Method for preparing fluorine-18 eluent with adjusted PH, and method for labelling fluorine-18 using same

Abstract

The present invention relates to a method for labelling fluorine-18, which is a radioisotope, and more specifically, to a method for labelling a [.sup.18F]fluoride in a method for preparing an organic [.sup.18F]fluoro compound by reacting an alkyl halide or an alkyl sulfonate with a [.sup.18F]fluoride, wherein a [.sup.18F]fluoride supported on a quaternary alkyl ammonium polymer support is eluted using a solution containing a metal salt or a quaternary ammonium salt with an adjusted pH, and a base is not additionally used. The present invention enables a labeling reaction without an additional base after precisely reflecting the concentration of a base absolutely necessary for the nucleophilic substitution of a [.sup.18F]fluoride or eluting a [.sup.18F]fluoride using a [.sup.18F]fluoride eluent with an adjusted pH, thereby stably obtaining a [.sup.18F]fluoride-labelled compound in a high yield, and is thus useful for production of fluorine-18-labelled radioactive medical supplies.

Claims

1. A method for preparing an organic [.sup.18F]fluoro compound, the method comprising the steps of: (a) preparing an eluent by a method comprising reacting compounds represented by Formula 1 and Formula 2 as shown in Scheme 1: ##STR00019## wherein R.sub.1 is a C.sub.1-C.sub.10 primary or secondary alkyl group or aryl group;
MX[Formula 2] wherein M is lithium, sodium, potassium, cesium, or rubidium, and X is a hydroxyl ion, a carbonate ion, a bicarbonate ion, a phosphate ion, a diphosphate ion, a triphosphate ion, or t-butoxide; ##STR00020## wherein R.sub.1, M, and X are as defined in Formulas 1 and 2, and wherein the pH of the eluent is adjusted to 6.0 to 8.0; (b) eluting an [.sup.18F]fluoride adsorbed on a quaternary ammonium support into a reactor using the eluent; (c) removing the eluent in the reactor after the elution; and (d) reacting an alkyl halide or alkyl sulfonate with the eluted [.sup.18F]fluoride in the presence of a reaction solvent, wherein the alkyl halide or alkyl sulfonate is selected from the group consisting of N-(3-methanesulfonyloxypropyl)-2-carbomethoxy-3--(4-iodophenyl)tropane, N-(3-toluenesulfonyloxypropyl)-2-carbomethoxy-3--(4-iodophenyl)tropane, 3-(2-nitroimidazol-1-yl)-2-O-tetrahydropyranyl-1-O-toluenesulfonyl propanediol, (5-O-DMTr-2-deoxy-3-O-nosyl--D-threo-pentofuranosyl)-3-N-BOC-thymine, (E)-2-(2-(2-(4-(4-(tert-butoxycarbonyl (methyl)amino)styryl)phenoxy)ethoxy)ethoxy)ethyl methanesulfonate and (E)-2-(2-(2-(5-(4-(tert-butoxycarbonyl(methyl)amino)styryl)pyridin-2-yloxy)ethoxy)ethoxy)ethyl methanesulfonate.

2. The method of claim 1, wherein the reactor solvent is an aprotic solvent or protic solvent.

3. The method of claim 2, wherein the aprotic solvent is any one selected from the group consisting of acetonitrile, dimethylformamide, and dimethylsulfoxide.

4. The method of claim 2, wherein the protic solvent is a primary alcohol selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, n-amyl alcohol, n-hexyl alcohol, n-heptanol, and n-octanol; a secondary alcohol selected from the group consisting of isopropanol, isobutanol, isoamyl alcohol, and 3-pentanol; and a tertiary alcohol selected from the group consisting of t-butanol, t-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, and 1-methylcycloheptanol.

