HK1188126A - Method for rapid preparation of suitable [18f]fluoride for nucleophilic [18f]fluorination - Google Patents

Description

Fast preparation of nucleophilic [ 2 ]18F]Fluorinated of suitable value18F]Fluoride process

Technical Field

The invention mainly relates to¹⁸Preparation of F-labelled radiopharmaceutical. In particular, the invention relates to the effective elution of the [ alpha ], [ beta ] -state captured in a filter element¹⁸F]Advanced process for fluoride, said cartridge being filled with a quaternary ammonium polymer comprising inert non-basic and non-nucleophilic counter anions. The method and polymer filter element allow for rapid preparation of suitable [ alpha ], [ beta ]¹⁸F]Fluoride solutions, also less basic to reduce by-product formation, to ultimately increase¹⁸Radiochemical yield and purity of the F-radiopharmaceutical.

Keyword

¹⁸F-labelled radiopharmaceutical, tertiary alcohol, quaternary ammonium polymer, elution solution, flash drying.

Object of the Invention

The present invention is directed to a process for the preparation of a composition comprising a volatile elution solution and a filter element made by using an inert quaternary ammonium polymer¹⁸F]Rapid separation/elution of fluoride ions for preparation with high radiochemical yield and purity¹⁸An F-labelled radiopharmaceutical.

Background

Positron Emission Tomography (PET) is an emerging technology for imaging and diagnosing many early-stage human diseases. Miller, N.J.Long, R.Vilar, A.D.Gee, Angew.chem.int.Ed.2008, 47, 8998 to 9033]. Among several positron-emitting radionuclides produced by a cyclotron, it is considered that¹⁸F]Fluoride has chemical and physical properties that are most useful for diagnostic radiopharmaceuticals. Atomic size of fluorine and hydrogenSimilarly and fluorine provides improved lipophilicity and inertness to metabolic transformations for fluorine-containing compounds.

[¹⁸F]Fluoride can be readily prepared from medical cyclotrons and has an appropriate half-life of about 110 minutes. [ M.C.Lanne, C.Perrio, J.Rouden, L.Barre, D.Roeda, F.Dolle, C.Crouzel, Contrast Agents II, Topics in Current Chemistry, Springer-Verlag, Berlin, 2002, 222, 201 to 258 ]; bolton, j. labelledcompd. radiopharm.2002, 45485 to 528]。

Usually, produced by a cyclotron¹⁸F]Fluoride is present in the highly diluted O-18 rich aqueous solution. [ M.R.Kilbourn, J.T.hood, M.J.Welch, int.J.appl.radial Isot.1984, 35, 599; mulholland, r.d.hichwa, m.r.kilbourn, j.moskwa, j.label.comp.radiopharm.1989, 26, 140.]O-18 rich water is very expensive and contains traces of metal cations after irradiation, which may affect¹⁸F-labeling reaction.

The use of a filter cartridge containing an anion exchange resin is generally used to separate from O-18-rich water¹⁸F]Fluoride and trace amounts of metal cations are removed by solid phase extraction. [ K. -I, Nishijima, Y.Kuge, E.Tsukamoto, K. -I.Seki, K.Ohkura, Y.Magata, A.tanaka, K.Nagatsu, N.Tamaki.appl.Radiat.Isot.2002, 57, 43.; schoelter, obes.res.1999, 7, 519; SNM newslene, j.nuclear.med.1991, 32, 15N; schlyer, m.bases, a.p.wolf, j.nucl.med.1987, 28, 764; s.a.toorongian, g.k.mulholland, d.m.jewett, m.a.bachelor, m.r.kilbourn, nuclear.med.biol.1990, 17, 273; d.m.jewett, s.a.toorongian, g.k.mulholland, g.l.watkins, m.r.kilbourn, appl.radiat.iso.1988, 39, 1109; g.k.mulholland, r.d.t.j.manger, d.m.jewett, m.r.kilbourn, j.label.comp.radiopharm.1989, 26, 378; k.ohsaki, y.endo, s.yamazaki, m.tomoi, r.iwata, appl.radiat.isot.1998, 49, 373 to 378.]

And QMA cartridges are commonly used in automated radiolabeling as well as manual synthesis and are commercially available. They contain bicarbonate counter anions and chloride counter anions, respectively. These anions are slightly basic and nucleophilic so that they may cause stability problems during long-term storage. In other words, these basic anions can attack the internal labile benzylic carbon atom, producing a free volatile tertiary amine.

To activate the QMA cartridge, the chlorine counter anions were exchanged with carbonate anions by eluting aqueous potassium carbonate solution prior to use. After the respective activation process, the activation process is carried out,and QMA are both nucleophilic within the cartridge¹⁸F]The fluorination reaction has sufficient basic anion. In addition, an excess of potassium carbonate is usually used in the aqueous solution to cause [ 2 ], [¹⁸F]Fluoride is completely released from these cartridges. Final [ 2 ] after elution¹⁸F]The fluoride solution contains an excess of base and water.

An excess of base may cause many side reactions including elimination and hydroxylation. These by-product analogs lead to the desired¹⁸The F-labelled product is difficult to purify and has a low specific activity.

The use of repeated azeotropic evaporation with acetonitrile requires the removal of a large amount of water to prepare the reactive anhydrous [ alpha ], [ beta¹⁸F]Fluoride ion. It is known that a protic solvent comprising water passes through¹⁸F]The fluoride forms a strong hydrogen bond and decreases¹⁸F]Nucleophilicity of fluoride. The complete evaporation takes 15 to 20 minutes and the product is consumed¹⁸F]8 to 12% of the radioactivity of the fluoride. This time-consuming evaporation process also plays a key role in the low and fluctuating reproducibility of both manual and automated synthesis.

And 2¹⁸F]The earliest attempts related to fluorination were disclosed in [ j.w.seo, e.p.hong, b.s.lee, s.j.lee, s.j.oh, d.y.chi, j.laboratory compound. radiopharm.2007, 50 (increase)Periodical 1), S164]Wherein the volatile alcohol solution containing an ammonium-based neutral organic salt is used to elute the [ solution ] trapped in the polymeric filter element¹⁸F]Fluoride, causes a great reduction in drying time of 1-2 minutes and significantly suppresses side reactions.

However, neutral ammonium salts may make HPLC purification difficult by contaminating the HPLC column. Therefore, this method is limited to manual radiolabelling in cases of small radioactivity. This practical limitation accounts for the need for other advanced methods suitable for automated synthesis systems.

In the invention described herein, the nucleophilic [ 2 ] is carried out using a tertiary alcohol solvent¹⁸F]Fluorinated to avoid the formation of by-products according to the prior art. [ D.W.Kim, D. -S.Ahn, Y. -H.Oh, S.Lee, H.S.Kil, S.J.Oh, S.J.Lee, J.S.Kim, J. -S.Ryu, D.H.Moon, D.Y.Chi, J.Am.chem.Soc.2006, 126, 16394 to 16397.; d.h. moon, d.y.chi, d.w.kim, s.j.oh, j. -s.ryu.pct, WO2006/065038a1]

Drawings

FIG. 1 is a schematic diagram of the present invention. (A) Quaternary ammonium polymers consisting of tertiary amines and inert counter anions which are not nucleophilic; (B) from K222, KOMs and TBAHCO₃Alcohol elution solution of composition for rapid evaporation and mild alkalinity.

