HK1187548A - Method for production of f-18 labeled amyloid beta ligands - Google Patents

Description

Method for producing F-18 labeled amyloid beta ligand

Technical Field

The present invention relates to compounds and methods that provide a route to F-18 labeled stilbene derivatives.

Background

4- [ (E) -2- (4- {2- [2- (2-fluoroethoxy) ethoxy ] ethoxy } phenyl) ethenyl ] -N-methylaniline has been labelled with F-18 fluoride and is claimed by patent application WO2006066104 and members of the corresponding patent family.

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] -ethoxy } phenyl) ethenyl ] -N-methylaniline.

The usefulness of such radiotracers for the detection of A β plaques has been reported in the literature (W.Zhang et al, nucleic Medicine and Biology 32(2005) 799-.

The synthesis of 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) -vinyl ] -N-methylaniline has been previously described:

a) zhang et al, Nuclear Medicine and Biology 32(2005) 799-809.

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] -ethoxy } phenyl) ethenyl ] -N-methylaniline

4mg of precursor 2a (2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] -phenyl } ethenyl ] phenoxy } ethoxy) ethoxy ] ethyl methanesulfonate) was reacted with [ F-18] fluoride/kryptofix/potassium carbonate complex in 0.2mL of DMSO. The intermediate was deprotected with HCl and neutralized with NaOH. The mixture was extracted with ethyl acetate. The solvent was dried and evaporated, the residue was dissolved in acetonitrile and purified by semi-preparative HPLC. 20% (corrected for decay) and 11% (uncorrected for decay) of 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) vinyl ] -N-methylaniline were obtained in 90 min.

b）WO2006066104

4mg of the precursor 2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] -phenyl } ethenyl ] phenoxy } ethoxy) ethoxy ] ethyl methanesulfonate in 0.2mL of DMSO was reacted with [ F-18] fluoride/kryptofix/potassium carbonate complex. The intermediate was deprotected with HCl and neutralized with NaOH. The mixture was extracted with ethyl acetate. The solvent was dried and evaporated, the residue was dissolved in acetonitrile and purified by semi-preparative HPLC. 30% (corrected for decay) and 17% (uncorrected for decay) of 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) vinyl ] -N-methylaniline were obtained in 90 min.

c）WO2010000409

4mg of the perfluorinated precursor was reacted with 1.3GBq [ F-18] fluoride to yield N-Boc protected 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) vinyl ] -N-methylaniline. The unreacted perfluorinated precursor is removed using a fluorine phase cartridge. Deprotection, final purification and formulation to obtain a product suitable for injection into humans is not disclosed. Furthermore, the usefulness of this approach at higher radioactivity levels (e.g., for unwanted F-19/F-18 exchanges) is not demonstrated. Finally, this method requires a two-pot (two-pot) set-up (first reaction vessel: fluorination reaction, followed by solid phase extraction and deprotection in a second reaction vessel)

However, the focus of the present invention is on improved "one pot" compounds and methods for making 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) vinyl ] -N-methylaniline.

More recently, other approaches have been described:

d）US20100113763

mesylate precursor 2a was reacted with [ F-18] fluoride species in a solvent mixture consisting of 100. mu.L acetonitrile and 500. mu.L tertiary alcohol. After fluorination at 100 ℃ and 150 ℃ for 10min, the solvent was evaporated. After deprotection (1N HCl, 5min, 100-.

e) Wang et al, Nuclear Medicine and Biology 38(2011)121-

5mg of precursor 2a (2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] -phenyl } ethenyl ] phenoxy } ethoxy) ethoxy ] ethyl methanesulfonate) was reacted with [ F-18] fluoride/kryptofix/potassium carbonate complex in 0.5mL of DMSO. The intermediate was deprotected with HCl and neutralized with NaOH. The crude product was diluted with acetonitrile/0.1M ammonium formate (6/4),

and purified by semi-preparative HPLC. The product fractions were collected, diluted with water, passed through a C18 column and eluted with ethanol to yield 17% in 50min (not corrected for decay)

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) ethenyl ] -N-methylaniline.