5. A method for preparing an organic [.sup.18F]fluoro compound, the method comprising the steps of: (a) preparing an eluent by a method comprising reacting compounds represented by Formula 1 and Formula 2 as shown in Scheme 1: ##STR00021## wherein R.sub.1 is a C.sub.1-C.sub.10 primary or secondary alkyl group or aryl group;
MX[Formula 2] wherein M is lithium, sodium, potassium, cesium, or rubidium, and X is a hydroxyl ion, a carbonate ion, a bicarbonate ion, a phosphate ion, a diphosphate ion, a triphosphate ion, or t-butoxide; ##STR00022## wherein R.sub.1, M, and X are as defined in Formulas 1 and 2, and wherein the pH of the eluent is adjusted to 6.0 to 8.0; (b) eluting an [.sup.18F]fluoride adsorbed on a quaternary ammonium support into a reactor using the eluent; and (c) reacting an alkyl halide or alkyl sulfonate with the eluted [.sup.18F]fluoride in the presence of the eluent in the reactor after the elution as a reaction solvent, wherein the alkyl halide or alkyl sulfonate is selected from the group consisting of N-(3-methanesulfonyloxypropyl)-2-carbomethoxy-3--(4-iodophenyl)tropane, N-(3-toluenesulfonyloxypropyl)-2-carbomethoxy-3--(4-iodophenyl)tropane, N-3-(2-nitroimidazol-1-yl)-2-O-tetrahydropyranyl-1-O-toluenesulfonyl propanediol, (5-O-DMTr-2-deoxy-3-O-nosyl--D-threo-pentofuranosyl)-3-N-BOC-thymine, (E)-2-(2-(2-(4-(4-(tert-butoxycarbonyl (methyl)amino)styryl)phenoxy)ethoxy)ethoxy)ethyl methanesulfonate and (E)-2-(2-(2-(5-(4-(tert-butoxycarbonyl(methyl)amino)styryl)pyridin-2-yloxy)ethoxy)ethoxy)ethyl methanesulfonate.

Description

DESCRIPTION OF DRAWINGS

(1) FIG. 1 is a conceptual view showing a [.sup.18F]fluoride labeling method according to a prior art;

(2) FIG. 2 is a conceptual view showing a [.sup.18F]fluoride labeling method in accordance with an embodiment of the present invention; and

(3) FIG. 3 is a conceptual view showing a [.sup.18F]fluoride labeling method in accordance with another embodiment of present invention.

MODE FOR INVENTION

(4) To achieve the above objects, the present invention provides a method for preparing a fluorine-18 eluent with an adjusted pH.

(5) Moreover, whether to use an additional base in a reactor is determined based on the concentration of the eluent prepared by the above method and, at this time, the present invention provides a method for labeling with fluorine-18 by reacting the eluted [.sup.18F]fluoride with an alkyl halide or alkyl sulfonate in the presence of a reaction solvent.

(6) Hereinafter, the present invention will be described in detail.

(7) The first step is to prepare a fluorine-18 eluent with an adjusted pH.

(8) In the method for preparing an eluent according to the present invention, in the sulfonic acid represented by Formula 1, R.sub.1 is an alkyl group or aryl group. More specifically, the alkyl group is preferably a C.sub.1-C.sub.18 alkyl sulfonic acid or halo C.sub.1-C.sub.10 alkyl group, and examples thereof include methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid, chloromethanesulfonic acid, trifluoromethanesulfonic acid, and chloroethanesulfonic acid. Moreover, the aryl group is preferably selected from the group consisting of a phenyl group, a C.sub.1-C.sub.4 alkyl phenyl group, a halo phenyl group, a C.sub.1-C.sub.4 alkoxy phenyl group, and a nitrophenyl group, and preferred examples thereof include methylphenylsulfonic acid, ethylphenylsulfonic acid, chlorophenylsulfonic acid, bromophenylsulfonic acid, methoxyphenylsulfonic acid, and nitrophenylsulfonic acid.

(9) In the method for preparing an eluent according to the present invention, in the base represented by Formula 2, M is a metal or quaternary ammonium, preferably lithium, sodium, potassium, cesium, rubidium or ammonium, and X is a base, preferably a hydroxyl ion, a carbonate ion, a bicarbonate ion, a phosphate ion, a diphosphate ion, a triphosphate ion, or t-butoxide, more preferably potassium hydroxide (KOH) or tetrabutylammonium hydroxide (TBAOH), which is mixed with the compound of Formula 1 to prepare an eluent having a pH of 6.0 to 8.0. When the pH of the eluent is less than 6.0, the amount of a base additionally required is increased, and when the pH exceeds 8.0, the precursor is decomposed by the eluent itself, which is problematic in the [.sup.18F]fluoride labeling efficiency.

(10) In the method for preparing an eluent according to the present invention, the solvent used for the elution is acetonitrile or alcohol containing water, and the alcohol may be selected from the group consisting of a primary alcohol such as methanol, ethanol, n-propanol, n-butanol, amyl alcohol, n-hexyl alcohol, n-heptanol, n-octanol, etc.; a secondary alcohol such as isopropanol, isobutanol, isoamyl alcohol, 3-pentanol, etc.; and a tertiary alcohol such as t-butanol, t-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, 1-methylcycloheptanol, etc., but may preferably be selected from primary alcohols such as methanol and ethanol.

