Field of the Invention The present invention relates to novel processes for the production of F- 18 labeled radiotracers for Positron Emission Tomography (PET). The invention also comprises radiopharmaceutical kits using these processes.

Background of the Invention Due to its favorable half- life of 110 minutes and the low R ⁺ energy (635 keV) F- 18 is currently the most important isotope for Positron Emission Tomography (Wiist, F. (2005) Amino Acids, 29, 323-339.) However, the relatively short half-live requires fast processes for synthesis and purifaction of F- 18 labeled compounds.

A common protocol for the nucleophilic production of a F- 18 labeled radiotracer involves the steps of:

• Production of F- 18 isotope in a cyclotron by ¹⁸ O(p,n) ¹⁸ F reaction.

• Passing of the aqueous [F-18] fluoride solution through a anion exchange resin (e.g. QMA, PS-30).

• Elution of [F- 18] fluoride using a base/solvent mixture (commonly used: Kryptofix™ (4,7,13, 16,21,24-Hexaoxa-l,10-diazabicyclo[8.8.8]-hexacosane), potassium carbonate in acetonitrile/water or tetraalkylammonium salts in acetonitrile/water).

• Drying of the mixture by heating, gas stream and/or vacuum, optionally addition of acetonitrile and repeated drying. • Addition of a precursor in an organic solvent.

• Nucleophilic fluorination at RT- 180 ⁰ C or by microwave irradiation.

• Optionally, subsequent reactions or protecting group transformations. It is also possible to add the base/solvent mixture directly to the aqueous [F- 18] fluoride solution without trapping of the [F-18] fluoride on a cartridge. However, the drying procedure is similar and might take longer in case of large volume of the aqueous [F- 18] fluoride solution.

As mentioned before, due to the short half live of F- 18 (110 min) fast and reliable processes for the production of F- 18 radiotracers are needed. The step of removing water by azeotropic drying/evaporation demands up to 30% of the total time for the production of the labeled molecule starting from the aqueous [F-18] fluoride solution. To separate [F-18] fluoride from target water, electrochemical methods were described, e.g.: K. Hamacher, et al.; Appl. Rad. hot. 2002, 519-523; WO/2008/001098. Anodic deposition of [F- 18] fluoride allows a separation from target water. By rinsing the electrochemical cell with an anhydrous solvent, no further azeoptropic drying step is necessary prior fluorination processes. However, special electrochemical cells are needed for those kind of protocols.

The use of ionic liquids for nucleophilic radiofluorination processes was reported (K. D. Wook et al., Nucl. Med. Biol., 2003, 345-350; WO2003076366). A typical procedure involves the steps of addition of aqueous [F- 18] fluoride solution to an ionic liquid ([bmim][0Tf]) and Cs ₂ CO ₃ in H ₂ O at room temperature, the addition of a precursor in acetonitrile at 120 °C, stirred for 8 min without capping to allow water and acetonitrile to escape from the reaction vial, cooling of the reaction, extraction using diethyl ether and purification of the crude reaction mixture by chromatography.

The problem to be solved by the invention is to provide a method, that allows a nucleophilc radiofluorination in organic solvents without azeotropic drying/evaporation prior addition of the precursor.

Description of the Invention

One aspect of the present invention relates to methods for manufacturing radiofluorinated compounds, involving the steps of: • Passing aqueous [F-18]fluoride solution through a material A for trapping of [F- 18]fluoride on the material A.

• Optionally, drying of material A by gas stream G or by passing a solvents S through material A. • Elution of [F- 18] fluoride from material A using a base/solvent mixture B.

• Optionally, passing base/solvent mixture B through a material C prior and/or after passing B through material A.

• Optionally, additional washing of material C with another portion of mixture B or solvent L. • Addition of precursor D.

• Nucleophilic fluorination to synthesize radiofluorinated compound R- 18τ F.

• Optionally, subsequent reactions to convert R- ¹⁸ F to R'- ¹⁸ F.

• Optionally, purification OfR- ¹⁸ F or R'- ¹⁸ F.

• Optionally, formulation OfR- ¹⁸ F or R'- ¹⁸ F.

without an azeotropic drying / evaporation step prior addition of the precursor D.

A is a resin or solid, that allows trapping of [F- 18] fluoride.

Optionally cartridges or columns consisting of A could be used. In a preferred embodiment, A is an anion exchange material.

In a more preferred embodiment, A is a QMA or PS-30 cartridge.

G is a gas.