In the paper, the conversion of unprotected mesylate precursors is described:

5mg of unprotected mesylate precursor (2- {2- [2- (4- { (E) -2- [4- (methylamino) phenyl ] vinyl } phenoxy) ethoxy ] -ethoxy } ethyl 4-methanesulfonate) in 0.5mL of DMSO was reacted with [ F-18] fluoride/kryptofix/potassium carbonate complex. The crude product was diluted with acetonitrile/0.1M ammonium formate (6/4) and purified by semi-preparative HPLC. The product fractions were collected, diluted with water, passed through a C18 column and eluted with ethanol,

23% (uncorrected for decay) of 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) vinyl ] -N-methylaniline was obtained in 30 min.

In addition to purification by HPLC, methods based on solid phase extraction were investigated, but the purity was not as good as purification using HPLC.

To date, one-pot radiolabelling has been performed using mesylate precursors. It is known that for the labeling of F-18 of the stilbene type, the advantages of methanesulfonates compared with the corresponding tosylates,

in that it provides a cleaner reaction with a lower amount of by-products (W.Zhang et al, journal of Medicinal Chemistry 48(2005) 5980-.

In contrast to these teachings of the prior art, we have discovered advantages for tosylate and other aryl sulfonate precursors of 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) vinyl ] -N-methylaniline over the corresponding mesylate. If an arylsulfonate precursor (example 2-example 6) is used, the non-radioactive byproducts eluted close to the retention time of 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) vinyl ] -N-methylaniline are less than the crude mixture obtained after conversion of the mesylate precursor (example 1).

The favorable byproduct distribution after radiolabelling of tosylate precursor 2b (fig. 10) compared to radiolabelling of mesylate precursor 2a (fig. 7) supports improved column-based purification (example 8, example 9).

Summary of The Invention

The present invention provides compounds of formula II useful in the production of radiolabeled compounds of formula I and suitable inorganic or organic acid salts thereof, hydrates, complexes, esters, amides, solvates and prodrugs thereof, and optionally a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

The method comprises the following steps:

radiofluorination of the Compound of formula II

Optionally cleaving the protecting group

Purification and preparation of the Compound of formula I

The present invention also provides compositions comprising a radiolabeled compound of formula I or a suitable inorganic or organic acid salt thereof, hydrates, complexes, esters, amides, solvates and prodrugs thereof, and optionally a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

The invention also provides a kit for preparing a radiopharmaceutical preparation by the methods described herein, which kit comprises a sealed vial containing a predetermined amount of a compound of formula II.

Description of the invention

In a first aspect, the invention relates to compounds of formula II

Wherein:

r is selected from

a）H，

b）PG，

PG is an "amine protecting group".

In a preferred embodiment, PG is selected from:

a）Boc，

b) trityl, and

c) 4-methoxytrityl.

More preferably, PG is Boc.

LG is arylsulfonyloxy.

In a preferred embodiment, LG contains 0-3 fluorine atoms.

In a preferred embodiment, the arylsulfonyloxy group is selected from:

p-toluenesulfonyloxy, 4-cyanophenylsulfonyloxy, 4-bromophenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 2-nitrophenylsulfonyloxy, 4-isopropyl-phenylsulfonyloxy, 2,4, 6-triisopropyl-phenylsulfonyloxy, 2,4, 6-trimethylphenylsulfonyloxy, 4-tert-butyl-phenylsulfonyloxy, 4-adamantylphenylsulfonyloxy and 4-methoxyphenylsulfonyloxy.

In a more preferred embodiment, the arylsulfonyloxy group is selected from:

a) a p-toluenesulfonyloxy group,

b) (2-nitrophenyl) sulfonyloxy group,

c) (4-cyanophenyl) sulfonyloxy group,

d) (4-bromophenyl) sulfonyloxy group,

e) (4-adamantylphenyl) sulfonyloxy.