(11) In the method for labeling with fluorine-18 according to the present invention, the eluent prepared by the above method is used to elute [.sup.18F]fluoride trapped in an anion exchange polymer support to a reactor, and a base required for [.sup.18F]fluoride labeling reaction is added dropwise to the reactor. Referring to the following Tables 1 and 2, it can be seen that the use of a conventional eluent affects the concentration of the base in the reactor, which changes the [.sup.18F]fluoride labeling efficiency; however, the use of the eluent prepared by the above method enables stable labeling with [.sup.18F]fluoride at high yield.

(12) Here, the base added to the reactor is the base of Formula 2 and may preferably be selected from the group consisting of potassium carbonate (K.sub.2CO.sub.3), potassium hydrogen carbonate (KHCO.sub.3), potassium hydroxide (KOH), tetrabutylammonium hydrogen carbonate (TBAHCO.sub.3), and tetrabutylammonium hydroxide (TBAOH).

(13) When the pH of the eluent is in the range of 7.0 to 8.0, the [.sup.18F]fluoride labeling reaction is possible even without the addition of a base to the reaction, and it can be seen from the following Table 3 that the labeling efficiency varies depending on the pH of the eluent, and even when the amount of the precursor is reduced, a high labeling efficiency is maintained at an optimal pH.

(14) In the method for labeling with organofluorine-18, the reaction solvent is an aprotic solvent or protic solvent. The aprotic solvent may preferably be acetonitrile, dimethylformamide, and dimethylsulfoxide, and the protic solvent may preferably be alcohol, more preferably a tertiary alcohol selected from the group consisting of t-butanol, t-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, and 1-methylcycloheptanol, and most preferably a tertiary alcohol selected from the group consisting of t-butanol, t-amyl alcohol, and 2,3-dimethyl-2-butanol.

(15) In a method for preparing an organofluoro-18 compound according to the present invention, the organofluoro-18 compound prepared by the above method may be [.sup.18F]fluoropropyl-carbomethoxytropane represented by the following Formula 5:

(16) ##STR00004##

(17) In the method for preparing an organofluoro-18 compound according to the present invention, the organofluoro-18 compound prepared by the above method may be [.sup.18F]fluoromisonidazole represented by the following Formula 8:

(18) ##STR00005##

(19) In the method for preparing an organofluoro-18 compound according to the present invention, the organofluoro-18 compound prepared by the above method may be [.sup.18F]fluorothymidine represented by the following Formula 11:

(20) ##STR00006##

(21) In the method for preparing an organofluoro-18 compound according to the present invention, the organofluoro-18 compound prepared by the above method may be [.sup.18F]fluoroestradiol represented by the following Formula 12:

(22) ##STR00007##

(23) In the method for preparing an organofluoro-18 compound according to the present invention, the organofluoro-18 compound prepared by the above method may be [.sup.18F]fluorodeoxyglucose represented by the following Formula 13:

(24) ##STR00008##

(25) In the method for preparing an organofluoro-18 compound according to the present invention, the organofluoro-18 compound prepared by the above method may be [.sup.18F]fluoroDDNP represented by the following Formula 14:

(26) ##STR00009##

(27) In the method for preparing an organofluoro-18 compound according to the present invention, the organofluoro-18 compound prepared by the above method may be [.sup.18F]fluorobetaben represented by the following Formula 17:

(28) ##STR00010##

(29) In the method for preparing an organofluoro-18 compound according to the present invention, the organofluoro-18 compound prepared by the above method may be [.sup.18F]fluorobetapir represented by the following Formula 20:

(30) ##STR00011##

(31) In the method for preparing an organofluoro-18 compound according to the present invention, the organofluoro-18 compound prepared by the above method may be [.sup.18F]FHBG represented by the following Formula 21:

(32) ##STR00012##

(33) In the method for preparing an organofluoro-18 compound according to the present invention, the organofluoro-18 compound prepared by the above method may be [.sup.18F]HX4 represented by the following Formula 22:

(34) ##STR00013##

(35) Next, the present invention will be described in more detail with reference to FIG. 1.

(36) FIG. 1 is a conceptual view showing a [.sup.18F]fluoride labeling method according to a prior art;

(37) Specifically, [.sup.18F]fluoride trapped in an anion exchange polymer support is eluted into a reactor using an eluent containing an inert salt. The reactor contains a base required for [.sup.18F]fluoride labeling reaction. At this time, the concentration of the base present in the reactor may be changed by the eluent. As a result, the base required for the [.sup.18F]fluoride labeling reaction may be lost, which reduces the [.sup.18F]fluoride labeling efficiency and makes it difficult to predict the change in the concentration of the base present in the reactor, which is more problematic.

