Solid-phase electrophilic fluorination

1. A process for the production of 6-L- 18 F-fluorodopa ( 18 F-FDOPA) which comprises treatment of a solid support-bound FDOPA precursor of formula (I):

wherein R 1 and R 2 independently selected from C 1-6 alkyl;

P 1 , P 2 , P 3 , and P 4 are each independently hydrogen or a protecting group;

with a source of 18 F selected from the group consisting of 18 F 2 , 18 F—CH 3 COOF and 18 F—OF 2 ;

to give the labelled tracer of formula (II)

wherein P 1 , P 2 , P 3 , and P 4 are each independently hydrogen or a protecting group;

optionally followed by:

(i) removal of excess fluorinating agent and 18 F − ions produced in the generation of the fluorinating agent or in the reaction of a compound of formula (I) with a source of 18 F; and/or

(ii) removal of any protecting groups; and/or

(iii) removal of organic solvent; and/or

(iv) formulation of the resultant compound of formula (II) as an aqueous solution.

2. A process for the production of 6-L- 18 F-fluorodopa ( 18 F-FDOPA) according to claim 1 which comprises treatment of a solid support-bound FDOPA precursor of formula (Ia):

wherein R 1 and R 2 independently selected from C 1-6 alkyl;

P 1 , P 2 , P 3 , and P 4 are each independently hydrogen protecting group;

with a source of 18 F selected from the group consisting of 18 F 2 , 18 F—CH 3 COOF, and 18 F—OF 2

to give the labelled tracer of formula (II):

wherein P 1 , P 2 P 3 , and P 4 are each independently hydrogen or a protecting group; optionally followed by

(i) removal of excess fluorinating agent and 18 F − ions produced in the generation of the fluorinating agent or in the reaction of a compound of formula (I) with a source of 18 F; and/or

(ii) removal of any protecting groups such that P 1 , P 2 , P 3 , and P 4 are each hydrogen; and/or

(iii) removal of organic solvent; and/or

(iv) formulation of the resultant compound of formula (II) as an aqueous solution.

3. A compound of formula (I):

as defined in claim 1 .

4. A compound of formula (Ia):

as defined in claim 2 .

5. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises reaction of a compound of formula (III)

wherein either R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from C 1-6 alkyl; or

R 1 , R 2 ,R 3 , and R 5 are each independently selected from C 1-6 alkyl and R 4 is

with a compound of formula (IV)

wherein P 1 , P 2 , P 3 , and P 4 are each independently hydrogen or a protecting group.

6. A process according to claim 5 for the preparation of a compound of formula (Ia) which comprises reaction of a compound of formula (IIIa)

wherein either

R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from C 1-6 alkyl; or

R 1 , R 2 , R 3 , and R 5 are each independently selected from C 1-6 alkyl and R 4 is

with a compound of formula (IV) as defined in claim 5 .

7. A process for the preparation of a compound of formula (V)

wherein R 1 and R 2 are independently C 1-6 alkyl, and phenyl ring “A” is optionally substituted with 1 to 5 organic groups selected from the group consisting of (a) halo, cyano, hydroxy, C 1-6 alkoxy, C 1-6 carboxylic acid or ester, an amine or amide group; and (b) saturated or unsaturated straight or branched chain, or cyclic systems comprising from 1 to 12 carbon atoms and 0 to 4 heteroatoms each of which may be optionally substituted by the groups listed in (a); which comprises:

reaction of a compound of formula (III)

wherein either:

R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from C 1-6 alkyl; or

R 1 , R 2 , R 3 , and R 5 are each independently selected from C 1-6 alkyl and R 4 is

with the corresponding compound of formula (VI)

wherein phenyl ring “A” is substituted with 1 to 5 organic groups selected from the group consisting of(a) halo, cyano, hydroxy, C 1-6 alkoxy, C 1-6 carboxylic acid or ester, an amine or amide group; and (b) saturated or unsaturated straight or branched chain, or cyclic systems comprising from 1 to 12 carbon atoms and 0 to 4 heteroatoms each of which may be optionally substituted by the groups listed in (a).

8. A process according to claim 7 for the preparation of a compound of formula (Va)

wherein R 1 and R 2 are independently C 1-6 alkyl and phenyl ring “A” is optionally substituted with 1 to 5 organic groups selected from the group consisting of (a) halo, cyano, hydroxy, C 1-6 alkoxy, C 1-6 carboxylic acid or ester, an amine or amide group; and (b) saturated or unsaturated straight or branched chain, or cyclic systems comprising from 1 to 12 carbon atoms and 0 to 4 heteroatoms each of which may be optionally substituted by the groups listed in (a); which comprises:

reaction of a compound of formula (IIIa):

wherein either R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from C 1-6 alkyl; or

R 1 , R 2 , R 3 , and R 5 are each independently selected from C 1-6 alkyl and R4 is

with a compound of formula (VI) as defined in claim 7 .

9. A process according to claim 7 wherein the compound of formula (VI) is

2-beta-carbomethoxy-3-beta-(4-iodophenyl)-8-(3-fluoropropyl)-nortropane.

10. A process for the manufacture of a 18 F-labelled tracer of formula (II) as defined in claim 1 for use in PET.

11. A radiopharmaceutical kit for the preparation of 18 F-FDOPA for use in PET, which comprises:

(i) a vessel containing a compound of formula (I) as defined in claim 1 respectively; and

(ii) means for eluting the vessel with a source of 18 F; and optionally

(iii) a cartridge for removal of excess fluorinating agent and 18 F − ions; and optionally

(iv) a cartridge for solid-phase deprotection of the resultant product of formula (II) as defined in claim 1 .

12. A cartridge for a radiopharmaceutical kit for the preparation of 18 F-FDOPA according to claim 11 for use in PET which comprises:

(i) a vessel containing a compound of formula (I) as defined in claim 1 respectively; and

(ii) means for eluting the vessel with a source of 18 F.

13. A method for obtaining a diagnostic PET image which comprises the step of using a radiopharmaceutical kit according to claim 11 .