FIG. 2 is a diagram showing release of [ 2 ] from the quaternary ammonium polymer 6 by an elution solution (eluent A)¹⁸F]Graph of the radioactivity of fluoride.

FIG. 3 is a diagram showing release of [ 2 ] from the quaternary ammonium polymer 6-3 by an elution solution (eluents A, B and C)¹⁸F]Graph of the radioactivity of fluoride.

Object of the Invention

The present invention relates to a method for effecting nucleophilicity¹⁸F]The term of fluorination reaction¹⁸F]And (4) pretreating fluoride.

The present invention provides a stable neutral ionic polymer.

The invention also provides a method for synthesizing the neutral ionic polymer.

The invention provides a filter element filled with the ionic polymer.

The present invention also provides a method for separating [ 2 ] from water rich in O-18¹⁸F]A method for fluoride production.

The present invention provides releasing the [ alpha ], [ beta¹⁸F]Volatile solutions of fluoride.

The invention also provides a method for preparing the volatile elution solution.

The present invention provides a method of releasing the protein captured in the cartridge using the elution solution¹⁸F]A method for fluoride production.

The invention also provides a method for reducing evaporation time by using the filter element and the elution solution.

The present invention provides a method of increasing the nucleophilicity by reducing the evaporation time¹⁸F]Fluorinated radiochemical yield (RCY).

The present invention also provides a method for increasing the nucleophilicity by using the elution solution having a lower basicity¹⁸F]Method of fluorided RCY.

The present invention provides a method for reducing the nucleophilicity¹⁸F]The basicity of the fluorination conditions reduces the amount of precursor for ease of purification.

Detailed Description

The present invention relates generally to the field of nucleophiles¹⁸F]Fluorination, which occurs in a liquid reaction medium. As shown in fig. 1, the present invention includes two important advanced techniques. An advanced technology is related to quaternary ammonium polystyrenes having neutral counter anions, which are free ofNucleophilicity and basicity. Another advanced technique relates to volatile elution solutions consisting of K222, KOMs (or KOTf, or K)₃PO₄) And TBAHCO₃(or TBAOH, or KOH, or K)₂CO₃Or KHCO₃) And (4) forming. The invention not only realizes the short-time preparation¹⁸F]Fluorinating the solution to save [ 2 ]¹⁸F]Radioactivity of fluoride and the resultant product is used for the selectivity¹⁸F]Fluorinated lower basic [ alpha ]¹⁸F]A fluoride solution.

The present invention is described in detail below.

In the context of the present invention, a series of quaternary ammonium polymers are as shown in formula 1.

[ formula 1]

Polystyrene

Wherein R is selected from the group consisting of C1-C4 alkyl chains; a 5-or 6-membered heterocyclic compound having a nitrogen atom;

x is an inert alkylsulfonic acid ion or per fluoride ion (perfluoride) without nucleophilicity;

polystyrene is a copolymer consisting of styrene, styrene derivatives and Divinylbenzene (DVB).

In more detail, the present invention is described in more detail,

NR₃selected from the group consisting of trimethylamine, triethylamine, tri-N-propylamine, tri-N-butylamine, N-methylimidazole and pyridine;

x is selected from methanesulfonic acid ions (OMs), trifluoromethanesulfonic acid ions (OTf), p-toluenesulfonic acid ions (OTs), p-nitrobenzenesulfonic acid ions (ONs), tetrafluoroboric acid ions (BF)₄) Hexafluorophosphate ion (PF)₆) Hexafluoroantimonate ion (SbF)₆) And N, N-bis (trifluoromethanesulfonyl) amideSon (N (Tf)₂）；

Polystyrene is an insoluble copolymer composed of styrene and styrene derivatives, crosslinked with 10-90v/v% of divinylbenzene.

In an embodiment of the invention, the polymer may be prepared by two synthetic routes as shown in scheme 1.

Scheme 1

(wherein NR)₃And polystyrene as defined above

The first path (upper arrow) consists of two steps. The 4-vinylbenzyl ammonium chloride (3) intermediate was synthesized by the reaction of 4-vinylbenzyl chloride (2) with an excess of a tertiary amine as defined above (step 1). In situ polymerization of intermediate 3 with a divinylbenzene crosslinking agent was initiated by Azobisisobutyronitrile (AIBN) without purification to give solid polystyrene 5 (step 2). In the first step, the reaction medium is chosen from THF, CCl₄、CHCl₃1, 2-dichloroethane, acetonitrile, DMF, DMSO, and water. A mixed solvent of water and DMF is suitable as a reaction medium. The reaction in step 1 is carried out at 50 ℃ for 3 to 12 hours. In the second step, the reaction is carried out at 70 ℃ for 3 to 12 hours.

The second path (lower arrow) comprises two separate steps. Polymerization of 4-vinylbenzyl chloride (2) with DVB cross-linker was initiated by AIBN to give solid polystyrene 4, which was purified by washing and solid phase extraction using a soxhlet extractor (step 3). Ammonium chloride polymer 5 is prepared by quaternization of polymer 4 with an excess of a tertiary amine as described above (step 4).

In step 3, the reaction medium is selected from THF, CCl₄、CHCl₃1, 2-dichloroethane, 1Chlorobenzene, acetonitrile, DMF, DMSO, and water. Monochlorobenzene or DMF is suitable as reaction medium. The reaction in step 3 is carried out at 70 ℃ for 3 to 12 hours. In step 4, the reaction medium is selected from THF, CCl₄、CHCl₃1, 2-dichloroethane, acetonitrile, DMF, DMSO, and water. A mixed solvent of water and DMF is suitable as a reaction medium. The reaction in step 4 is carried out at 70 ℃ for 3 to 24 hours.

In an embodiment of the invention, the ammonium chloride polymer 5 is treated with aqueous MX solution to perform anion exchange from chloride anions to inert X anions, as shown in scheme 2.

Scheme 2

(wherein NR)₃X and polystyrene are as defined above)

In scheme 2, M is selected from lithium (Li), sodium (Na), potassium (K), 1-n-butyl-3-methylimidazole（[bmim]) Pyridine, and their useSubstituted pyridinesAnd NR₄(R = Me, Et, n-Pr, n-Bu). The anion exchange process proceeds as follows:

1) the ammonium chloride polymer 5 was placed in a funnel or syringe equipped with a polyethylene frit.

2) Aqueous MX solution was added to the funnel or syringe.

3) The suspension was stirred well for 3-10 minutes.

4) The solution was filtered off under reduced pressure.

5) The resulting polymer was washed with distilled water.

6) Repeating the steps 2-5 for several times.

7) The polymer was washed with acetone and dried under vacuum.

In an embodiment of the invention, the polymer 1 is used to prepare a more stable and efficient solid phase extraction cartridge to isolate¹⁸F]Fluoride and the preparation of [ alpha ], [ alpha ] having a low basicity¹⁸F]A fluoride solution.