In a second aspect, the present invention relates to a process for the production of a compound of formula I by reacting a compound of formula II,

the method comprises the following steps:

step l: radiolabelling a compound of formula II with an F-18 fluorinating agent to obtain a compound of formula I if R = H or a compound of formula III if R = PG,

step 2: optionally, if R = PG, cleaving the protecting group PG to obtain a compound of formula I,

and step 3: the purification and preparation of the compounds of formula I,

wherein the compound of formula II is as described above.

Step 1 comprises performing a direct [ F-18] fluoro labelling reaction from a compound of formula II for obtaining a compound of formula I (if R = H) or a compound of formula III (if R = PG).

The radiolabelling method comprises the step of reacting a compound of formula II with a F-18 fluorinating agent to obtain a compound of formula III or a compound of formula I. In a preferred embodiment, the [ F-18] fluoride derivative is 4,7,13,16,21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8] -hexacosane K [ F-18] F (crown ether salt Kryptofix K [ F-18] F), K [ F-18] F, H [ F-18] F, KH [ F-18] F2, Cs [ F-18] F, Na [ F-18] F, or a tetraalkylammonium salt of [ F-18] F (e.g., [ F-18] tetrabutylammonium fluoride). More preferably, the fluorinating agent is K [ F-18] F, H [ F-18] F, [ F-18] tetrabutylammonium fluoride, Cs [ F-18] F or KH [ F-18] F2, and most preferably K [ F-18], Cs [ F-18] F or [ F-18] tetrabutylammonium fluoride.

The radiofluorination reaction is carried out in acetonitrile, dimethylsulfoxide or dimethylformamide or a mixture thereof. But other solvents known to those skilled in the art may also be used. Water and/or alcohols may be included in such reactions as co-solvents. The time for carrying out the radiofluorination reaction is less than 60 minutes. Preferred reaction times are less than 30 minutes. More preferably the reaction time is less than 15 min. This and other conditions for this radiofluorination reaction are known to The expert (Coenen, "Fluorine-18 Labeling Methods: Features and Possibilities of The basic reaction" (Fluorine-18 Labeling Methods: Features and Possibilities of basic reactions), (2006), in Schubiger P.A., Friebe M., driving force for PET Chemistry-Molecular Imaging, compiled by Lehmann L, Springer, Bein Heidelberg, pages 15-50).

In a preferred embodiment, the radiofluorination of the compound of formula II is carried out in acetonitrile or a mixture of acetonitrile and a cosolvent, wherein the ratio of acetonitrile is at least 50%, more preferably 70%, still more preferably 90%.

In one embodiment, 1.5 to 75. mu. mol, preferably 7.5 to 40. mu. mol, more preferably 10 to 30. mu. mol, still more preferably 12 to 25. mu. mol of the compound of formula II is used in step 1.

In other embodiments, a solution of 1.5-50. mu. mol/mL, preferably 5-25. mu. mol/mL, more preferably 7-20. mu. mol/mL of the compound of formula II in acetonitrile or an acetonitrile/co-solvent mixture is used in step 1.

Optionally, if R = PG, step 2 comprises deprotection of the compound of formula III to obtain the compound of formula I. The reaction conditions are known or obvious to the person skilled in the art and are selected from, but not limited to, the reaction conditions described in textbooks Greene and Wuts, protective groups in Organic Synthesis, third edition, page 494-653, which are incorporated herein by reference. The preferred reaction conditions are the addition of acid and stirring at 0 ℃ to 180 ℃; adding an alkali and heating at 0-180 ℃; or a combination thereof.

Preferably, step 1 and step 2 are performed in the same reaction vessel.

Step 3 involves purification and preparation of the compound of formula I. Methods for purifying radiotracers are well known to those skilled in the art and include HPLC methods as well as solid phase extraction methods.

In one embodiment, the crude product mixture is purified by HPLC and the collected product fractions are further passed through a solid phase column to remove HPLC solvent (e.g., acetonitrile) and provide the compound of formula I in an injectable formulation.

