US2022062445A1PendingUtilityA1
Substituted organofluoroborates as imaging agents
Est. expiryMar 8, 2033(~6.6 yrs left)· nominal 20-yr term from priority
A61K 51/04A61K 51/0453C07F 5/02C07B 59/00C07K 1/13A61K 51/0455A61K 51/00A61K 51/082A61K 51/0421A61K 51/088C07F 5/027
68
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Claims
Abstract
Fluoridated organofluoroborates comprising at least one 18F atom and precursors thereto, for use in PET scanning.
Claims
exact text as granted — not AI-modified1 . A positron emitting compound or salt thereof, wherein the compound is of the formula I:
wherein:
B is boron;
A is a linear or branched C 1 -C 15 alkyl group, a linear or branched C 1 -C 15 alkenyl, group, a linear or branched C 1 -C 15 alkynyl group, or a C 3 -C 18 non-aromatic cycloalkyl group, wherein each of the C 1 -C 15 alkyl group, the C 1 -C 15 alkenyl, group, the C 1 -C 15 alkynyl, group, and the C 3 -C 18 non-aromatic cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P;
A is joined to B through a carbon atom;
each Y 1 is independently selected from the group consisting of R 1 , 18 F and 19 F;
n=1 or 2;
Y 2 is selected from the group consisting of R 2 , 18 F and 19 F;
R 1 is a non-interfering substituent with regard to fluoridation of B;
R 2 is a non-interfering substituent with regard to fluoridation of B; and
at least one of (Y 1 ) n and Y 2 is 18 F;
providing that A is selected such that the pK a of H a of an acid of the formula II:
is less than or equal to about 2.8.
2 . The positron emitting compound or salt of claim 1 , wherein when A is substituted at the carbon alpha to the
group with a group that has a dissociable proton, the dissociable proton has a pKa greater than about 9 and contributes to a net positive charge on the group that has the dissociable proton.
3 . The positron emitting compound or salt of claim 1 or 2 , wherein A is selected such that the pK a of H a of the acid of the formula II is less than or equal to about 2.4.
4 . The positron emitting compound or salt of claim 1 or 2 , wherein A is selected such that the pK a of H a of the acid of the formula II is less than or equal to about 2.0.
5 . The positron emitting compound or salt of claim 1 or 2 , wherein A is selected such that the pK a of H a of the acid of formula II is less than or equal to about 1.5.
6 . The positron emitting compound or salt of claim 1 or 2 , wherein A is selected such that the pK a of H a of the acid of formula II is less than or equal to about 1.0.
7 . The positron emitting compound or salt of any one of claims 1 to 6 , wherein A is substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, —N + (C 1-15 alkyl) 3 , —N + (C 2-15 alkenyl) 3 , —N + (C 2-15 alkynyl) 3 , —N + H(C 1-15 alkyl) 2 , —N + H(C 2-15 alkenyl) 2 , —N + H(C 2-15 alkynyl) 2 , P + (C 1-15 alkyl) 3 , P + (C 2-15 alkenyl) 3 , P + (C 2-15 alkynyl) 3 , S + (C 1-15 alkyl) 2 , S + (C 2-15 alkenyl) 2 , S + (C 2-15 alkynyl) 2 , oxo (i.e., ═O), OH, —OC 1-15 alkyl, unsubstituted or substituted aromatic C 3 -C 18 cycloalkyl, unsubstituted or substituted non-aromatic C 3 -C 18 heterocyclic group, unsubstituted or substituted aromatic C 3 -C 18 heterocyclic group, ═NH, —C 1 -C 15 alkyl, non-aromatic C 3 -C 18 cycloalkyl, —N(C 1-15 alkyl) 2 , —N(C 2-15 alkenyl) 2 , —N(C 2-15 alkynyl) 2 , —COOH, —NH 2 , —SH, a biomolecule, and a linking group optionally joined to a biomolecule.
8 . The positron emitting compound or salt of any one of claims 1 to 7 , wherein A is substituted with at least one substituent that is a biomolecule or a linking group optionally joined to a biomolecule.