In order to release completely from the filter cartridge¹⁸F]Fluoride and rapidly evaporates by reacting K222, KOMs (or KOTf, or K)₃PO₄) And TBAHCO₃(or TBAOH, or KOH, or K)₂CO₃Or KHCO₃) Combined to prepare an effective elution solution. Wherein K222 is a nucleophilic [ alpha ], [¹⁸F]The most effective phase transfer catalyst in fluorination; KOMs and KOTf are sources of inert anions in place of the TBAOMs disclosed in KP application #10-2008-0078233 for complete solid phase extraction [, ]¹⁸F]A fluoride compound; using K₃PO₄、TBAHCO₃、TBAOH、KOH、K₂CO₃And KHCO₃To keep the reaction solution alkaline. Diluting these components in an alcoholic solvent selected from primary alcohols such as methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol and n-octanol; or secondary alcohols such as isopropanol, isobutanol, isoamyl alcohol and 3-pentanol; or tertiary alcohols, for example tert-butanol, tert-amyl alcohol, 2, 3-dimethyl-2-butanol, 2- (trifluoromethyl) -2-propanol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-2-pentanol (2-emthyl-2-pentanol), 2, 3-dimethyl-3-pentanol, 2, 4-dimethyl-2-pentanol, 2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-cyclopropyl-2-butanol, 2-cyclopropyl-3-methyl-2-butanol, 1-methylcyclopentanol, 1-ethylcyclopentanol, 1-propylcyclopentanol, 2-dimethyl-2-propanol, 2-cyclopropyl-pentanol, 2-cyclopropyl-methyl-2-butanol, 1-methylcyclopentanol, 1-ethylcyclopentanol, 1-propylcyclopentanol, 2-methyl-2,1-methylcyclohexanol, 1-ethylcyclohexanol, 1-methylcycloheptanol.

In an embodiment of the invention, the [ 2 ] will be eluted from the polymeric filter element¹⁸F]Fluoride solutions at mild N₂Or He gas flow and evaporation under low vacuum. Then by heating at mild N₂Or He stream and azeotropic evaporation with acetonitrile under low vacuum to remove small amounts of water.

The contents of the present invention are not limited to the following examples.

Examples

Example 1: synthesis of trimethyl ammonium chloride polystyrene (5-1)

After 4-vinylbenzyl chloride (2, 1.00mL, 7.096 mmol) was dissolved in a mixed solution of water (0.5 mL) and DMF (5.0 mL), 40% aqueous trimethylamine solution (2.098 mL, 14.190 mmol) was added to the solution. The reaction mixture was stirred at 50 ℃ for 3 hours to obtain N- (4-vinylbenzyl) trimethylammonium chloride (3-1) (step 1). After cooling to room temperature, divinylbenzene (2.00 mL, 11.233 mmol) and AIBN (301 mg, 1.833 mmol) were added and allowed to dissolve completely. The reaction mixture was heated at 70 ℃ for 5 hours and then cooled to room temperature. The resulting polymer solid (5-1) was roughly pulverized and transferred to a 400-mesh sieve, and then washed with acetone several times (step 2). After the polymer solid was dried in air, it was ground in a mortar to produce small particles, which were then sorted by particle size using 4 different sieves in a stack to give trimethylammonium chloride polystyrene (5-1); 50-100 meshes: 2.25g, 100-200 mesh: 0.248g, 200-400 mesh: 0.208 g.

Example 2: synthesis of triethylammonium chloride polystyrene (5-2)

Triethylamine (1.978 mL, 14.190 mmol) was used instead of trimethylamine in example 1 above, and the same procedure and reaction scale as in example 1 were followed to obtain triethylammonium chloride polystyrene (5-2) as follows; 50-100 meshes: 2.374g, 100-200 mesh: 0.487g, 200-400 mesh: 0.221 g.

Example 3: synthesis of N-methylchloridazolePolystyrene (5-3)

Using N-methylimidazole (1.131 mL, 14.190 mmol) in place of trimethylamine in example 1 above and following the same procedure and reaction scale as in example 1, the following N-methylimidazole chloride was obtainedPolystyrene (5-3); 50-100 meshes: 1.120g, 100-200 mesh: 1.377g, 200-400 mesh: 0.189 g.

Example 4: synthesis of pyridine chloridePolystyrene (5-4)

Using pyridine (1.148 mL, 14.190 mmol) in place of trimethylamine in example 1 above, and following the same procedure and reaction scale as in example 1, pyridine chloride was obtained as followsPolystyrene (5-4); 50-100 meshes: 1.719g, 100-200 mesh: 0.206g, 200-400 mesh: 0.582 g.

Elemental analysis of the four ammonium chloride polymers obtained from examples 1-4 above was obtained, and the amount of ammonium ion of the resin was calculated based on the nitrogen content (%) as shown in table 1.

TABLE 1

EXAMPLE 5 preparation of trimethylammonium methanesulfonate polystyrene (1-1)

The polymer 5-1 (100-200 mesh, 200 mg) obtained from example 1 was placed in a syringe equipped with a polyethylene frit. Distilled water (10 mL) was added to the syringe and eluted out after 1 minute. The syringe was rinsed with 0.2M aqueous NaOMs (5 mL) and covered with a cap, then shaken for 3 minutes. The solution was removed by filtration under reduced pressure, and the resin was washed with distilled water. After repeating the ion exchange step four times, the resin was washed with distilled water (5 mL. times.5) and acetone (5 mL. times.5), and then dried under vacuum to give trimethylammonium methanesulfonate polystyrene (1-1, 235 mg).

EXAMPLE 6 preparation of triethylammonium methane sulfonate polystyrene (1-2)

Triethylammonium methanesulfonate polystyrene (1-2, 222 mg) was prepared from polymer 5-2 (100-200 mesh, 200 mg) by following the same procedure as in example 5.

Example 7 preparation of N-methylimidazole methanesulfonatePolystyrene (1-3)

Preparation of N-methylimidazole methanesulfonate from Polymer 5-3 (100-200 mesh, 200 mg) by following the same procedure as in example 5Polystyrene (1-3, 225 mg).

Example 8 preparation of pyridine methanesulfonatePolystyrene (1-4)

Preparation of N-methylimidazole methanesulfonate from Polymer 5-4 (100-200 mesh, 200 mg) by following the same procedure as in example 5Polystyrene (1-4, 220 mg).

TABLE 2

Compound (I)	Tertiary amines	Calculated value (mmol/g)
			1-1	NMe3	1.813
1-2	NEt3	1.823
			1-3	N-methylimidazole	1.805
1-4	Pyridine compound	1.817

EXAMPLE 9 preparation of Polymer Filter elements containing neutral ammonium polystyrene

20mg to 100mg of neutral ammonium methanesulfonate polymer 1 were filled into a filter cartridge equipped with a polyethylene frit.

The polymer cartridge 6-1 is prepared by filling with polymer 1-1.

The polymer cartridge 6-2 is prepared by filling with polymer 1-2.

The polymer cartridge 6-3 is prepared by filling with polymer 1-3.

The polymer cartridge 6-4 is prepared by filling with polymer 1-4.

EXAMPLE 10 preparation of the elution solution

The [ 2 ] for releasing the trapped in the filter element is prepared by combining the following three components and dissolving it in an alcohol solvent¹⁸F]An elution solution of fluoride.