In another embodiment, the crude product mixture is purified by HPLC, where an HPLC solvent mixture (e.g., a mixture of ethanol and an aqueous buffer) may be part of an injectable formulation of a compound of formula I. The collected product fractions may be diluted with or mixed with other parts of the formulation.

In another embodiment, the crude product mixture is purified by passing through a solid phase column.

In a preferred embodiment, The method is carried out by using modules which allow automated synthesis (reviewed in Krasikowa, "Synthesis modules and Automation in F-18 labeling" (Synthesis and Automation in F-18 labeling), (2006), in Schubiger P.A., Friebe M., Driving Force in PET chemical-Molecular Imaging, compiled by Lehmann L., major, Springer, Berlin Heidelberg, p.289 316). More preferably, the method is performed by using a single tank module. More preferably, the method is performed on both well-known non-cassette (non-cassette) modules (e.g. Eckert & Ziegler Modular-Lab, GE Tracerlab FX, raytest synchrom) and cassette modules (e.g. GE Tracerlab MX, GE Fastlab, IBASynthera, Eckert & Ziegler Modular-Lab PharmTracer), optionally with other equipment such as HPLC or liquid separation devices attached to the modules.

In a third aspect, the present invention relates to a fully automated and/or remote controlled process for the production of a compound of formula I, comprising the steps and compounds as disclosed above.

In a preferred embodiment, the method is a fully automated process, in accordance with GMP protocols, which provides formulations of formula I for administration (injection) to humans.

In a fourth aspect, the present invention relates to a process for the production of a compound of formula II (with the proviso that R = PG) by reacting a compound of formula IV with an aryl sulfonyl halide or an aryl sulfonic anhydride or an aryl sulfonic acid, preferably with an aryl sulfonyl halide or an aryl sulfonic anhydride. Formation of the compound of formula II from the compound of formula IV may be mediated by bases or coupling reagents known to those skilled in the art.

Wherein PG is as described above.

In a fifth aspect, the present invention relates to a process for the production of a compound of formula II (with the proviso that R = H) by reacting a compound of formula IV with an aryl sulfonyl halide or an aryl sulfonic anhydride or an aryl sulfonic acid, preferably with an aryl sulfonyl halide or an aryl sulfonic anhydride. Formation of the compound of formula II from the compound of formula IV may be mediated by bases or coupling reagents known to those skilled in the art.

Subsequent cleavage of PG yields compounds of formula II.

Wherein PG is as described above.

In a sixth aspect, the present invention relates to a kit for the manufacture of a pharmaceutical composition of a compound of formula I.

In one embodiment, the kit comprises a sealed vial containing a predetermined amount of a compound of formula II disclosed in the first aspect.

Preferably, the kit contains 1.5-75. mu. mol, preferably 7.5-50. mu. mol, more preferably 10-30. mu. mol, still more preferably 12-25. mu. mol of the compound of formula II.

Optionally, the kit contains other components for the manufacture of the compound of formula I, such as solvents, solid phase extraction columns, reagents for fluorination (as described above), reagents for cleaving off protecting groups, solvents or solvent mixtures for purification, solvents for formulation and excipients.

In one embodiment, the kit contains a platform (e.g., cassette) for a "cassette module" (e.g., TracerlabMX or IBA Synthera).

Definition of

In the context of the present invention, preferred salts are pharmaceutically acceptable salts of the compounds of the present invention. The invention also encompasses salts which are not suitable for pharmaceutical applications on their own, but which can be used, for example, for isolating or purifying the compounds of the invention.

Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts of inorganic acids, carboxylic and sulfonic acids, for example salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

Pharmaceutically acceptable salts of the compounds of the invention also include salts of the usual bases, such as and preferably alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, benzhydrylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

The term halogen means Cl, Br, F or I.

The term arylsulfonyloxy means-O-S (O)₂-Q, wherein Q is optionally substituted aryl.

The term "aryl" when used herein alone or as part of another group refers to a monocyclic or bicyclic aromatic group containing 6 to 10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.