9 . The positron emitting compound or salt as defined in any one of claims 1 to 8 , wherein the compound is of the formula (IV):
wherein:
Q 1 is —CR 3 R 4 R 5 , —C≡CR 8 ,
or —R 10 C═CR 11 R 12 ;
each of R 3 , R 4 , and R 5 is independently H, D, F, Cl, Br, I, CX 3 , —N + R 15 R 16 R 17 , —P + R 18 R 19 R 20 , —S + R 21 R 22 , —NR 23 R 24 , NHR 23 , a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and is optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the carbon atom of —CR 3 R 4 R 5 through a carbon atom, and each X is the same or different and is F, Cl, Br, or I;
each of R 15 , R 16 and R 17 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the nitrogen atom of —N + R 15 R 16 R 17 through a carbon atom, or R 15 is absent and R 16 and R 17 are joined so that —N + R 15 R 16 R 17 forms a positively charged nitrogen containing heterocyclic group which is substituted or unsubstituted;
each of R 18 , R 19 , and R 20 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the phosphorus atom of —P + R 18 R 19 R 20 through a carbon atom;
each of R 21 and R 22 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the sulfur atom of —S + R 21 R 22 through a carbon atom;
each of R 23 and R 24 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the nitrogen atom of —NR 23 R 24 through a carbon atom;
R 8 is —NR 25 R 26 R 27 , —P + R 28 R 29 R 30 , —SR 31 R 32 , —NR 33 R 34 ,
a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is substituted with at least one substituent that is a biomolecule and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the carbon atom of —C≡CR 8 through a carbon atom;
each of R 25 , R 26 and R 27 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the nitrogen atom of —N + R 25 R 26 R 27 through a carbon atom, or R 25 is absent and R 26 and R 27 are joined so that —N + R 25 R 26 R 27 forms a positively charged nitrogen containing heterocyclic group which is unsubstituted or substituted;
each of R 28 , R 29 , and R 30 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the phosphorus atom of —P + R 28 R 29 R 30 through a carbon atom;
each of R 31 and R 32 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the sulfur atom of —S + R 31 R 32 through a carbon atom;
each of R 33 and R 34 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the nitrogen atom of —NR 33 R 34 through a carbon atom;
R 35 is a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is substituted with at least one substituent that is a biomolecule and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the carbon atom of
through a carbon atom;
R 9 is —NR 38 R 39 ,
a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is substituted with at least one substituent that is a biomolecule and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the carbon atom of
through a carbon atom;
each of R 38 and R 39 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the nitrogen atom of —NR 38 R 39 through a carbon atom;
R 40 is a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is substituted with at least one substituent that is a biomolecule and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the carbon atom of
through a carbon atom;
each of R 10 , R 11 , and R 12 is independently H, D, F, Cl, Br, I, CX 3 , —N + R 41 R 42 R 43 , —P + R 44 R 45 R 46 , —S + R 47 R 48 , a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the carbon atom of —R 10 C═CR 11 R 12 through a carbon atom, and each X is the same or different and is F, Cl, Br, or I;
each of R 41 , R 42 and R 43 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the nitrogen atom of —NR 41 R 42 R 43 through a carbon atom, or R 41 is absent and R 42 and R 43 are joined so that —N + R 41 R 42 R 43 forms a positively charged nitrogen containing heterocyclic group which is substituted or unsubstituted;
each of R 44 , R 45 , and R 46 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the phosphorus atom of —P + R 44 R 45 R 46 through a carbon atom;
each of R 47 and R 48 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the sulfur atom of —S + R 47 R 48 through a carbon atom;
at least one of R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , and R 48 is a biomolecule, a linking group optionally joined to a biomolecule, or a group that is substituted with at least one substituent that is a biomolecule, or forms a group that is substituted with at least one substituent that is a biomolecule; and
B, Y 1 , n and Y 2 are as defined in claim 1 ,
provided that when Q 1 is —CR 3 R 4 R 5 , at least one of R 3 , R 4 and R 5 is F, Cl, Br, I, CX 3 , —N + R 15 R 16 R 17 , —P + R 18 R 19 R 20 , —S + R 21 R 22 or —NR 23 R 24 .