Component A: kryptofix2,2,2 (K222); 10-20mg

Component B: KOMs, KOTf or K at 0.05-0.2M in water₃PO₄；0.05-0.2mL

Component C: TBAHCO₃(1-20. mu.L), TBAOH (1-20. mu.L) or 0.05-0.2M KOH, K₂CO₃Or KHCO₃；0.01-0.2mL

Ingredients were selected from groups A, B and C, and they were mixed together to prepare several elution solutions as follows;

eluent A

1)Kryptofix2,2,2（K222）；10-20mg

2) KOMs 0.2M in water; 0.05-0.2mL

3)TBAHCO₃；1-20μL

4) An alcohol; 1mL of

Eluent B

1)Kryptofix2,2,2（K222）；10-20mg

2)0.2M KOTf in water; 0.05-0.2mL

3)TBAHCO₃；1-20μL

4) An alcohol; 1mL of

Eluent C

1)Kryptofix2,2,2（K222）；10-20mg

2)0.2M K in Water₃PO₄；0.05-0.2mL

3)TBAHCO₃；1-20μL

4) An alcohol; 1mL of

Eluent D

1)Kryptofix2,2,2（K222）；10-20mg

2) KOMs 0.2M in water; 0.05-0.2mL

3)TBAOH；1-20μL

4) An alcohol; 1mL of

Eluent E

1)Kryptofix2,2,2（K222）；10-20mg

2) KOMs 0.2M in water; 0.05-0.2mL

3)0.05-0.2M KOH in water; 0.01-0.2mL

4) An alcohol; 1mL of

Eluent F

1)Kryptofix2,2,2（K222）；10-20mg

2) KOMs 0.2M in water; 0.05-0.2mL

3) K in water at 0.05-0.2M₂CO₃；0.01-0.2mL

4) An alcohol; 1mL of

Eluent G

1)Kryptofix2,2,2（K222）；10-20mg

2) KOMs 0.2M in water; 0.05-0.2mL

3)0.05-0.2M KHCO in water₃；0.01-0.2mL

4) An alcohol; 1mL of

Example 11 Using the alcohol elution solution (eluent A), the product trapped in the Filter core¹⁸F]Elution test of fluoride

Let's 2¹⁸F]An aqueous fluoride solution (about 3-6 mCi) is passed through the filter cartridge (6-1-6-4) prepared in the present invention to capture¹⁸F]A fluoride compound. Then the capture [ 2 ]¹⁸F]The fluoride cartridge was washed with distilled water (1.0 mL) and methanol solvent (1.0 mL) in that order. The [ 2 ] trapped in the filter element is released by eluting the solution prepared in the present invention (eluent A)¹⁸F]A fluoride compound. Released from the filter element¹⁸F]The amount of fluoride was counted per 0.1mL of eluate. The results of elution using the present invention are summarized in table 3.

Table 3 units: mCi

The steps are as follows;

step 1 in the step of [ 1]¹⁸F]The radioactivity remaining in the cartridge after the fluoride solution eluted through the cartridge (in all cases, no detectable in the filtered solution)Radioactive).

Step 2-radioactivity released from the filter after washing with distilled water (1.0 mL).

Step 3-radioactivity released from the filter after washing with methanol (1.0 mL).

Steps 4-13-radioactivity released from the cartridge after each elution with 0.1mL of the alcohol elution solution prepared in the present invention.

Step 14 — radioactivity remaining in the cartridge after step 13.

The results of this elution test are shown in figure 2.

Example 12 application of alcohol eluting solution (eluent A-eluent C) to the [ 2 ], [ solution ] trapped in the Filter element 6-3¹⁸F]Elution test of fluoride

Table 4 units: is based on

The steps are as follows;

step 1 in the step of [ 1]¹⁸F]The radioactivity remaining in the cartridge after the fluoride solution eluted through the cartridge (100%) (in all cases, no radioactivity was detected in the filtered solution).

Step 2-radioactivity (%) released from the filter after washing with distilled water (1.0 mL).

Step 3-radioactivity (%) released from the filter after washing with methanol (1.0 mL).

Step 4-8-radioactivity (%) released from the cartridge after each elution with 0.1mL of the alcohol elution solution prepared in the present invention.

Step 9-radioactivity (%) remaining in the cartridge after step 8.

The results of this elution test are shown in figure 3.

Example 13 use of 2-, [ 2 ] fluoride of the present invention¹⁸F]Fluoro-deoxyglucose (,)¹⁸F]FDG) precursor

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]Fluoride and 92.1 to 115.4MBq [ 2 ]¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]Fluoride was eluted into the reaction vial with eluent (A, B or C) solution of the present invention. The residual radioactivity in the filter element is 1.85-2.96 MBq. Eluting the solution at 100 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (5 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 100 ℃ for 10 minutes and then cooled to room temperature. radio-TLC scan showed 90.9% radiolabeling.

Eluent	Precursor body	5 minutes	10 minutes
				A	5mg	97.4	87.0
B	5mg	96.0	90.9
				C	5mg	90.6	88.3

Example 14 preparation of [ alpha ], [ alpha ] a¹⁸F]FP-CIT

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]195.4MBq of fluoride¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent a solution of the present invention. The remaining activity in the cartridge was 11.47 MBq. Eluting the solution at 100 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Completely removing comprisesThe solvent of water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (4 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.05 mL) was added to the reaction vial. The reaction mixture was heated at 100 ℃ for 20 minutes and then cooled to room temperature. radio-TLC scan showed 86.8% radiolabel. HPLC purification (Varian, Bondclone C18 column, 250 mm. times.10 mm, H)₂O:EtOH:Et₃N =250:750:2, 4 mL/min at 229 nm) to give [ 2 ], [ RCY, decay corrected ] in radiochemical yield of 67.9%¹⁸F]FP-CIT. All preparations including HPLC purification took 50 minutes.

Example 15 preparation of [ alpha ], [ alpha ] a¹⁸F]FP-CIT

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]2 of fluoride and 356.3MBq¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent D solution of the invention. The remaining activity in the cartridge was 54.8 MBq. Eluting the solution at 100 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (4 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.05 mL) was added to the reaction vial. The reaction mixture was heated at 120 ℃ for 20 minutes and then cooled to room temperature. radio-TLC scan showed 52.2% radiolabel. HPLC purification was performed to obtain [ 2 ], [ RCY, decay-corrected ] in a radiochemical yield of 42.4%¹⁸F]FP-CIT. All preparations including HPLC purification took 50 minutes.

Example 16 preparation of [ alpha ], [ alpha ] using the present invention¹⁸F]FP-CIT

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]Fluoride and 207.9MBq of¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent E solution of the present invention. The remaining activity in the cartridge was 9.25 MBq. Eluting the solution at 100 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (4 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.05 mL) was added to the reaction vial. The reaction mixture was heated at 100 ℃ for 20 minutes and then cooled to room temperature. radio-TLC scan showed 95.1% radiolabel. HPLC purification was performed to obtain 2 [ 2 ] in a radiochemical yield (RCY, decay corrected)¹⁸F]FP-CIT. All preparations, including HPLC purification, took 51 minutes.

Example 17 preparation of [ alpha ], [ alpha ] a¹⁸F]FP-CIT

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]2 of fluoride and 147.9MBq¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent F solution of the present invention. The remaining activity in the filter was 1.25 MBq. Eluting the solution at 100 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (4 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.05 mL) was added to the reaction vial. The reaction mixture was heated at 100 ℃ for 20 minutes and then cooled to room temperature. radio-TLC scan showed 53.6% radiolabeling.