The term "substituted" whenever used, means that one or more hydrogens on the designated atom in the expression using "substituted" is replaced with one or more moieties selected from the group consisting of halogen, nitro, cyano, trifluoromethyl, alkyl, and O-alkyl, as long as the normal valency of the corresponding atom is not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently stable to survive isolation to a useful purity from the reaction mixture.

The term "alkyl" when used herein alone or as part of another group refers to C₁-C₁₀Straight-chain or branched alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl or adamantyl. Preferably, the alkyl group is C₁-C₆Straight or branched alkyl or C₇-C₁₀Straight or branched chain alkyl. Lower alkyl is C₁-C₆Straight or branched chain alkyl.

The term "amine Protecting group" as used herein alone or as part of another group is known or apparent to those skilled in the art and is selected from, but not limited to, a class of Protecting groups, namely carbamates, amides, imides, N-alkylamines, N-arylamines, imines, enamines, boranes, N-P Protecting groups, N-sulfinyl, N-sulfonyl, and N-silyl groups, and is selected from, but not limited to, Protecting groups in organic synthesis (Protecting groups in organic synthesis), third edition, page 494-653, described in textbook Greene and Wuts, incorporated herein by reference. The amine protecting group is preferably benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), t-Butoxycarbonyl (BOC), 9-Fluorenylmethoxycarbonyl (FMOC), benzyl (Bn), p-methoxybenzyl (PMB), 3, 4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), or the protected amino group is 1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl (benzenedi (meth) imido) or azido.

The term "leaving group" when used herein alone or as part of another group is known or apparent to those skilled in the art and means an atom or group of atoms that can be detached from a chemical species by a nucleophile. Examples of which are provided, for example, in the following documents: synthesis (Synthesis) (1982), pages 85-125, Table 2 (page 86; the last entry in Table 2 requiring correction by "n-C")₄F₉S(O)₂-O-nonaflatat "instead of" n-C₄H₉S(O)₂-O-nonaflat "), Carey and Sundberg, organic Synthesis (Organische Synthesis), (1995), page 279-281, Table 5.8; or Netscher, Recent res.dev.org.chem.,2003,7,71-83, reaction schemes 1,2, 10, and 15, etc.), (Coenen, "fluorine-18 labeling method: the nature and The possibility of The basic reaction "(Fluorine-18 laboratory Methods: Features and Possibilities of basic reactions), (2006), in Schubiger P.A., Friebe M., The driving force for PET Chemistry-Molecular Imaging, compiled by Lehmann L. (PET-Chemistry-The driving force in Molecular Imaging), Springer, Berlin Heidelberg, pages 15 to 50, to be precise: page 25, reaction scheme 4, page 28, reaction scheme 5, page 30, page 4, page 33, figure 7).

Unless otherwise indicated, when referring to a compound of formula (la) of the invention per se and any pharmaceutical composition thereof, the invention includes all hydrates, salts and complexes.

The term "F-18" refers to an isotope of fluorine¹⁸F. The term "F-19" refers to an isotope of fluorine¹⁹F。

Examples

EXAMPLE 1 radiolabeling of mesylate precursor 2a

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] -ethoxy } phenyl) ethenyl ] -N-methylaniline

Radiolabelling on a remote Synthesis Module (Tracerlab FX)_N) The above process is carried out. Precursor 2a (2 mg) in 0.5mL of LDMSO +0.5mL of acetonitrile was treated with anhydrous potassium carbonate/kryptofix/[ F-18]]The fluoride complex was treated at 100 ℃ for 6 min. 1M HCl (1 mL) +10mg ascorbic acid was added and the mixture was heated at 100 ℃ for 4 min. 2M NaOH (0.5 mL), water (6 mL), and ethanol (1 mL) were added, and the crude mixture was captured on a C18 column. The crude product mixture was eluted with acetonitrile and diluted with 0.1M ammonium formate buffer (1 mL) +5mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (fig. 1). After purification by semi-preparative HPLC, the product was diluted with water +5mg ascorbic acid, captured on a C18 column and eluted with 1mL ethanol.