10 . The positron emitting compound or salt of claim 9 , wherein Q 1 is —CR 3 R 4 R 5 ,
or —R 10 C═CR 11 R 12 ; and each R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , and R 12 is as defined in claim 9 .
11 . The positron emitting compound or salt of claim 9 , wherein Q 1 is —CR 3 R 4 R 5 , —C≡CR 8 , or
and each of R 3 , R 4 , R 5 , R 8 , and R 9 is as defined in claim 9 .
12 . The positron emitting compound or salt of claim 9 , wherein Q 1 is —CR 3 R 4 R 5 or —C≡CR 8 ; and each of R 3 , R 4 , R 5 , and R 8 is as defined in claim 9 .
13 . The positron emitting compound or salt of claim 9 , wherein Q 1 is —CR 3 R 4 R 5 ; and each of R 3 , R 4 , and R 5 is as defined in claim 9 .
14 . The positron emitting compound or salt of claim 9 , wherein:
Q 1 is —CR 3 R 4 R 5 ; each of R 3 , R 4 , and R 5 is as defined in claim 9 ; at least two of R 3 , R 4 and R 5 are independently F, Cl, Br, I, or CX 3 , or at least one of R 3 , R 4 and R 5 is —N + R 15 R 16 R 17 , —P + R 18 R 19 R 20 , —S + R 21 R 22 , or —NR 23 R 24 ; each of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 is as defined in claim 9 ; and at least one of R 3 , R 4 , R 5 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 is a biomolecule, a linking group optionally joined to a biomolecule, or a group that is substituted with at least one substituent that is a biomolecule, or forms a group that is substituted with at least one substituent that is a biomolecule.
15 . The positron emitting compound or salt of claim 9 , wherein:
Q 1 is —CR 3 R 4 R 5 ; each of R 3 , R 4 , and R 5 are selected from H, D, F, Cl, Br, I, CX 3 , —N + R 15 R 16 R 17 , a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, and a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the carbon atom of —CR 3 R 4 R 5 through a carbon atom, and each X is the same or different and is F, Cl, Br, or I; each of R 15 , R 16 and R 17 is as defined in claim 9 ; at least two of R 3 , R 4 and R 5 are independently F, Cl, Br, I, or CX 3 , or at least one of R 3 , R 4 and R 5 is —N + R 15 R 16 R 17 ; and at least one of R 3 , R 4 , R 5 , R 15 , R 16 and R 17 is a biomolecule, a linking group optionally joined to a biomolecule, or a group that is substituted with at least one substituent that is a biomolecule, or forms a group that is substituted with at least one substituent that is a biomolecule.
16 . The positron emitting compound or salt of claim 9 , wherein:
Q 1 is —CR 3 R 4 R 5 ; each of R 3 , R 4 , and R 5 are selected from F, Cl, Br, I, CX 3 , a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, and a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the carbon atom of —CR 3 R 4 R 5 through a carbon atom, and each X is the same or different and is F, Cl, Br, or I; two of R 3 , R 4 and R 5 are independently F, Cl, Br, I, or CX 3 ; and one of R 3 , R 4 and R 5 is a biomolecule, a linking group optionally joined to a biomolecule, or is a group that is substituted with at least one substituent that is a biomolecule.
17 . The positron emitting compound or salt of claim 9 , wherein:
Q 1 is —CR 3 R 4 R 5 ; each of R 3 and R 4 is independently F or C 1 ; R 5 a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is substituted with at least one substituent that is a biomolecule and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the carbon atom of —CR 3 R 4 R 5 through a carbon atom.
18 . The positron emitting compound or salt of claim 9 , wherein:
Q 1 is —CR 3 R 4 R 5 ; R 3 is —N + R 15 R 16 R 17 ; each of each of R 4 and R 5 is independently are selected from H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the carbon atom of —CR 3 R 4 R 5 through a carbon atom; each of R 15 , R 16 and R 17 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the nitrogen atom of —N + R 15 R 16 R 17 through a carbon atom, or R 15 is absent and R 16 and R 17 are joined so that —N + R 15 R 16 R 17 forms a positively charged nitrogen containing heterocyclic group which is substituted or unsubstituted; and at least one of R 4 , R 5 , R 15 , R 16 and R 17 is a biomolecule, a linking group optionally joined to a biomolecule, or a group that is substituted with at least one substituent that is a biomolecule, or forms a group that is substituted with at least one substituent that is a biomolecule.