In a preferred embodiment, S is selected from the group comprising air, nitrogen, helium, argon, carbon dioxide.

S is a solvent or solvent mixture.

In a preferred embodiment, S is an anhydrous solvent or solvent mixture. In a more preferred embodiment, S is selected from the group comprising acetonitrile, DMF, DMSO, DMAA, THF, alcohols, toluene, benzene, dichlorobenzenes, dichloromethane, xylenes, sulfolanes, and mixtures thereof.

B is a mixture of a base E and a organic solvent or a mixture of organic solvents L.

Optionally, B contains a complexing agent or a phase transfer catalyst (e.g. kryptofix, crown ether). Optionally, B contains water.

E is an inorganic or organic base.

In a preferred embodiment, E is selected from the group comprising potassium salts, caesium salts, tetraalkylammonium salts, tetraalkylphosphonium salts, hi a more preferred embodiment, E is selected from the group comprising potassium carbonate, potassium bicarbonate, potassium oxalate, potassium sulfonates, potassium alkoxylates, potassium hydroxide, caesium carbonate, caesium bicarbonate, caesium alkoxylates tetraalkylammonium hydroxides, tetraalkylammonium bicarbonates, tetraalkylammonium halides, tetraalkylammonium sulfonates, tetraalkylphosphonium hydroxides, tetraalkylphosphonium bicarbonates, tetraalkylphosphonium halides, tetraalkylphosphonium sulfonates.

In a even more preferred embodiment, E is selected from the group comprising potassium carbonate, potassium bicarbonate, potassium oxalate, potassium mesylate, potassium tert-butylate, caesium carbonate, caesium bicarbonate, tetrabutylammonium hydroxide, tetrabutylammonium bicarbonate, tetrabutylammonium mesylate.

L is an organic solvent or mixture of organic solvents. L is not an ionic liquid. hi a preferred embodiment, L is selected from the group comprising acetonitrile, DMF, DMSO, DMAA, THF, alcohols, toluene, benzene, dichlorobenzenes, dichloromethane, xylenes, sulfolanes, and mixtures thereof. In a more preferred embodiment, L is is selected from the group comprising acetonitrile, DMF, DMSO, sulfolane, THF, ter/-butanol, amyl alcohol, DMAA or mixtures thereof.

C is a material, appropriate to remove water from solvents or solvents mixtures. Optionally, cartridges or columns consisting of C could be used. In a preferred embodiment, C is selected from the group comprising inorganic salts, inorganic oxides, resins, molecular sieves or mixtures thereof. In a more preferred embodiment, C is selected from the group comprising sodium sulfate, magnesium sulfate, potassium carbonate, calcium chloride, calcium sulfate, barium oxide, magnesium oxide, calcium oxide, phosphorous oxide, potassium hydroxide, caesium carbonate, caesium hydroxide, molecular sieves or mixtures thereof.

D is a precursor for nucleophilc radio fluorination.

Optionally, D is dissolved in a solvent L, as described before. hi a preferred embodiment, D is selected from the group comprising R-Q.

Q is a leaving group, suitable for a substitution with [F-18] fluoride. hi a preferred embodiment, Q is selected from the group comprising iodide, bromide, chloride, sulfonates, trialkyl ammonium salts, nitro, aryl iodonium salts, heteroaryl iodonium salts.

R is an organic molecule.

R' is an organic molecule.

Another aspect of the present invention relates to methods for manufacturing radiofluorinated compounds, involving the steps of:

• Mixing of aqueous [F-18] fluoride solution with a base/solvent mixture B. • Passing the mixture of B and [F-18] fluoride through a material C.

• Optionally, additional washing of material C with another portion of mixture B or solvent L.

• Addition of precursor D. • Nucleophilic fluorination to synthesize radiofluorinated compound R- ¹⁸ F.

• Optionally, subsequent reactions to convert R- ¹⁸ F to R'- ¹⁸ F.

• Optionally, purification OfR- ¹⁸ F or R'- ¹⁸ F.

• Optionally, formulation OfR- ¹⁸ F or R'- ¹⁸ F.

without an azeotropic drying / evaporation step prior addition of the precursor D.

B is a mixture of a base E and a organic solvent or a mixture of organic solvents L.

Optionally, B contains a complexing agent or a phase transfer catalyst (e.g. kryptofix, crown ether). Optionally, B contains water.

