Methods of radiofluorination of biologically active vectors

1. A method for radiofluorination comprising reaction of a compound of formula (I) with a compound of formula (II):

or,

a compound of formula (III) with a compound of formula (IV)

wherein

R1 is an aldehyde moiety, a ketone moiety, a protected aldehyde such as an acetal, a protected ketone, such as a ketal, or a functionality, such as diol or N-terminal serine residue, which can be rapidly and efficiently oxidised to an aldehyde or ketone using an oxidising agent;

R2 is a group selected from primary amine, secondary amine, hydroxylamine, hydrazine, hydrazide, aminoxy, phenylhydrazine, semicarbazide, and thiosemicarbazide and is preferably a hydrazine, hydrazide or aminoxy group;

R3 is a group selected from primary amine, secondary amine, hydroxylamine, hydrazine, hydrazide, aminoxy, phenylhydrazine, semicarbazide, or thiosemicarbazide, and is preferably a hydrazine, hydrazide or aminoxy group;

R4 is an aldehyde moiety, a ketone moiety, a protected aldehyde such as an acetal, a protected ketone, such as a ketal, or a functionality, such as diol or N-terminal serine residue, which can be rapidly and efficiently oxidised to an aldehyde or ketone using an oxidising agent;

to give a conjugate of formula (V) or (VI) respectively:

wherein X is —CO—NH—, —NH—, —O—, —NHCONH—, or —NHCSNH—, and is preferably —CO—NH—, —NH— or —O—; Y is H, alkyl or aryl substituents; and

the Linker group in the compounds of formulae (II), (IV), (V) and (VI) is selected from

wherein:

n is an integer of 0 to 20;

m is an integer of 1 to 10;

p is an integer of 0 or 1;

Z is O or S.

2. A method according to claim 1 wherein the vector is Arg-Gly-Asp peptide or an analogue thereof.

3. A method according to claim 2 wherein the vector comprises the fragment

4. A method according to claim 2 wherein the vector is of formula (A):

wherein X 7 is either —NH 2 or

wherein a is an integer of from 1 to 10, preferably a is 1.

5. A compound of formulae (V) or (VI) prepared according to method of claim 1 .

6. A compound according to claim 5 wherein the vector is Arg-Gly-Asp peptide or an analogue thereof.

7. A compound according to claim 6 wherein the vector comprises the fragment:

8. A compound according to claim 6 wherein the vector is of formula (A):

wherein X 7 is either —NH 2 or

wherein a is an integer of from 1 to 10, preferably a is 1.

9. A radiopharmaceutical composition comprising an effective amount of a compound according to claim 5 ; together with one or more pharmaceutically acceptable adjuvants, excipients or diluents.

10. A method for radiofluorination comprising reaction of a compound of formula (Ia) with a compound of formula (IIa):

or,

a compound of formula (IIIa) with a compound of formula (IVa)

wherein R1 and R4 are as defined in claim 1 ;

the Linker group in the compounds of formulae (IIa) and (IVa) are each a C 1-60 hydrocarbyl group, suitably a C 1-30 hydrocarbyl group, optionally including 1 to 30 heteroatoms, suitably 1 to 10 heteroatoms such as oxygen or nitrogen;

to give a conjugate of formula (Va) or (VIa) respectively:

wherein Y is H, alkyl or aryl substituents; and the Linker group is as defined for the compound of formula (IIa) or (IVa).

11. A compound of formula (Va) or (VIa) prepared according to method of claim 10 .

12. A method for radiofluorination comprising reaction of a compound of formula (VII):

with a compound of formula (VIII), (IX), (X) or (XI):

wherein:

n is an integer of 0 to 20;

m is an integer of 1 to 10;

X is —CO—NH—, —NH— or —O— and is preferably —O—

Y is H, alkyl or aryl substituents to give a compounds of formula (XII-XV) respectively:

wherein X is as defined for the compound of formula (VII), m and n are defined as for the compounds of formula (VIII to XI).

13. A compound of formula (XII), (XIII), (XIV), (XV) prepared according to method of claim 12 .

14. A method for radiofluorination comprising reaction of a compound of formula (XVI):

where Y is H, alkyl or an aryl substituent preferably with compounds of the formula (XVII), (XVIII),(XIX) or(XX):

wherein m is an integer of 1 to 10, n is an integer of 0 to 20, and W═—CONH—, —NH— or —O— to give a compound of formula (XXI), (XXII), (XXIII) or (XXIV) respectively:

wherein W═—CONH—, —NH— or —O—,

m, n, are as defined for the compounds of formula (XIII to XI) and Y is H, alkyl or aryl moiety.

15. A compound of formula (XXI), (XXII), (XXIII), (XXIV) prepared according to method of claim 14 .

16. A compound of formula (II) 18 F-(Linker)-R2 or a compound of formula (IIa) 18 F-(Linker)-O—NH 2 , with the proviso that:

in the compounds of formula (II), if the linker is phenyl then R2 is aminoxy (suitably —ONH 2 ).

17. A compound of formula (XVII), (XVIII), (XIX), or (XX):

wherein m is an integer of 1 to 10, n is an integer of 1 to 20, and W ═—CONH—, —NH— or —O—.

18. A compound of formula (IV) 18 F-(Linker)-R4 or a compound of formula (IVa) 18 F-(Linker)-R4; with the provisos that:

(i) in the compounds of formula (IV), the linker is not phenyl

(ii) in the compounds of formula (IVa), the linker is not phenyl or phenyl substituted by halo, hydroxy, or benzyloxy.

19. A compound of formula (VIII), (IX), (X), or (XI):

wherein:

n is an integer of 1 to 20;

m is an integer of 1 to 10;

Y is H, alkyl or aryl substituents

with the proviso that in the compounds of formula (X), n is 1 to 20.

20. A compound of formula

(I) or a compound of formula

(III) wherein R1 is an aldehyde moiety, a ketone moiety, a protected aldehyde such as an acetal, a protected ketone, such as a ketal, or a functionality, such as diol or N-terminal serine residue, which can be rapidly and efficiently oxidised to an aldehyde or ketone using an oxidising agent; and R3 is a group selected from primary amine, secondary amine, hydroxylamine, hydrazine, hydrazide, aminoxy, phenylhydrazine, semicarbazide, or thiosemicarbazide, and is preferably a hydrazine, hydrazide or aminoxy group.

21. A compound according to claim 20 wherein the vector is Arg-Gly-Asp peptide or an analogue thereof.

22. A compound according to claim 20 wherein the vector is of formula (A):

wherein X 7 is either —NH 2 or

wherein a is an integer of from 1 to 10, preferably a is 1.

23. The compound of formula:

24. A compound of formula

(Ia) or a compound of formula

(IIIa) wherein R1 is an aldehyde moiety, a ketone moiety, a protected aldehyde such as an acetal, a protected ketone, such as a ketal, or a functionality, such as diol or N-terminal serine residue, which can be rapidly and efficiently oxidised to an aldehyde or ketone using an oxidising agent; and

R3 is a group selected from primary amine, secondary amine, hydroxylamine, hydrazine, hydrazide, aminoxy, phenylhydrazine, semicarbazide, or thiosemicarbazide, and is preferably a hydrazine, hydrazide or aminoxy group.

25. A compound according to claim 24 wherein the vector is Arg-Gly-Asp peptide or an analogue thereof.

26. A compound according to claim 24 wherein the vector is of formula (A):

wherein X 7 is either —NH 2 or

wherein a is an integer of from 1 to 10, preferably a is 1.