19 . The positron emitting compound or salt of claim 9 , wherein:
Q 1 is —CR 3 R 4 R 5 ; R 3 is —N + R 15 R 16 R 17 ; each of R 4 and R 5 is independently H, D, a biomolecule, or a linking group optionally joined to a biomolecule; each of R 15 , R 16 and R 17 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, or a linear or branched C 1 -C 6 alkyl group which is unsubstituted or substituted, or R 15 is absent and R 16 and R 17 are joined so that —N + R 15 R 16 R 17 forms a positively charged nitrogen containing C 4 -C 6 heterocyclic group which is substituted or unsubstituted; and at least one of R 4 , R 5 , R 15 , R 16 and R 17 is a biomolecule, a linking group optionally joined to a biomolecule, or a group that is substituted with at least one substituent that is a biomolecule, or forms a group that is substituted with at least one substituent that is a biomolecule.
20 . The positron emitting compound or salt of claim 9 , wherein Q 1 is —C≡CR 8 ; and R 8 is as defined in claim 9 .
21 . The positron emitting compound or salt of claim 9 , wherein:
Q 1 is —C≡CR 8 ; R 8 is a biomolecule, a linking group optionally joined to a biomolecule, a linear or branched C 1 -C 15 alkyl group, or a C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is substituted with at least one substituent that is a biomolecule and is optionally intercepted with at least one heteroatom selected from the group consisting of O, S, N and P, and each of the C 1 -C 15 alkyl group and the C 3 -C 18 cycloalkyl group is joined to the carbon atom of —C≡CR 8 through a carbon atom.
22 . The positron emitting compound or salt of claim 9 , wherein Q 1 is
and R 9 is as defined in claim 8 .
23 . The positron emitting compound or salt of claim 8 , wherein Q 1 is —R 10 C═CR 11 R 12 ; and each of R 10 , R 11 , and R 12 is as defined in claim 9 .
24 . The positron emitting compound or salt of claim 1 or 2 , wherein A is:
25 . The positron emitting compound or salt of any one of claims 1 to 23 , wherein each of R 1 and R 2 is independently a linear or branched C 1 -C 15 alkyl group or a non-aromatic C 3 -C 18 cycloalkyl group, wherein each of the C 1 -C 15 alkyl group and the non-aromatic C 3 -C 18 cycloalkyl group is unsubstituted or substituted and is optionally intercepted with at least one heteroatom selected from the group consisting of O, S, N and P.
26 . A positron emitting compound or salt of any one of claims 1 to 25 , wherein n is 2, each Y 1 is F and Y 2 is F.
27 . A positron emitting compound or salt as defined in any one of claims 1 to 25 , wherein at least one of (Y 1 ) n and Y 2 is 18 F.
28 . A positron emitting compound or salt as defined in any one of claims 1 to 27 , having a solvolytic de-18F-fluoridation half-life at physiological pH of about 1000 minutes or more.
29 . A positron emitting compound or salt as defined in any one of claims 1 to 27 , having a solvolytic de-18F-fluoridation half-life at physiological pH of about 5000 minutes or more.
30 . A positron emitting compound or salt as defined in any one of claims 1 to 26 , having a solvolytic de-18F-fluoridation half-life at physiological pH of about 10000 minutes or more.
31 . A positron emitting compound or salt as defined in any one of claims 1 to 27 , having a solvolytic de-18F-fluoridation half-life at physiological pH of about 15000 minutes or more.
32 . A positron emitting compound or salt as defined in any one of claims 1 to 27 , having a solvolytic de-18F-fluoridation half-life at physiological pH of about 20000 minutes or more.
33 . A positron emitting compound or salt as defined in any one of claims 1 to 27 , having a solvolytic de-18F-fluoridation half-life at physiological pH of about 25000 minutes or more.
