Tetrazine compounds for in vivo imaging

1 . A tetrazine compound comprising a tetrazine moiety and having the following Formula I:

wherein:

one of R 1 -R 5 is 18 F,

at least two of the remaining R 1 -R 5 are H, and the other remaining R 1 -R 5 are the same or different and are selected from H, alkyl, halogen, —CF 3 , —CN, —O-alkyl, —S-alkyl, —NH-alkyl, —N(alkyl) 2 , —NH(C═O)-alkyl, —N-alkyl-(C═O)-alkyl, —SO 2 -alkyl, —SO 2 —NH 2 , —SO 2 —NHalkyl, —SO 2 —N(alkyl) 2 -C(═O)—NH 2 , —C(═O)—NH-alkyl, —C(═O)—N(alkyl) 2 , —C(═O)—OH, —C(═O)—O-alkyl, —CH 2 —NH 2 , —CH 2 —NH-alkyl, —OH, CH 2 —O-alkyl, CH 2 —O-aryl, CH 2 —O-phenyl, CH 2 —O-naphthyl, and

wherein n is an integer from 1 to 4, and

R 6 is selected from H, CH 3 , unsubstituted phenyl,

wherein the curly bond indicates a link to the tetrazine moiety.

2 . A compound according to claim 1 , wherein alkyl is selected from linear or branched C 1 -C 6 alkyl and cyclic C 1 -C 6 alkyl, optionally substituted with —OH, —NH 2 or halogen.

3 . A compound according to claim 1 , wherein alkyl is selected from linear or branched methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert, butyl, pentyl, and hexyl.

4 . A compound according to claim 1 , wherein halogen is selected from I, Br, and Cl.

5 . A compound according to claim 1 , wherein R 1 -R 6 are selected from:

a) R 1 is 18 F and R 2 -R 6 are H;

b) R 2 is 18 F and R 1 and R 3 -R 6 are H; and

c) R3 is 18 F and R 1 -R 2 and R 4 -R 6 are H.

6 . A compound according to claim 1 , wherein R 1 -R 6 are selected from:

a) R 1 is 18 F and R 2 , R 3 , R 4 , and R 5 are H, and R 6 is selected from H,

b) R 2 is 18 F and R 1 , R 3 , R 4 and R 5 are H, and R 6 is selected from H,

and

c) R 3 is 18 F and R 1 , R 2 , R 4 , and R 5 are H, and R 6 is selected from H,

7 . A bioorthogonal chemistry method, comprising administering a compound according to claim 1 to a subject.

8 . A diagnostic method, comprising administering a compound according to claim 1 to a subject.

9 . An in vivo imagining method, comprising administering a compound according to claim 1 to a subject.

10 . A compound according to claim 1 , wherein the compound is able to the blood-brain-barrier of a human subject.

11 . A method for preparing a compound according to claim 1 , wherein the method comprises reacting formamidine acetate and hydrazine monohydrate with a nitrile in the presence of Zn(OTf) 2 .

12 . A method according to claim 11 , wherein the method comprises reacting

in the presence of hydrazine monohydrate to obtain the tetrazine compound, wherein:

one of R 1 -R 5 is 18 F,

at least two of the remaining R 1 -R 5 are H, and the other remaining R 1 -R 5 are the same or different and are selected from H, alkyl, halogen, —CF 3 , —CN, —O-alkyl, —S-alkyl, —NH-alkyl, —N(alkyl) 2 , —NH(C═O)-alkyl, —N-alkyl-(C═O)-alkyl, —SO 2 -alkyl, —SO 2 —NH 2 , —SO 2 —NHalkyl, —SO 2 —N(alkyl) 2 -C(═O)—NH 2 , —C(═O)—NH-alkyl, —C(═O)—N(alkyl) 2 , —C(═O)—OH, —C(═O)—O-alkyl, —CH 2 —NH 2 , —CH 2 —NH-alkyl, —OH, CH 2 —O-alkyl, CH 2 —O-aryl, CH 2 —O-phenyl, CH 2 —O-naphthyl, and

wherein n is an integer from 1 to 4, and

R 6 is selected from H, CH 3 , unsubstituted phenyl, and,

wherein the curly bond indicates a link to the carbon atom.

13 . A method according to claim 11 , wherein the reaction is carried out at a temperature in a range of from 50° C. to 70° C.

14 . A method according to claim 12 , further comprising cooling to room temperature, adding water, subsequently adding HCl, and extracting with EtOAc.

15 . A compound according to claim 1 , wherein R 2 or R 4 is 18 F.

16 . A compound according to claim 1 , wherein R 2 is 18 F and R 1 and R 3 -R 6 are H.

17 . A compound according to claim 1 , wherein R 3 is 18 F and R 1 -R 2 and R 4 -R 6 are H.

18 . A tetrazine compound comprising a tetrazine moiety and having the following Formula I:

wherein:

R 2 or R 4 is 18 F,

at least two of R 1 -R 5 are H, and the other remaining R 1 -R 5 are the same or different and are selected from H, alkyl, halogen, —CF 3 , —CN, —O—alkyl, —S—alkyl, —NH—alkyl, N(alkyl) 2 , —NH(C═O)—alkyl, —N—alkyl—(C═O)—alkyl, —SO 2 —alkyl, —SO 2 —NH 2 , —SO 2 —NHalkyl, —SO 2 —N(alkyl) 2 —C(═O)—NH 2 , —C(═O)—NH—alkyl, —C(═O)—N(alkyl) 2 , —C(═O)—OH, —C(═O)—O—alkyl, —CH 2 —NH 2 , —CH 2 —NH—alkyl, —OH, CH 2 —O—alkyl, CH 2 —O—aryl, CH 2 —O—phenyl, CH 2 —O—naphthyl, and

wherein n is an integer from 1 to 4, and

R 6 is selected from H, CH 3 , phenyl,

wherein the curly bond indicates a link to the tetrazine moiety.

19 . A tetrazine compound comprising a tetrazine moiety and having the following Formula II:

wherein:

R 7 is selected from —CH 2 —NH 2 , —CH 2 —NH—alkyl, —C(═O)—NH 2 , —C(═O)NH—alkyl, —NH—CH(═O), —NH—C(═O)—alkyl, —OH, —O—alkyl, —CH 2 —O—alkyl, —CH 2 —O—phenyl, —CH 2 —O—naphthalene, —CH 2 —C(═O)NH 2 , and —CH 2 —C(═O)—NH—alkyl.