E is an inorganic or organic base. hi a preferred embodiment, E is selected from the group comprising potassium salts, caesium salts, tetraalkylammonium salts, tetraalkylphosphonium salts. In a more preferred embodiment, E is selected from the group comprising potassium carbonate, potassium bicarbonate, potassium oxalate, potassium sulfonates, potassium alkoxylates, potassium hydroxide, caesium carbonate, caesium bicarbonate, caesium alkoxylates tetraalkylammonium hydroxides, tetraalkylammonium bicarbonates, tetraalkylammonium halides, tetraalkylammonium sulfonates, tetraalkylphosphonium hydroxides, tetraalkylphosphonium bicarbonates, tetraalkylphosphonium halides, tetraalkylphosphonium sulfonates. hi a even more preferred embodiment, E is selected from the group comprising potassium carbonate, potassium bicarbonate, potassium oxalate, potassium mesylate, potassium tert-butylate, caesium carbonate, caesium bicarbonate, tetrabutylammonium hydroxide, tetrabutylammonium bicarbonate, tetrabutylammonium mesylate.

L is an organic solvent or mixture of organic solvents. L is not an ionic liquid.

In a preferred embodiment, L is selected from the group comprising acetonitrile, DMF, DMSO, DMAA, THF, alcohols, toluene, benzene, dichlorobenzenes, dichloromethane, xylenes, sulfolanes, and mixtures thereof. In a more preferred embodiment, L is is selected from the group comprising acetonitrile, DMF, DMSO, sulfolane, THF, tert-butanol, amyl alcohol, DMAA or mixtures thereof.

C is a material, appropriate to remove water from solvents or solvents mixtures. Optionally, cartridges or columns consisting of C could be used.

In a preferred embodiment, C is selected from the group comprising inorganic salts, inorganic oxides, resins, molecular sieves or mixtures thereof. In a more preferred embodiment, C is selected from the group comprising sodium sulfate, magnesium sulfate, potassium carbonate, calcium chloride, calcium sulfate, barium oxide, magnesium oxide, calcium oxide, phosphorous oxide, potassium hydroxide, caesium carbonate, caesium hydroxide, molecular sieves or mixtures thereof.

D is a precursor for nucieophilc radiofluorination. Optionally, D is dissolved in a solvent L, as described before.

In a preferred embodiment, D is selected from the group comprising R-Q.

Q is a leaving group, suitable for a substitution with [F-18]fluoride.

In a preferred embodiment, Q is selected from the group comprising iodide, bromide, chloride, sulfonates, trialkyl ammonium salts, nitro, aryl iodonium salts, heteroaryl iodonium salts. Furthermore, another aspect of the present invention relates to kits for carrying out a nucleophilic substitution according to the present invention.

Examples

Example 1: Use of Na?SO ₄ filled chromafix dry cartridge, synthesis of 2-(2-[F- 181Fluoro-ethylVnaphthalene in acetonitrile with K?CCh/krvptofix

Aqueous [F-18] fluoride solution was passed through a QMA cartridge (QMA light; LOT#023336307A; waters; preconditioned with 10 mL 0.5 M K ₂ CO ₃ -solution and 10 mL water). Measured activity of the QMA cartridge: 105 MBq. 10 mL air, 10 mL acetonitrile, 10 mL air were passer through the QMA cartridge. A Chromafix Dry cartridge (Chromafix Dry S Lot# 88.071; Macherey-Nagel) was connected to the QMA cartridge. 1 mL K ₂ CO ₃ /Kryptifix-solution (1 mg K ₂ CO ₃ , 5 mg kryptofix, 950 μL acetonitrile, 50 μL water) was passed first through the chromafix dry cartridge and then through the QMA cartridge. Remaining activity on the QMA cartridge: 18 MBq, activity of the solution: 83 MBq. 5 mg Methanesulfonic acid 2-naphthalen-2-yl-ethyl ester were added to the K ₂ CO ₃ /Kryptifix/[F-18]fluoride solution. The mixture was heated in a sealed vial at 100 °C for 10 min. After cooling to r.t., the conversion was determined by radio-TLC (silica gel, hexane/ethyϊ acetate = 9/1, non-radioactive 2-(2-Fluoro-ethyl)- naphthalene was used as standard): Radio-TLC:

S as

OS End Start

Ratio 2-(2-[F-18]Fluoro-ethyl)-naphthalene / [F- 18] fluoride: 93 : 7.