34 . A positron emitting compound or salt as defined in any one of claims 1 to 27 , having a solvolytic de-18F-fluoridation half-life at physiological pH of about 50000 minutes or more.
35 . A positron emitting compound or salt as defined in any one of claims 1 to 27 , having a solvolytic de-18F-fluoridation half-life at physiological pH of about 100000 minutes or more.
36 . A positron emitting compound or salt as defined in any one of claims 1 to 27 , having a solvolytic de-18F-fluoridation half-life at physiological pH of about 125000 minutes or more.
37 . A positron emitting compound or salt as defined in any one of claims 1 to 27 , having a solvolytic de-18F-fluoridation half-life at physiological pH of about 150000 minutes or more.
38 . A method of making a positron emitting compound or salt as defined in claim 1 , comprising contacting an 18 F source with a compound or salt thereof, wherein the compound is of the formula I:
wherein:
B is boron;
A is a linear or branched C 1 -C 15 alkyl group, a linear or branched C 1 -C 15 alkenyl, group, a linear or branched C 1 -C 15 alkynyl group, or a C 3 -C 18 non-aromatic cycloalkyl group, wherein each of the C 1 -C 15 alkyl group, the linear or branched C 1 -C 15 alkenyl group, the linear or branched C 1 -C 15 alkynyl group, and the C 3 -C 18 non-aromatic cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P;
A is joined to B through a carbon atom;
n=1 or 2;
each Y 1 is independently selected from the group consisting of R 1 and a leaving group that can be displaced by fluoride;
Y 2 is selected from the group consisting of R 2 and a leaving group that can be displaced by fluoride;
at least one of (Y 1 ) n and Y 2 is said leaving group when n is 2;
R 1 is a non-interfering substituent with regard to fluoridation of B;
R 2 is a non-interfering substituent with regard to fluoridation of B; and
providing that A is selected such that the pK a of H a of an acid of the formula II:
is less than or equal to about 2.8.
39 . The method claim 38 , wherein when A is substituted at a carbon alpha to the
group with a group that has a dissociable proton, the dissociable proton has a pKa greater than about 9 and contributes to a net positive charge on the group that has the dissociable proton.
40 . The method of claim 38 or 39 , comprising, prior to contacting the compound or salt thereof with the 18 F source, selecting the compound on the basis that the pK a of H a of an acid of the formula II:
is less than or equal to about 2.8.
41 . The method of claim 38 , 39 , or 40 wherein said 18 F source is a fluoride.
42 . The method of any one of claims 38 to 41 , wherein A is further substituted by a biomolecule, or a linking group optionally joined to a biomolecule.
43 . A method of performing PET imaging comprising administering an imaging effective amount of a positron emitting compound or salt according to any one of claims 1 to 35 to a subject or object to be subjected to PET.
44 . A method of selecting a PET imaging agent or precursor thereof having resistance to solvolytic fluoridationde-18F-fluoridationde-18F-fluoridation at physiological pH, the method comprising:
(i) providing one or more compounds or salt thereof wherein the compound is of the formula I:
wherein:
B is boron;
A is a linear or branched C 1 -C 15 alkyl group, a linear or branched C 1 -C 15 alkenyl, group, a linear or branched C 1 -C 15 alkynyl group, or a C 3 -C 18 non-aromatic cycloalkyl group, wherein each of the C 1 -C 15 alkyl group, the linear or branched C 1 -C 15 alkenyl group, the linear or branched C 1 -C 15 alkynyl group, and the C 3 -C 18 non-aromatic cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P;
A is joined to B through a carbon atom;
each Y 1 is independently selected from the group consisting of R 1 , 18 F and 19 F;
n=1 or 2;
Y 2 is selected from the group consisting of R 2 , 18 F and 19 F;
R 1 is a non-interfering substituent with regard to fluoridation of B;
R 2 is a non-interfering substituent with regard to fluoridation of B; and
at least one of (Y 1 ) n and Y 2 is 18 F;
providing that A is selected such that the pK a of H a of an acid of the formula II:
is less than or equal to about 2.8;
(ii) assessing the half-life of the presence of the fluorine bound to B; and
(iii) selecting a compound or compounds having said half-life of about 1000 minutes or more as said imaging agent or precursor thereof.