Example 18 preparation of 2-, [ 2 ], [ using the present invention¹⁸F]Fluoro-deoxyglucose (,)¹⁸F]FDG）

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]2 of fluoride and 214.49MBq¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent a solution of the present invention. The remaining activity in the cartridge was 61.5 MBq. Eluting the solution at 100 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (20 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 100 ℃ for 20 minutes and then cooled to room temperature. radio-TLC scan showed 92.8% radiolabeling. By heating at 100 ℃ N₂The solvent was removed by purging. Mixing the residueDissolved in acetonitrile (0.5 mL) and then diluted with water (20 mL). The diluted solution was passed through a C18SepPak filter cartridge, which was then filled with 2M aqueous NaOH (1 mL) and held at room temperature for 2 minutes for hydrolysis. The reaction mixture was passed through an IC-H cartridge and an alumina N SepPak cartridge in this order to obtain 2-, [ 2 ] at 61.9% RCY (decay corrected)¹⁸F]Fluoro-deoxyglucose (,)¹⁸F]FDG). All preparations including HPLC purification took 50 minutes.

Example 19 preparation of 2-, [ 2 ], [ using the present invention¹⁸F]Fluoro-deoxyglucose (,)¹⁸F]FDG）

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]Fluoride and 148.0MBq [ ]¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent E solution of the present invention. The remaining activity in the cartridge was 9.25 MBq. Eluting the solution at 100 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (5 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 120 ℃ for 10 minutes and then cooled to room temperature. radio-TLC scan showed 77.7% radiolabeling. By heating at 100 ℃ N₂The solvent was removed by purging. The residue was dissolved in acetonitrile (0.5 mL) and then diluted with water (20 mL). The diluted solution was passed through a C18SepPak filter cartridge, which was then filled with 2M aqueous NaOH (1 mL) and held at room temperature for 2 minutes for hydrolysis. The reaction mixture was passed through successivelyPassing through an IC-H filter and an alumina N SepPak filter to obtain 2-, [ 2 ] at 48.9% RCY (decay corrected)¹⁸F]Fluoro-deoxyglucose (,)¹⁸F]FDG). All preparations, including HPLC purification, took 42 minutes.

Example 20 preparation of [ alpha ], [ alpha ] a¹⁸F]Fluorothymidine ([ 2 ]¹⁸F]FLT）

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]Fluoride and 192.3MBq [ [ alpha ] ]¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent a solution of the present invention. The remaining activity in the filter was 15.2 MBq. Eluting the solution at 120 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (20 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 120 ℃ for 20 minutes and then cooled to room temperature. radio-TLC scan showed 93.3% radiolabeling. By heating at 100 ℃ N₂The solvent was removed by purging. The residue was dissolved in acetonitrile (0.1 mL) and diluted with 1M aqueous HCl (0.5 mL). The solution was heated at 85 ℃ for 5 minutes and then treated with 2M aqueous NaOH (0.25 mL). HPLC purification (TSP, Econosil C18 column, 250 mm. times.10 mm, H)₂EtOH =90:10, 5 mL/min at 267 nm), giving [ 2 ], [ RCY, decay corrected ] in 48.6% radiochemical yield¹⁸F]FLT. All preparations including HPLC purification took 55 minutes.

Example 21 preparation of [ alpha ], [ alpha ] using the present invention¹⁸F]Fluorothymidine ([ 2 ]¹⁸F]FLT）

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]212.7MBq of fluoride¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent E solution of the present invention. The remaining activity in the filter was 16.3 MBq. Eluting the solution at 120 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (20 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 100 ℃ for 10 minutes and then cooled to room temperature. radio-TLC scan showed 74.8% radiolabeling.

Example 22 preparation of [ alpha ], [ alpha ] olefin¹⁸F]Fluorothymidine ([ 2 ]¹⁸F]FLT）

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]Fluoride and 375.1MBq [ ]¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]Fluoride with eluent G solution of the inventionElute into reaction vial. The remaining activity in the cartridge was 27.9 MBq. Eluting the solution at 120 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (10 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 100 ℃ for 20 minutes and then cooled to room temperature. radio-TLC scan showed 77.5% radiolabeling.

Example 23 preparation of [ alpha ], [ alpha ] a¹⁸F]Fluoro misonidazole (2)¹⁸F]FMISO）

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]Fluoride and 145.9MBq [ 2 ]¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent a solution of the present invention. The remaining activity in the cartridge was 12.4 MBq. Eluting the solution at 120 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (10 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 120 ℃ for 10 minutes and then cooled to room temperature. radio-TLC scan showed 96.1% radiolabel. By heating at 100 ℃ N₂The solvent was removed by purging. The residue was dissolved in acetonitrile (0.1 mL) and diluted with 1M aqueous HCl (0.5 mL). The solution was heated at 85 ℃ for 5 minutesThen treated with 2M aqueous NaOH (0.25 mL). HPLC purification (TSP, Econosil C18 column, 250 mm. times.10 mm, H)₂EtOH =95:5, 5 mL/min at 254 nm) to give [ 2 ], [ RCY, decay corrected ] in a radiochemical yield of 42.3%¹⁸F]FMISO. All preparations including HPLC purification took 45 minutes.

Example 24 preparation of [ alpha ], [ alpha ] a¹⁸F]BAY94-9172

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]2 of fluoride and 294.2MBq¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent a solution of the present invention. The remaining activity in the cartridge was 35.5 MBq. Eluting the solution at 120 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (4 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 120 ℃ for 10 minutes and then cooled to room temperature. radio-TLC scan showed 81.1% radiolabeling. By heating at 120 ℃ N₂The solvent was removed by purging. The residue was dissolved in acetonitrile (0.3 mL) and diluted with 1M aqueous HCl (0.5 mL). The solution was heated at 120 ℃ for 5 minutes and then treated with 2M aqueous NaOH (0.25 mL). HPLC purification (Varian, Gemini C18 column, 250 mm. times.10 mm, 0.1M ammonium formate: MeCN =40:60, 4 mL/min at 254 nm) was performed to give [ 2 ] in a radiochemical yield (RCY, decay corrected) of 58.1%¹⁸F]BAY 94-9172. Bag (bag)All preparations including HPLC purification took 60 minutes.

Example 25 preparation of [ alpha ], [ alpha ] olefin¹⁸F]BAY94-9172

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]Fluoride and 154.3MBq of¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent D solution of the invention. The remaining activity in the cartridge was 13.0 MBq. Eluting the solution at 120 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (4 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 120 ℃ for 20 minutes and then cooled to room temperature. radio-TLC scan showed 86.91% radiolabel. By heating at 120 ℃ N₂The solvent was removed by purging. The residue was dissolved in acetonitrile (0.3 mL) and diluted with 1M aqueous HCl (0.5 mL). The solution was heated at 120 ℃ for 5 minutes and then treated with 2M aqueous NaOH (0.25 mL). HPLC purification (Varian, Gemini C18 column, 250 mm. times.10 mm, 0.1M ammonium formate: MeCN =40:60, 4 mL/min at 254 nm) was performed to give [ 2 ] in a radiochemical yield (RCY, decay corrected) of 68.9%¹⁸F]BAY 94-9172. The total preparation including HPLC purification took 60 minutes.