Example 2: Use of Na?SO ₄ filled chromafix dry cartridge, synthesis of 2-(2-[F- 181Fluoro-ethyl)-naphthalene in acetonitrile/t-BuOH with KϊCOVkrvptofix

Aqueous [F- 18] fluoride solution was passed through a QMA cartridge (QMA light; LOT#023336307A; waters; preconditioned with 10 mL 0.5 M K ₂ CO ₃ -solution and 10 mL water). Measured activity of the QMA cartridge: 92 MBq. 10 mL air, 10 mL acetonitrile, 10 mL air were passer through the QMA cartridge. A Chromafix Dry cartridge (Chromafix Dry S Lot# 88.071; Macherey-Nagel) was connected to the QMA cartridge. 1 mL K ₂ CO ₃ /Kryptifix-solution (1 mg K ₂ CO ₃ , 5 mg kryptofix, 750 μL t- BuOH, 200 μL acetonitrile, 50 μL water) was passed first through the chromafix dry cartridge and then through the QMA cartridge. Remaining activity on the QMA cartridge: 11 MBq, activity of the solution: 78 MBq. 5 mg Methanesulfonic acid 2- naphthalen-2-yl-ethyl ester were added to the K ₂ CO ₃ /Kryptifix/[F- 18] fluoride solution. The mixture was heated in a sealed vial at 100 ⁰ C for 10 min. After cooling to r.t., the conversion was determined by radio-TLC (silica gel, hexane/ethyl acetate = 9/1, nonradioactive 2-(2-Fluoro-ethyl)-naphthalene was used as standard): Radio-TLC: so

OS

O ON Ov

End Start

Ratio 2-(2-[F-18]Fluoro-ethyl)-naphthalene / [F-18]fluoride: 90 : 10.

Example 3: Use of Na^SO ₄ filled chromafix dry cartridge, synthesis of 2-(2-[F- lδiFluoro-ethvD-naphthalene in acetonitrile with Bu ₄ NOH

Aqueous [F- 18] fluoride solution was passed through a QMA cartridge (QMA light; LOT#023336307A; waters; preconditioned with 10 mL 0.5 M K ₂ CO ₃ -solution and 10 mL water). Measured activity of the QMA cartridge: 206 MBq. 10 mL air, 10 mL acetonitrile, 10 mL air were passer through the QMA cartridge. A Chromafix Dry cartridge (Chromafix Dry S Lot# 88.071; Macherey-Nagel) was connected to the QMA cartridge. 1 mL Bi^NOH-solution (10 μL 40 % Bu ₄ NOH in water, 990 μL acetonitrile) was passed first through the chromafix dry cartridge and then through the QMA cartridge. Remaining activity on the QMA cartridge: 31 MBq, activity of the solution: 175 MBq. 5 mg Methanesulfonic acid 2-naphthalen-2-yl-ethyl ester were added to the K ₂ Cθ ₃ /Kryptifix/[F- 18] fluoride solution. The mixture was heated in a sealed vial at 100 °C for 10 min. After cooling to r.t., the conversion was determined by radio-TLC (silica gel, hexane/ethyl acetate = 9/1, non-radioactive 2-(2-Fluoro-ethyl)-naphthalene was used as Standard): Radio-TLC:

0 ^s - f CO 0 ^s -

CO

End Start

Ratio 2-(2-[F-18]Fluoro-ethyl)-naphthalene / [F- 18] fluoride: 93 : 7.

Example 4:Synthesis Toluene-4-sulfonic acid 2-rF-181fluoro-ethyl ester in acetonitrile/t-

BuOH with KOtBu

TsO. /\ ^ TsO _Vs- ^- _18F

OTs -

Aqueous [F-18] fluoride solution was passed through a QMA cartridge (QMA light; LOT#023336307A; waters; preconditioned with 10 mL 0.5 M K ₂ CO ₃ -solution and 10 mL water). Measured activity of the QMA cartridge: 163 MBq. 10 mL air, 10 mL aceioniirilc, 10 /crε passed through the QMA cartridge. 1 mL kryptofix/potassium tert-butylate-solution (5 mg kryptofix, 0.8 mg KOtBu in 800 μL t- BuOH, 200 μL acetonitrile) was passed through the QMA cartridge. Remaining activity on the QMA cartridge: 24 MBq, activity of the solution: 132 MBq. 5 mg ethylene ditosylate were added to the solution. The mixture was heated in a sealed vial at 100 ⁰ C for 10 min. After cooling to r.t., the conversion was determined by radio-HPLC (C 18, water/acetonitrile = 100/0 - 5/95):

F-18 incorporation: 48 %.