(38) FIG. 2 is a conceptual view showing a [.sup.18F]fluoride labeling method in accordance with an embodiment of the present invention.

(39) Specifically, [.sup.18F]fluoride trapped in an anion exchange polymer support is eluted into a reactor using an eluent with an adjusted pH of 6.0 to 8.0, prepared using the sulfonic acid of Formula 1 and the base of Formula 2. At this time, the reactor contains a base required for [.sup.18F]fluoride labeling reaction. According to the above method, the concentration of the base present in the reactor is not changed by the eluent used for the elution, and thus the [.sup.18F]fluoride labeling efficiency at high yield can be maintained stable.

(40) FIG. 3 is a conceptual view showing a [.sup.18F]fluoride labeling method in accordance with another embodiment of present invention.

(41) Specifically, [.sup.18F]fluoride trapped in an anion exchange polymer support is eluted into a reactor using an eluent with adjusted pHs of 7.0 to 8.0, prepared using the sulfonic acid of Formula 1 and the base of Formula 2. At this time, the reactor contains no base required for [.sup.18F]fluoride labeling reaction in the reactor. According to the above method, the [.sup.18F]fluoride labeling reaction is performed using only the eluent used for the elution, which makes it possible to prevent a variation in the labeling efficiency caused by an error in the concentration of the base, which occurs upon further addition of the base, and thus the [.sup.18F]fluoride labeling efficiency at high yield can be maintained stable.

(42) In this aspect, the present invention can be effectively applied to the preparation of a radiopharmaceutical labeled with [.sup.18F]fluoride, a radioisotope, and in particular can be easily applied to any type of automated synthesis apparatus. The present invention has applications to the synthesis of radiopharmaceuticals labeled with [F]fluoride, a radioisotope.

BEST MODE FOR CARRYING OUT INVENTION

(43) Next, the present invention will be described in more detail with reference to the following Examples. However, these examples are merely illustrative of the preset invention, and the scope of the present invention is not limited by these examples. It will be appreciated by those skilled in the art that various modifications and changes can be made without departing from the scope of the present invention, and all such modifications and changes are intended to be included within the scope of the present invention.

Example 1

Preparation 1 of Organofluoro-18 Compound

Synthesis of [18F]fluoropropyl-carbomethoxytropane

(44) The synthesis process of [.sup.18F]fluoropropyl-carbomethoxytropane is shown in Scheme 2. [.sup.18F]fluoride was passed through a quaternary ammonium support (Chromafix or QMA) to be adsorbed thereon by exchanging anions, and the [.sup.18F]fluoride adsorbed on the quaternary ammonium support was eluted into a reactor containing a base (TBAOH: 2 mg) using an eluent with an adjusted pH, prepared using methanesulfonic acid and potassium hydroxide, and 100 L of acetonitrile solution containing Kryptofix (K222). After the elution, the eluent was completely removed by azeotropic distillation while introducing nitrogen gas at 100 C. 0.1 mL of acetonitrile, in which 4 mg of N-(3-methanesulfonyloxypropyl)-2-carbomethoxy-3--(4-iodophenyl)tropane or N-(3-toluenesulfonyloxypropyl)-2-carbomethoxy-3--(4-iodophenyl)tropane was dissolved, and 1.0 mL of t-amyl alcohol were placed in the reactor and reacted at 120 C. for 20 minutes to synthesize compound 5, and the labeling efficiency was analyzed by a radio thin-layer chromatography.

(45) ##STR00014##

Comparative Examples 1-8

Preparation 2 of Organofluoro-18 Compound

Synthesis of [18F]fluoropropyl-carbomethoxytropane

(46) In order to examine the effect of a conventional eluent using an inert metal salt on the labeling efficiency, the labeling efficiency was measured using inert metal salts having different manufacturing numbers and prepared by the same manufacturer.

(47) Compound 5 was synthesized by the same method as in Example 1, except that [.sup.18F]fluoride adsorbed on the quaternary ammonium support (Chromafix or QMA) was eluted with a conventionally used eluent, i.e., an eluent using an inert metal salt KOMs, and various concentrations of base (TBAOH 2 to 8 mg) were used for [.sup.18F]fluoride labeling reaction.

