Substituted organofluoroborates as imaging agents

1. A positron emitting compound or salt thereof having a half-life with respect to solvolytic de- 18 F-fluoridation at physiological pH of about 1000 minutes or more, wherein the compound is of the formula (IV):

wherein:

B is boron;

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;

at least one of (Y 1 ) n and Y 2 is 18 F;

Q 1 is —CR 3 R 4 R 5 ;

each of R 3 , R 4 , and R 5 is 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, linking group optionally joined to a biomolecule, a group that is substituted with at least one substituent that is a biomolecule, forms a group that is substituted with at least one substituent that is 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 —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;

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 and R 17 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a group that is substituted with at least one substituent that is a biomolecule, forms a group that is substituted with at least one substituent that is 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 group that is substituted with at least one substituent that is a biomolecule, forms a group that is substituted with at least one substituent that is 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 group that is substituted with at least one substituent that is a biomolecule, forms a group that is substituted with at least one substituent that is 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; and

each of R 23 and R 24 is independently H, D, a biomolecule, a linking group optionally joined to a biomolecule, a group that is substituted with at least one substituent that is a biomolecule, forms a group that is substituted with at least one substituent that is 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;

providing that Q 1 is selected such that the pK a of H a of an acid of the formula:

is less than or equal to about 2.8.

2. The positron emitting compound or salt of claim 1 , wherein:

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, 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.

3. The positron emitting compound or salt of claim 1 , wherein:

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;

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, 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.

4. The positron emitting compound or salt of claim 1 , wherein:

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.

5. The positron emitting compound or salt of claim 1 , wherein:

each of R 3 and R 4 is independently F or Cl;

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.

6. The positron emitting compound or salt of claim 1 , wherein:

R 3 is —N + R 15 R 16 R 17 ;

each of R 4 and R 5 is independently 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 —R +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.

7. The positron emitting compound or salt of claim 1 , wherein:

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.

8. A positron emitting compound or salt thereof, wherein the compound is:

wherein at least one F atom is 18 F.

9. The positron emitting compound or salt of claim 1 , wherein n is 2, each Y 1 is F and Y 2 is F.

10. The positron emitting compound or salt as defined in claim 1 , wherein at least two of (Y 1 ) n and Y 2 is 18 F.

11. A method of performing PET imaging comprising administering an imaging effective amount of a positron emitting compound or salt according to claim 1 to a subject or object to be subjected to and image via PET.

12. The positron emitting compound or salt of claim 1 , conjugated to a peptide.

13. A positron emitting compound or salt thereof as defined in claim 8 conjugated to a biomolecule.

14. The positron emitting compound of claim 13 , wherein the biomolecule is a peptide.

15. The positron emitting compound of claim 8 , wherein at least two F atoms are 18 F.

16. The positron emitting compound of claim 1 , wherein at least one of R 3 , R 4 , and R 5 is a C 3 -C 18 cycloalkyl group, wherein the C 3 -C 18 cycloalkyl group is an optionally substituted aromatic heterocyclic group containing one or more heteroatoms which may independently be nitrogen, sulfur, phosphorus or oxygen.

17. The positron emitting compound of claim 16 , wherein the aromatic heterocyclic group contains nitrogen.

18. The positron emitting compound of claim 17 , wherein the aromatic heterocyclic group is a 5-membered group.

19. The positron emitting compound of claim 16 , wherein the the aromatic heterocyclic group is a 5-membered group.

20. The positron emitting compound or salt of claim 1 , wherein when Q 1 is substituted at the carbon alpha to the

group with a group that has a dissociable proton, the dissociable proton has a pK a greater than about 9 and contributes to a net positive charge on the group that has the dissociable proton.

21. The positron emitting compound or salt of claim 1 , wherein Q 1 is selected such that the pK a of H a of the acid of the formula

is less than or equal to about 2.4, less than or equal to about 2.0, less than or equal to about 1.5, or less than or equal to about 1.0.