Example 26 preparation of [ alpha ], [ alpha ] olefin¹⁸F]BAY94-9172

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]Fluoride and 173.2MBq [ 2 ]¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent G solution of the present invention. The remaining activity in the cartridge was 1.48 MBq. Eluting the solution at 120 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (4 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 120 ℃ for 20 minutes and then cooled to room temperature. radio-TLC scan showed 86.9% radiolabel. By heating at 120 ℃ N₂The solvent was removed by purging. The residue was dissolved in acetonitrile (0.3 mL) and diluted with 1M aqueous HCl (0.5 mL). The solution was heated at 120 ℃ for 5 minutes and then treated with 2M aqueous NaOH (0.25 mL). HPLC purification was performed to give [ 2 ], [ RCY, decay-corrected ] in a radiochemical yield of 52.2%¹⁸F]BAY 94-9172. The total preparation including HPLC purification took 60 minutes.

Example 27 preparation of [ alpha ], [ alpha ] a¹⁸F]FDDNP

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]Fluoride and 330.8GBq [ ] [ 2 ]¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent a solution of the present invention. The remaining activity in the cartridge was 43.3 MBq. Eluting the solution at 120 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (2 mg) dissolved in a co-solvent of tert-amyl alcohol (1.0 mL) and acetonitrile (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 100 ℃ for 5 minutes and then cooled to room temperature. radio-TLC scan showed 92.4% radiolabeling. HPLC purification (Varian, Econosil C18 column, 250 mM. times.10 mM, 50mM triethylammonium phosphate: MeCN =40:60, 4 mL/min at 254 nm) was carried out to give [ 2 ] in 48.5% radiochemical yield (RCY, decay corrected)¹⁸F]FDDNP. All preparations, including HPLC purification, took 61 minutes.

Example 28 preparation of [ alpha ], [ alpha ] a¹⁸F]FDDNP

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]259.8GBq of fluoride¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent F solution of the present invention. The remaining activity in the filter was 23.3 MBq. Eluting the solution at 120 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. Dissolving in tert-amyl alcohol (1.0 mL) and acetonitrileA solution of precursor (2 mg) in a cosolvent (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 100 ℃ for 5 minutes and then cooled to room temperature. radio-TLC scan showed 85.1% radiolabeling. HPLC purification (Varian, Econosil C18 column, 250 mM. times.10 mM, 50mM triethylammonium phosphate: MeCN =40:60, 4 mL/min at 254 nm) was carried out to give [ 2 ] in 48.5% radiochemical yield (RCY, decay corrected)¹⁸F]FDDNP. All preparations, including HPLC purification, took 61 minutes.

Example 29 preparation of [ alpha ], [ alpha ] using the present invention¹⁸F]FDDNP

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]Fluoride and 210.7GBq [ ]¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent G solution of the present invention. The remaining activity in the filter was 16.3 MBq. Eluting the solution at 120 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (2 mg) dissolved in a co-solvent of tert-amyl alcohol (1.0 mL) and acetonitrile (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 100 ℃ for 5 minutes and then cooled to room temperature. The radio-TLC scan showed 95.9% radiolabel (RCY, decay corrected). The entire preparation including HPLC purification took 65 minutes.

Example 30 preparation of [ alpha ], [ alpha ] a¹⁸F]AV-45

Angle [ alpha ], [ beta¹⁸F]The aqueous fluoride solution passes through the filter element (6-3) of the invention. No detection was made in the filtered solution¹⁸F]2.49GBq of fluoride¹⁸F]Fluoride is trapped in the filter element. Will be captured¹⁸F]The fluoride is eluted into the reaction vial with eluent a solution of the present invention. The remaining activity in the cartridge was 51.8 MBq. Eluting the solution at 120 ℃ under mild N₂Heated under a stream of gas to remove volatile solvent, and acetonitrile (0.5 mL) was then added to the reaction vial. The azeotropic evaporation was repeated. Complete removal of the solvent including water takes 1 minute 30 seconds to 2 minutes. A solution of the precursor (4 mg) dissolved in a co-solvent of t-amyl alcohol (1.0 mL) and acetonitrile (0.1 mL) was added to the reaction vial. The reaction mixture was heated at 120 ℃ for 20 minutes and then cooled to room temperature. radio-TLC scan showed 92.4% radiolabeling. By heating at 120 ℃ N₂The solvent was removed by purging. The residue was dissolved in acetonitrile (0.3 mL) and diluted with 1M aqueous HCl (0.5 mL). The solution was heated at 120 ℃ for 5 minutes and then treated with 2M aqueous NaOH (0.25 mL). HPLC purification was performed to give [ 2 ], [ RCY, decay-corrected ] in a radiochemical yield of 59.4%¹⁸F]And AV-45. All preparations, including HPLC purification, took 81 minutes.

Specifically, the present invention relates to:

1. separating and eluting [ alpha ], [ alpha ]¹⁸F]Fluoride and rapid evaporation [ alpha ]¹⁸F]A method of fluoride solution comprising the steps of:

(a) step 1-preparation of quaternary ammonium polymer (formula 1);

(b) step 2-separation by solid phase extraction Using a quaternary ammonium polymer (formula 1¹⁸F]Fluoride ions;

(c) step (ii) of3-preparation from K222, KOMs (or KOTf, or K)₃PO₄) And TBAHCO₃(or TBAOH, or KOH, or K)₂CO₃Or KHCO₃) An alcoholic solution of the composition;

(d) step 4-eluting the captured [ 2 ] on the polymer of step 1 with the alcohol solution of step 3¹⁸F]Fluoride ions;

(e) step 5-Evaporation of the [ 2 ], [ solution ] obtained in step 4¹⁸F]A fluoride solution;

(f) step 6-nucleophilic [ 2 ] using the method of step 1 to step 5¹⁸F]And (4) fluorination.

2. Quaternary ammonium polymers [ formula 1]

[ formula 1]

Polystyrene

Wherein NR is₃Is a tertiary amine having an alkyl chain of C1-C4; a 5-or 6-membered heterocyclic compound having a nitrogen atom;

x is an inert alkylsulfonic acid ion or per-fluoro ion without nucleophilicity;

polystyrene is a copolymer composed of styrene, styrene derivatives and divinylbenzene.

3. The method according to item 1, wherein the NR₃Selected from the group consisting of trimethylamine, triethylamine, tri-N-propylamine, tri-N-butylamine, N-methylimidazole and pyridine.

4. The method according to item 1 or 3, wherein X is selected from the group consisting of methanesulfonic acid ions (OMs), trifluoromethanesulfonic acid ions (OTf), p-toluenesulfonic acid ions (OTs), p-nitrobenzenesulfonic acid ions (ONs), tetrafluoroboric acid ions (BF)₄) Hexafluorophosphate ion (PF)₆) Hexafluoroantimonate ion (SbF)₆) And N, N-bis (trifluoromethanesulfonyl) s) Amine ion (N (Tf)₂）。

5. A process for preparing a neutral quaternary ammonium polymer.

6. The method according to item 5, wherein said quaternary ammonium polystyrene having chloride anions is prepared in two synthetic ways as shown in scheme 1,

scheme 1

。

7. The method according to item 6, wherein 4-vinylbenzyl ammonium chloride (3) is synthesized by the reaction of 4-vinylbenzyl chloride and a tertiary amine (step 1).