(48) TABLE-US-00001 TABLE 1 Amount Manu- Manu- of facturing facturing base in number of number of Eluent reactor TLC yield Examples KOMs eluent pH (mg) (%) Example 1 Inventive 7.00 2 74.19 4.2 eluent Comparative BCBC4256 KOMs-1 7.01 2 0 Example 1 Comparative BCBC4256 KOMs-1 7.01 4 47.13 Example 2 Comparative BCBC4256 KOMs-2 5.97 5 0 Example 3 Comparative BCBC4256 KOMs-2 5.97 7 55.35 Example 4 Comparative BCBC4256 KOMs-3 5.21 7 65.58 Example 5 Comparative BCBC4256V KOMs-4 6.57 5 20.67 Example 6 Comparative BCBC4256V KOMs-4 6.57 6 37.22 Example 7 Comparative BCBC4256V KOMs-4 6.57 8 73.40 Example 8

(49) As shown in Table 1, it was found that the inventive eluent showed a stable yield of 74.194.2% with the use of 2 mg base, while in the case of Comparative Examples 1-5, even the use of KOMs having the same manufacturing number showed various pHs during the preparation, resulting in a significant change in TLC yield. Even the use of KOMs having different manufacturing numbers resulted in a difference in yield of more than 20% at the same base concentration (Comparative Examples 3 and 6).

Experimental Example 1

Preparation 3 of Organofluoro-18 Compound

Synthesis of [18F]fluoropropyl-carbomethoxytropane

(50) In order to examine whether the concentration of the base present in the reactor was affected by the use of the conventional inert metal salt KOMs, compound 5 was synthesized by the same method as in Example 1, except that [.sup.18O]H.sub.2O solution containing [.sup.18O]fluoride was placed in a reactor containing a base (TBAOH: 2 mg) without the use of a quaternary ammonium support (Chromafix or QMA), and then the eluent was completely removed by azeotropic distillation while introducing nitrogen gas at 100 C.

Experimental Examples 2-5

Preparation 4 of Organofluoro-18 Compound

Synthesis of [18F]fluoropropyl-carbomethoxytropane

(51) Compound 5 was synthesized by the same method as in Example 1, except that insert metal salts KOMs and various concentrations of base (TBAOH 2 to 5 mg) were previously placed in the reactor.

(52) TABLE-US-00002 TABLE 2 0.2M KOMs Amount of base in Examples solution (L) reactor (mg) TLC yield (%) Expeimental 2 37.62 Example 1 Expeimental 100 2 0 Example 2 Expeimental 100 3 1.16 Example 3 Expeimental 100 4 47.13 Example 4 Expeimental 100 5 17.29 Example 5

(53) As shown in Table 2, it was found that the addition of the KOMs solution resulted in a decrease in the TLC yield from 37.62% to 0% even during the reaction using the same base and the increased amount of base from 2 mg to 4 mg results in a TLC yield of 47.13%. Therefore, it was indirectly confirmed that about 2 mg of salt required for the reaction was lost by KOMs.

Example 2

Preparation 5 of Organofluoro-18 Compound

Synthesis of [18F]fluoropropyl-carbomethoxytropane

(54) Compound 5 was synthesized by the same method as in Example 1, except that [.sup.18F]fluoride adsorbed on the quaternary ammonium support (Chromafix or QMA) was eluted using eluents with various pHs of 7.0 to 7.8, prepared using methanesulfonic acid and various bases, without the addition of a base to the reactor.

(55) TABLE-US-00003 TABLE 3 Types of bases used for preparation of Eluents eluent Eluent pH TLC yield (%) 1 KOH 7.2 12.31 2 KOH 7.4 6.37 3 t-BuOK 7.2 9.22 4 t-BuOK 7.4 4.35 5 K2CO3 7.2 60.15 6 K2CO3 7.4 70.55

(56) As shown in Table 3, it was found that the use of various types of bases for the preparation of the eluents at the same pH resulted in a difference in the TLC yield of up to 66% and the use of K.sub.2CO.sub.3 resulted in a labeling efficiency of up to 70.55%. Therefore, it can be seen that the [.sup.18F]fluoride labeling reaction can be stably performed by adjusting the pH of the eluent without the addition of a small amount of base to the rector.