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) -vinyl ] -N-methylaniline yield: 21% (corrected for decay).

Example 2 Synthesis and radiolabelling of tosylate precursor 2b

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] -ethoxy } phenyl) ethenyl ] -N-methylaniline

To a solution of 1.0g of tert-butyl {4- [ (E) -2- (4- {2- [2- (2-hydroxyethoxy) ethoxy ] ethoxy } phenyl) vinyl ] phenyl } methyl carbamate (4) in dichloromethane (12 mL) at 0 deg.C was added 4-dimethylaminopyridine (26.7 mg) and triethylamine (225. mu.L). A solution of p-toluenesulfonyl chloride (417 mg) in dichloromethane (13.5 mL) was added at 0 deg.C. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica gel, 0-80% ethyl acetate in hexanes). 850mg of 2b was obtained as a colorless solid.

¹H NMR(300MHz,CDCl₃)δppm 1.46(s,9H),2.43(s,3H),3.27(s,3H),3.59-3.73(m,6H),3.80-3.86(m,2H),4.05-4.19(m,2H),6.88-7.05(m,4H),7.21(d,J=8.3Hz,2H),7.32(d,J=8.3Hz,2H),7.39-7-47(m,4H),7.80(d,J=8.3Hz,2H)。

MS(ESIpos)：m/z=612(M+H)⁺

Radiolabelling on a remote Synthesis Module (Tracerlab FX)_N) The above process is carried out. Precursor 2b (2 mg) in 0.5mL of LDMSO +0.5mL of acetonitrile was treated with anhydrous potassium carbonate/kryptofix/[ F-18]]The fluoride complex was treated at 100 ℃ for 6 min. 1M HCl (1 mL) +10mg ascorbic acid was added and the mixture was heated at 100 ℃ for 4 min. 2M NaOH (0.5 mL), water (6 mL), and ethanol (1 mL) were added, and the crude mixture was captured on a C18 column. The crude product mixture was eluted with acetonitrile and diluted with 0.1M ammonium formate buffer (1 mL) +5mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (fig. 2). After purification by semi-preparative HPLC, the product was diluted with water +5mg ascorbic acid, captured on a C18 column and eluted with 1mL ethanol.

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) -vinyl ] -N-methylaniline yield: 25% (corrected for decay).

EXAMPLE 32 c Synthesis and radiolabelling of 2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] phenyl } vinyl ] phenoxy } ethoxy) ethoxy ] ethyl 4-bromobenzenesulfonate)

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] -ethoxy } phenyl) ethenyl ] -N-methylaniline

To a stirred solution of 100mg (0.219 mmol) of tert-butyl- {4- [ (E) -2- (4- {2- [2- (2-hydroxyethoxy) ethoxy ] ethoxy } phenyl) vinyl ] phenyl } methyl carbamate (WO 2006/066104) in 2mL THF was added dropwise a solution of 140mg (0.548 mmol) of 4-bromobenzenesulfonyl chloride in 3mL THF. The mixture was cooled to 0 ℃. 156.8mg (1.1 mmol) of potassium trimethylsilanolate were added. The milky suspension was stirred at 0 ℃ for 2 hours and at 80 ℃ for a further 2 hours. The reaction mixture was poured into ice-cooled water. The aqueous solution was extracted several times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified using silica gel using an ethyl acetate/hexane gradient as flow. 77mg (0.114 mmol, 52.0% yield) of the expected product 2c are obtained.