8. The method according to item 7, wherein the tertiary amine is selected from the group consisting of trimethylamine, triethylamine, tri-N-propylamine, tri-N-butylamine, N-methylimidazole and pyridine.

9. The method according to clause 6, wherein the ammonium chloride polystyrene (5) is synthesized by free radical polymerization of 4-vinylbenzylammonium chloride (3) and DVB initiated with AIBN (step 2).

10. The method according to item 6, wherein Merrifield-type chloromethyl polystyrene (formula 4) is synthesized by free radical polymerization of 4-vinylbenzyl chloride (2) and divinylbenzene initiated with AIBN (step 3).

11. The method according to step 4 of clause 6, wherein the ammonium chloride polystyrene (5) is synthesized by quaternization of chloromethyl polystyrene (4) with a tertiary amine.

12. The method according to item 11, wherein the tertiary amine is selected from the group consisting of trimethylamine, triethylamine, tri-N-propylamine, tri-N-butylamine, N-methylimidazole and pyridine.

13. The method of clause 5, wherein the ammonium chloride polystyrene is sorted by using sieves of different sizes to give >50 mesh; 50-100 meshes; 100-200 mesh; 200-400 meshes; <400 mesh.

14. A process for preparing the quaternary ammonium polymer of the present invention.

15. The method according to clause 14, wherein the quaternary ammonium polymer (1) is prepared in anion exchange by repeatedly shaking/filtering a suspension of ammonium chloride polymer (5) in aqueous MX solution as shown in scheme 2,

scheme 2

。

16. The method according to item 15, wherein M is selected from the group consisting of lithium (Li), sodium (Na), potassium (K), 1-n-butyl-3-methylimidazole（[bmim]) Pyridine, and their useSubstituted pyridinesAnd NR₄（R=Me、Et、n-Pr、n-Bu）。

17. The method according to clause 15, wherein X is selected from the group consisting of methanesulfonic acid ions (OMs), trifluoromethanesulfonic acid ions (OTf), p-toluenesulfonic acid ions (OTs), p-nitrobenzenesulfonic acid ions (ONs), tetrafluoroboric acid ions (BF)₄) Hexafluorophosphate ion (PF)₆) Hexafluoroantimonate ion (SbF)₆) And N, N-bis (trifluoromethanesulfonyl) amide ion (N (Tf))₂）。

18. The method according to clause 15, wherein the aqueous solvent is selected from water or aqueous organic solvents of acetonitrile, methanol, ethanol, isopropanol, tert-butanol, acetone, DMF and DMSO.

19. A polymeric filter cartridge 6 for solid phase anion extraction comprising neutral ammonium polystyrene.

20. A process for separating the alpha-olefin from aqueous solution¹⁸F]A method of fluoride, wherein the [ 2 ] dissolved in an aqueous solution¹⁸F]The fluoride passes through the polymer cartridge of item 19.

21. A method for preparing the elution solution of the present invention.

22. The method according to clause 21, wherein the elution solution is prepared by combining the three components (component a, component B, and component C) and dissolving it in an alcohol solvent.

23. The method according to items 21 and 22, wherein the ingredient A is K222, which is used as [ 2 ], [ 10 to 20mg¹⁸F]Fluorinated phase transfer catalysts.

24. The method according to items 21 and 22, wherein component B comprises 0.05-0.2M KOMs, KOTf and K₃PO₄Aqueous solution, which is used at 0.05 to 0.2 mL.

25. The method of clauses 21 and 22, wherein ingredient C comprises TBAHCO₃And TBAOH, which is used at 1 to 20 μ L.

26. The process according to items 21 and 22, wherein component C further comprises 0.05-0.2M KOH, K₂CO₃And KHCO₃Aqueous solution, which is used at 0.01 to 0.2 mL.

27. The method according to clauses 21 and 22, wherein the elution solution is prepared by combining components selected from the component groups (component a, component B and component C) and dissolving them in an alcohol solvent.

28. The method according to clauses 21, 22 and 27, wherein the alcoholic solvent is selected from primary alcohols, such as methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol and n-octanol; or secondary alcohols such as isopropanol, isobutanol, isoamyl alcohol and 3-pentanol; or tertiary alcohols, for example tert-butanol, tert-amyl alcohol, 2, 3-dimethyl-2-butanol, 2- (trifluoromethyl) -2-propanol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-2-pentanol, 2, 3-dimethyl-3-pentanol, 2, 4-dimethyl-2-pentanol, 2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-cyclopropyl-2-butanol, 2-cyclopropyl-3-methyl-2-butanol, 1-methylcyclopentanol, 1-ethylcyclopentanol, 1-propylcyclopentanol, 1-methylcyclohexanol, 1-ethylcyclohexanol, cyclohexanol, 1-methylcycloheptanol.

29. A composition for releasing a polypeptide trapped in the polymeric filter element¹⁸F]A method of fluoride, wherein the [ 2 ] captured in the polymer filter element¹⁸F]The fluoride was washed with distilled water (0.5-5.0 mL) and alcohol (0.5-5.0 mL) in this order, and then eluted with the elution solution prepared according to item 21.

30. The method according to item 29, wherein the alcoholic solvent is selected from primary alcohols such as methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol, and n-octanol; or secondary alcohols such as isopropanol, isobutanol, isoamyl alcohol and 3-pentanol; or tertiary alcohols, for example tert-butanol, tert-amyl alcohol, 2, 3-dimethyl-2-butanol, 2- (trifluoromethyl) -2-propanol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-2-pentanol, 2, 3-dimethyl-3-pentanol, 2, 4-dimethyl-2-pentanol, 2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-cyclopropyl-2-butanol, 2-cyclopropyl-3-methyl-2-butanol, 1-methylcyclopentanol, 1-ethylcyclopentanol, 1-propylcyclopentanol, 1-methylcyclohexanol, 1-ethylcyclohexanol, cyclohexanol, 1-methylcycloheptanol.

31. A liquid medicine for evaporating liquid medicine containing alpha-alpha¹⁸F]A method for the elution of a solution of fluoride, wherein the solution eluted from the polymeric filter element is subjected to mild N at 60-120 ℃ in the presence of a catalyst₂Or He gas flow and gentle vacuum for 1-3 minutes and repeated after addition of acetonitrile (0.5-1.0mL) until all solvents including water have been removed azeotropically completely.

32. Used for nucleophilic [ alpha ], [ alpha ]¹⁸F]Fluorination processWherein the method of the present invention is used to perform nucleophilic [ alpha ]¹⁸F]And (4) fluorination.

Claims (18)

1. A quaternary ammonium polymer of the formula (1),

[ formula 1]

Polystyrene

Wherein NR is₃Is tertiary amine, wherein R is C1-C4 alkyl chain; or NR₃Is a 5-or 6-membered heterocyclic compound having a nitrogen atom;

x is an inert alkylsulfonic acid ion or per-fluoro ion without nucleophilicity;

polystyrene is a copolymer composed of styrene, styrene derivatives or divinylbenzene.