Example 3

Preparation 6 of Organofluoro-18 Compound

Synthesis of [18F]fluoromisonidazole

(57) The synthesis process of [.sup.18F]fluoromisonidazole is shown in Scheme 3. [.sup.18F]fluoride was labeled by the same method as in Example 1, except that [.sup.18F]fluoride was eluted from a quaternary ammonium support using eluents with various pHs of 7.0 to 7.8, prepared using methanesulfonic acid and potassium carbonate (KHCO.sub.3), and 1 to 5 mg of 3-(2-nitroimidazol-1-yl)-2-O-tetrahydropyranyl-1-O-toluenesulfonyl propanediol was dissolved in 1 mL of acetonitrile and reacted at 100 C. The [.sup.18F]fluoride labeling efficiency was analyzed by a radio thin-layer chromatography scanner (radio TLC scanner), and then compound 8 was synthesized by adding 0.5 mL of 1 M hydrochloric acid, followed by hydrolysis at 100 C. for 5 minutes. Subsequently, 250 mL of 2 M sodium hydroxide was added for neutralization, and then 250 mL of citrate buffer was added, and purified by HPLC.

(58) ##STR00015##

(59) TABLE-US-00004 TABLE 4 Eluents Amount of precursor (mg) Eluent pH TLC yield (%) 1 5 7.4 98.76 2 1 7.4 68.30 3 1 7.6 93.60 4 1 7.8 92.41

Example 4

Preparation 7 of Organofluoro-18 Compound

Synthesis of [18F]fluorothymidine

(60) The synthesis process of [.sup.18F]fluorothymidine is shown in Scheme 4. [.sup.18F]fluoride was labeled by the same method as in Example 1, except that [.sup.18F]fluoride was eluted from a quaternary ammonium support using an eluent with a pH of 7.4, prepared using methanesulfonic acid and potassium carbonate (KHCO.sub.3), and 5 mg of (5-O-DMTr-2-deoxy-3-O-nosyl--D-threo-pentofuranosyl)-3-N-BOC-thymine was dissolved in 1 mL of acetonitrile and reacted at 100 C. The [.sup.18F]fluoride labeling efficiency was analyzed by a radio thin-layer chromatography scanner (radio TLC scanner), and the labeling efficiency was measured to be 75.67%. After the labeling reaction, compound 11 was synthesized by adding 0.5 mL of 1 M hydrochloric acid, followed by hydrolysis at 100 C. for 5 minutes. Subsequently, 250 mL of 2 M sodium hydroxide was added for neutralization, and then 250 mL of citrate buffer was added, and purified by HPLC.

(61) ##STR00016##

Example 5

Preparation 8 of Organofluoro-18 Compound

Synthesis of [18F]fluorobetaben

(62) The synthesis process of [.sup.18F]fluorobetaben is shown in Scheme 5. [.sup.18F]fluoride was labeled by the same method as in Example 1, except that [.sup.18F]fluoride was eluted from a quaternary ammonium support using an eluent with a pH of 7.4, prepared using methanesulfonic acid and potassium carbonate (KHCO.sub.3), and 4 mg of (E)-2-(2-(2-(4-(4-(tert-butoxycarbonyl(methyl)amino)styryl)phenoxy)ethoxy)ethoxy)ethyl methanesulfonate was dissolved in 1 mL of acetonitrile and reacted at 120 C. The [.sup.18F]fluoride labeling efficiency was analyzed by a radio thin-layer chromatography scanner (radio TLC scanner), and the labeling efficiency was measured to be 75.67%. After the labeling reaction, compound 17 was synthesized by adding 0.5 mL of 1 M hydrochloric acid, followed by hydrolysis at 100 C. for 5 minutes. Subsequently, 250 mL of 2 M sodium hydroxide was added for neutralization and then purified by HPLC.

(63) ##STR00017##

Example 6

Preparation 9 of Organofluoro-18 Compound

Synthesis of [18F]fluorobetapir

(64) The synthesis process of [.sup.18F]fluorobetapir is shown in Scheme 6. Compound 20 was synthesized by the same method as in Example 1, except that [.sup.18F]fluoride was eluted from a quaternary ammonium support using an eluent with a pH of 7.4, prepared using methanesulfonic acid and potassium carbonate (KHCO.sub.3), and 4 mg of (E)-2-(2-(2-(5-(4-(tert-butoxycarbonyl(methyl)amino)styryl)pyridin-2-yloxy)ethoxy)ethoxy)ethyl methanesulfonate was dissolved in 1 mL of acetonitrile and reacted at 120 C. The [.sup.18F]fluoride labeling efficiency was analyzed by a radio thin-layer chromatography scanner (radio TLC scanner), and the labeling efficiency was measured to be 80.38%.

(65) ##STR00018##