 1 , R 2 are independently of each other 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, wherein 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, halosubstituted C1-C12 alkanoyl,
R 5 is H, CN, Hal, NO 2 , C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, and (C1-C12 alkylamino)carbonyl,
R 6 , R 7 are independently of each other H or straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 ,
S 2 is straight-chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2 groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof,
p is 0, 1 or 2, and
q has a value of 1 to 7.
13 . A method of synthesis according to claim 1 of a 18 F-labeled compound of general formulae VI or VIa,
wherein
X 1 to X 5 are independently of each other C or N,
X 6 , X 7 are independently of each other C, O or N,
R 1 , R 2 are independently of each other 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, wherein 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, halosubstituted C1-C12 alkanoyl,
R 5 is H, CN, Hal, NO 2 , C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, and (C1-C12 alkylamino)carbonyl,
R 6 , R 7 are independently of each other H or straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 ,
S 2 is straight-chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2 groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof,
p is 0, 1 or 2, and
q has a value of 1 to 7,
comprising the steps of
(a) providing a precursor of formulae VII or VIIa,
wherein Z is a leaving group, and X 1 to X 7 , R 1 to R 7 , S 2 , p, and q are defined as hereinabove, and (b) subjecting said precursor to direct radiolabeling with 18 F.
14 . A method according to claim 12 , wherein S 2 is straight chain or branched C1-C8 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof.
15 . A method according to claim 1 , wherein the obtained compound has the formulae VIII or VIIIa,
wherein,
X 6 , X 7 are independently of each other C, N or O,
Y 1 , Y 2 are independently of each other selected from H, formyl, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 ,
Y 3 is selected from H, formyl, nitroso, straight chain or branched C 1 -C 12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 ,
R 6 , R 7 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
S 2 is straight-chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2 groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof.
16 . A method according to claim 15 , wherein S 2 is straight-chain or branched C1-C8 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , or a five- or six-membered aromatic ring, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof.
17 . A compound of formula I obtainable by a method according to claim 1 .
18 . A compound according to claim 17 having formula III.
19 . A compound according to claim 16 with the proviso that S 1 does not represent benzyl para-substituted with 18 F.
20 . (canceled)
21 . Method of claim 22 for convenient and effective administration to a subject in need for diagnostic imaging.
22 . Method for diagnostic imaging of a cell or population of cells expressing a folate-receptor, said method comprising the steps of administering at least one compound according to claim 17 in a diagnostic imaging amount, and obtaining a diagnostic image of said cell or population of cells.
23 . Method according to claim 22 , wherein the diagnostic imaging is performed of a cell or population of cells expressing a folate-receptor in vitro or in vivo.
24 . Method for in vitro detection of a cell expressing the folate receptor in a tissue sample which includes contacting said tissue sample with a compound according to claim 17 in effective amounts and for sufficient time and conditions to allow binding to occur and detecting such binding by PET imaging.
25 . Method of diagnostic imaging or monitoring a subject comprising the steps of (i) administering at least one compound according to claim 17 in a diagnostic imaging amount, and (ii) performing diagnostic imaging using PET by detecting a signal from said at least one compound.
26 . Method of monitoring therapy of cancer or inflammatory and autoimmune diseases in a subject comprising the steps of (i) administering to a subject in need thereof at least one compound according to claim 17 in a diagnostic imaging amount in combination with a therapeutically active, and (ii) performing diagnostic imaging using PET by detecting a signal from said at least one compound to follow the course of therapy of cancer or inflammatory and autoimmune diseases.
27 . Method of claim 25 used in combination with any other methods of diagnosis or therapy of cancer or inflammatory and autoimmune diseases.