¹H NMR(300MHz,CDCl₃)δppm 1.39(s,10H)3.20(s,3H)3.50-3.57(m,2H)3.57-3.61(m,2H)3.61-3.66(m,2H)3.72-3.80(m,2H)4.02-4.10(m,2H)4.10-4.17(m,2H)6.79-6.85(m,2H)6.91(d,J＝8.10Hz,2H)7.10-7.17(m,2H)7.32-7.41(m,5H)7.57-7.65(m,2H)7.67-7.74(m,2H)。

MS(ESIpos)：m/z=676/678(M+H)⁺

Radiolabelling on a remote Synthesis Module (Tracerlab FX)_N) The above process is carried out. Precursor 2c (2 mg) in 0.5mL of LDMSO +0.5mL of acetonitrile was treated with anhydrous potassium carbonate/kryptofix/[ F-18]]The fluoride complex was treated at 100 ℃ for 6 min. 1M HCl (1 mL) +10mg ascorbic acid was added and the mixture was heated at 100 ℃ for 4 min. 2M NaOH (0.5 mL), water (6 mL), and ethanol (1 mL) were added, and the crude mixture was captured on a C18 column. The crude product mixture was eluted with acetonitrile and diluted with 0.1M ammonium formate buffer (1 mL) +5mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (fig. 3). After purification by semi-preparative HPLC, the product was diluted with water +5mg ascorbic acid, captured on a C18 column and eluted with 1mL ethanol.

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) -vinyl ] -N-methylaniline yield: 43% (corrected for decay).

EXAMPLE 42 Synthesis and radiolabelling of 2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] phenyl } vinyl ] phenoxy } ethoxy) ethoxy ] ethyl 4- (adamantan-1-yl) benzenesulfonate)

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] -ethoxy } phenyl) ethenyl ] -N-methylaniline

To a stirred solution of 151mg (0.330 mmol) of tert-butyl- {4- [ (E) -2- (4- {2- [2- (2-hydroxyethoxy) ethoxy ] ethoxy } phenyl) vinyl ] phenyl } methyl carbamate (WO 2006/066104), 4.03mg (0.033 mmol) DMAP and 36.7mg (363 mmol) triethylamine in 4mL dichloromethane was added a solution of 97.4mg (0.313 mmol) of 4- (adamantan-1-yl) benzenesulfonyl chloride in 1mL dichloromethane at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour and at room temperature overnight. To the reaction mixture were added 7.3mg (0.072 mmol) triethylamine and 19.5mg (0.062 mmol) 4- (adamantan-l-yl) benzenesulfonyl chloride. The reaction mixture was stirred at room temperature for 3 days. It was concentrated in vacuo. The crude product was purified using silica gel using an ethyl acetate/hexane gradient as flow. 104mg (0.142 mmol, 43.4% yield) of the expected product 2d are obtained.

¹H NMR(300MHz,CDCl₃)δppm 1.51(s,9H),1.62(s,1H),1.74-1.91(m,6H),1.94(d,J＝3.20Hz,6H),2.16(br.s.,3H),3.31(s,3H),3.63-3.69(m,2H),3.69-3.73(m,2H),3.76(dd,J＝5.27,4.52Hz,2H),3.89(d,J＝4.90Hz,2H),4.13-4.26(m,4H),6.95(d,J＝8.85Hz,2H),7.02(d,J＝8.29Hz,2H),7.25(d,J＝8.48Hz,2H),7.40-7.52(m,4H),7.55(m,J＝8.67Hz,2H),7.89(m,J＝8.67Hz,2H)

MS(ESIpos)：m/z=732(M+H)⁺

Radiolabelling on a remote Synthesis Module (Tracerlab FX)_N) The above process is carried out. 0.5ml DMPrecursor 2d (2 mg) in SO +0.5mL acetonitrile was treated with anhydrous potassium carbonate/kryptofix/[ F-18]]The fluoride complex was treated at 100 ℃ for 6 min. 1M HCl (1 mL) +10mg ascorbic acid was added and the mixture was heated at 100 ℃ for 4 min. 2M NaOH (0.5 mL), water (6 mL), and ethanol (1 mL) were added, and the crude mixture was captured on a C18 column. The crude product mixture was eluted with acetonitrile and diluted with 0.1M ammonium formate buffer (1 mL) +5mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (fig. 4). After purification by semi-preparative HPLC, the product was diluted with water +5mg ascorbic acid, captured on a C18 column and eluted with 1mL ethanol.

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) -vinyl ] -N-methylaniline yield: 27% (corrected for decay).