2. The quaternary ammonium polymer of claim 1, wherein NR₃Selected from the group consisting of trimethylamine, triethylamine, tri-N-propylamine, tri-N-butylamine, N-methylimidazole and pyridine.

3. A quaternary ammonium polymer according to claim 1 or 2, wherein X is selected from the group consisting of methanesulfonic acid ions (OMs), trifluoromethanesulfonic acid ions (OTf), p-toluenesulfonic acid ions (OTs), p-nitrobenzenesulfonic acid ions (ONs), tetrafluoroboric acid ions (BF)₄) Hexafluorophosphate ion (PF)₆) Hexafluoroantimonate ion (SbF)₆) And N, N-bis (trifluoromethanesulfonyl) amide ion (N (Tf))₂）。

4. A process for the preparation of a neutral quaternary ammonium polymer according to claims 1 to 3, wherein quaternary ammonium polymer chlorides as intermediates are prepared by a synthetic route selected from two synthetic routes as shown in scheme 1:

the quaternary ammonium polymer according to claims 1 to 3 is then obtained by anion exchange.

5. A method of preparing the quaternary ammonium polymer according to claims 1 to 3, wherein the quaternary ammonium polymer (1) is prepared in an anion exchange manner by repeatedly shaking/filtering a suspension of ammonium chloride polymer (5) in aqueous MX solution as shown in scheme 2,

scheme 2

。

6. A polymer cartridge 6 for solid phase anion extraction comprising the neutral ammonium polystyrene of claims 1 to 3.

7. A process for separating the alpha-olefin from aqueous solution¹⁸F]A method of fluoride, wherein the [ 2 ] dissolved in an aqueous solution¹⁸F]Fluoride passes through the polymer cartridge of claim 6.

8. A process for preparing a filter cartridge for elution from the filter cartridge of claim 6¹⁸F]The method of eluting solution of (1), wherein the eluting solution is prepared by combining three components (component a, component B and component C) and dissolving it in an alcohol solvent.

9. The method according to claim 8, wherein the component A is K222, which is used as [ alpha ], [ alpha ] in an amount of 10 to 20mg¹⁸F]Fluorinated phase transfer catalysts.

10. The process according to claim 8 or 9, wherein the alcoholic solvent is selected from primary alcohols such as methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol and n-octanol; or secondary alcohols such as isopropanol, isobutanol, isoamyl alcohol and 3-pentanol; or tertiary alcohols, for example tert-butanol, tert-amyl alcohol, 2, 3-dimethyl-2-butanol, 2- (trifluoromethyl) -2-propanol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-2-pentanol, 2, 3-dimethyl-3-pentanol, 2, 4-dimethyl-2-pentanol, 2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-cyclopropyl-2-butanol, 2-cyclopropyl-3-methyl-2-butanol, 1-methylcyclopentanol, 1-ethylcyclopentanol, 1-propylcyclopentanol, 1-methylcyclohexanol, 1-ethylcyclohexanol, cyclohexanol, 1-methylcycloheptanol.

11. A kind ofFor releasing the trapped in the polymeric filter element of claim 6¹⁸F]A method of fluoride, wherein the [ 2 ] captured in the polymer filter element¹⁸F]The fluoride was washed with distilled water (0.5-5.0 mL) and alcohol (0.5-5.0 mL) in this order, and then eluted with the elution solution prepared according to claims 8 to 10.

12. A liquid medicine for evaporating liquid medicine containing alpha-alpha¹⁸F]Method of elution of a solution of fluorides, wherein the solution eluted from the polymeric cartridge according to claim 6 by the method according to claims 8 to 10 is at 60-120 ℃ under mild N₂Or He gas flow and gentle vacuum for 1-3 minutes and repeated after addition of acetonitrile (0.5-1.0mL) until all solvents including water have been removed azeotropically completely.

13. Used for nucleophilic [ alpha ], [ alpha ]¹⁸F]A method of fluorination, wherein the [ 2 ] obtained by the separation method using the quaternary ammonium polymer according to claim 1 to 3 is used¹⁸F]Performing nucleophilic [ alpha ], [ alpha¹⁸F]And (4) fluorination.

14. The method of claim 13, wherein the [ alpha ], [ beta ]¹⁸F]-FDG、[¹⁸F]-CIT、[¹⁸F]-FLT、[¹⁸F]-FMISO、[¹⁸F]-BAY94-9172、[¹⁸F]-FDDNP or [ 2 ]¹⁸F]Fluorination of the precursor of AV-45 to obtain respectively [ 2 ]¹⁸F]-FDG、[¹⁸F]-CIT、[¹⁸F]-FLT、[¹⁸F]-FMISO、[¹⁸F]-BAY94-9172、[¹⁸F]-FDDNP or [ 2 ]¹⁸F]-AV-45。

15. Separating and eluting [ alpha ], [ alpha ]¹⁸F]Fluoride and rapid evaporation [ alpha ]¹⁸F]A method of fluoride solution comprising the steps of:

(a) step 1-separation by solid phase extraction Using the quaternary ammonium polymer according to claim 1 to 3¹⁸F]Fluoride ions;

(b) step 2-preparation of a composition comprising K222, KOMs (or KOTf, or K)₃PO₄) And TBAHCO₃(or TBAOH, or KOH, or K)₂CO₃Or KHCO₃) An alcohol solution of (a);

(c) step 3-eluting the captured [ 2 ] on the polymer of step 1 with the alcohol solution of step 3¹⁸F]Fluoride ions; and

(d) step 4-Evaporation of the [ 2 ] obtained in step 4¹⁸F]A fluoride solution.

16. Separating and eluting [ alpha ], [ alpha ]¹⁸F]Fluoride and rapid evaporation [ alpha ]¹⁸F]A method of fluoride solution comprising the steps of:

(a) step 1-preparation of a quaternary ammonium polymer according to claims 1 to 3;

(b) step 2-separation by solid phase extraction Using the quaternary ammonium polymer according to claim 1 to 3¹⁸F]Fluoride ions;

(c) step 3-preparation of a composition comprising K222, KOMs (or KOTf, or K)₃PO₄) And TBAHCO₃(or TBAOH, or KOH, or K)₂CO₃Or KHCO₃) An alcohol solution of (a);

(d) step 4-eluting the captured [ 2 ] on the polymer of step 1 with the alcohol solution of step 3¹⁸F]Fluoride ions; and

(e) step 5-Evaporation of the [ 2 ], [ solution ] obtained in step 4¹⁸F]A fluoride solution.

17. Nucleophilic [ alpha ]¹⁸F]A method of fluorination comprising the method of claim 15 or 16.

18. The method of claim 17, wherein the [ alpha ], [ beta ]¹⁸F]-FDG、[¹⁸F]-CIT、[¹⁸F]-FLT、[¹⁸F]-FMISO、[¹⁸F]-BAY94-9172、[¹⁸F]-FDDNP or [ 2 ]¹⁸F]Fluorination of the precursor of AV-45 to obtain respectively [ 2 ]¹⁸F]-FDG、[¹⁸F]-CIT、[¹⁸F]-FLT、[¹⁸F]-FMISO、[¹⁸F]-BAY94-9172、[¹⁸F]-FDDNP or [ 2 ]¹⁸F]-AV-45。