45 . The method of claim 45 , wherein when A is substituted at the carbon alpha to the
group with a group that has a dissociable proton, the dissociable proton has a pKa greater than about 9 and contributes to a net positive charge on the group that has the dissociable proton.
46 . The method of claim 44 or 45 , wherein the solvolytic de-18F-fluoridation half-life at physiological pH is about 1000 minutes or more.
47 . The method of claim 44 or 45 , wherein the solvolytic de-18F-fluoridation half-life at physiological pH is about 5000 minutes or more.
48 . The method of claim 44 or 45 , wherein the solvolytic de-18F-fluoridation half-life at physiological pH is about 10000 minutes or more.
49 . The method of claim 44 or 45 , wherein the solvolytic de-18F-fluoridation half-life at physiological pH is about 15000 minutes or more.
50 . The method of claim 44 or 45 , wherein the solvolytic de-18F-fluoridation half-life at physiological pH is about 20000 minutes or more.
51 . The method of claim 44 or 45 , wherein the solvolytic de-18F-fluoridation half-life at physiological pH is about 25000 minutes or more.
52 . The method of claim 44 or 45 , wherein the solvolytic de-18F-fluoridation half-life at physiological pH is about 50000 minutes or more.
53 . The method of claim 44 or 45 , wherein the solvolytic de-18F-fluoridation half-life at physiological pH is about 100000 minutes or more.
54 . The method of claim 44 or 45 , wherein the solvolytic de-18F-fluoridation half-life at physiological pH is about 125000 minutes or more.
55 . The method of claim 44 or 45 , wherein the solvolytic de-18F-fluoridation half-life at physiological pH of about 150000 minutes or more.
56 . The method of any one of claims 44 to 55 , wherein said fluorine comprises 18 F.
57 . The method of any one of claims 44 to 56 , wherein said selected compound or compounds are for use as a whole body PET imaging agent or precursor thereof.
58 . A positron emitting compound or salt thereof as defined in any one of claims 1 to 37 for use as a whole body PET imaging agent or precursor thereof.
59 . Use of a compound or salt thereof as a precursor in the manufacture of an 18 F containing PET imaging agent, wherein the compound is of the formula I:
wherein:
B is boron;
A is a linear or branched C 1 -C 15 alkyl, a linear or branched C 1 -C 15 alkenyl group, a linear or branched C 1 -C 15 alkynyl group, or a C 3 -C 18 non-aromatic cycloalkyl group, wherein each of the C 1 -C 15 alkyl group, the linear or branched C 1 -C 15 alkenyl group, the linear or branched C 1 -C 15 alkynyl group, and the C 3 -C 18 non-aromatic cycloalkyl group is unsubstituted or substituted and optionally includes at least one heteroatom interposed between two carbon atoms of the carbon chain of the group, wherein each of the at least one heteroatom is independently selected from the group consisting of O, S, N and P;
A is joined to B through a carbon atom;
n=1 or 2;
each Y 1 is independently selected from the group consisting of R 1 and a leaving group that can be displaced by 18 F-fluoride;
Y 2 is selected from the group consisting of R 2 and a leaving group that can be displaced by 18 F-fluoride;
at least one of (Y 1 ) n and Y 2 is said leaving group when n is 2;
R 1 is a non-interfering substituent with regard to fluoridation of B;
R 2 is a non-interfering substituent with regard to fluoridation of B; and
providing that A is selected such that the pK a of H a of an acid of the formula II:
is less than or equal to about 2.8.
60 . The use of claim 59 , wherein when A is substituted at a carbon alpha to the
group with a group that has a dissociable proton, the dissociable proton has a pKa greater than about 9 and contributes to a net positive charge on the group that has the dissociable proton.
61 . The use of claim 59 or 60 , wherein at least one leaving group is 19F.
62 . A conjugate or a salt thereof, wherein the conjugate comprises a peptide conjugated to a positron-emitting compound as defined in any one of claims 1 to 37 .Join the waitlist — get patent alerts
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