EXAMPLE 52 Synthesis and radiolabelling of 2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] phenyl } vinyl ] phenoxy } ethoxy) ethoxy ] ethyl 4-cyanobenzenesulfonate)

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] -ethoxy } phenyl) ethenyl ] -N-methylaniline

To a stirred solution of 151mg (0.330 mmol) of tert-butyl- {4- [ (E) -2- (4- {2- [2- (2-hydroxyethoxy) ethoxy ] ethoxy } phenyl) vinyl ] phenyl } methyl carbamate (WO 2006/066104), 4.03mg (0.033 mmol) of DMAP and 36.7mg (0.363 mmol) of triethylamine in 4mL of dichloromethane at 0 ℃ is added a solution of 63.2mg (0.313 mmol) of 4-cyanobenzenesulfonyl chloride in 1mL of dichloromethane. The reaction mixture was stirred overnight and concentrated in vacuo. The crude product was purified using silica gel using an ethyl acetate/hexane gradient as flow. 118mg (0.190 mmol, 57.6% yield) of the expected product 2e are obtained.

¹H NMR(400MHz,CDCl₃)δppm 1.47(s,9H)3.28(s,3H)3.58-3.63(m,2H)3.63-3.68(m,2H)3.70-3.75(m,2H)3.81-3.87(m,2H)4.11-4.18(m,2H)4.24-4.30(m,2H)6.91(d,J＝8.59Hz,2H)6.99(dt,2H)7.22(d,J＝8.34Hz,2H)7.39-7.50(m,4H)7.83(m,J＝8.59Hz,2H)7.98-8.11(m,2H)。

MS(ESIpos)：m/z=623(M+H)⁺

Radiolabelling on a remote Synthesis Module (Tracerlab FX)_N) The above process is carried out. Precursor 2e (2 mg) in 0.5mL of LDMSO +0.5mL of acetonitrile was treated with anhydrous potassium carbonate/kryptofix/[ F-18]]The fluoride complex was treated at 100 ℃ for 6 min. 1M HCl (1 mL) +10mg ascorbic acid was added and the mixture was heated at 100 ℃ for 4 min. 2M NaOH (0.5 mL), water (6 mL), and ethanol (1 mL) were added, and the crude mixture was captured on a C18 column. The crude product mixture was eluted with acetonitrile and diluted with 0.1M ammonium formate buffer (1 mL) +5mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (fig. 5). After purification by semi-preparative HPLC, the product was diluted with water +5mg ascorbic acid, captured on a C18 column and eluted with 1mL ethanol.

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) -vinyl ] -N-methylaniline yield: 31% (corrected for decay).

EXAMPLE 62 f Synthesis and radiolabelling of (2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] phenyl } vinyl ] phenoxy } ethoxy) ethoxy ] ethyl 2-nitrobenzenesulfonate)

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] -ethoxy } phenyl) ethenyl ] -N-methylaniline

To a stirred solution of 200mg (0.437 mmol) of tert-butyl- {4- [ (E) -2- (4- {2- [2- (2-hydroxyethoxy) ethoxy ] ethoxy } phenyl) vinyl ] phenyl } methyl carbamate (WO 2006/066104), 5.34mg (0.044 mmol) DMAP and 47.5mg (0.470 mmol) triethylamine in 4mL dichloromethane was added a solution of 92mg (0.415 mmol) 2-nitrobenzenesulfonyl chloride in 1mL dichloromethane at 0 ℃. The reaction mixture was stirred overnight and concentrated in vacuo. The crude product was purified using silica gel using an ethyl acetate/hexane gradient as flow. 77mg (0.119 mmol, 59.5% yield) of the expected product 2f are obtained.

¹H NMR(400MHz,CDCl₃)δppm 1.39(s,9H)3.20(s,3H)3.55-3.63(m,4H)3.59(m,4H)3.69-3.74(m,2H)3.75-3.80(m,2H)4.06(dd,J＝5.68,3.92Hz,2H)4.32-4.37(m,2H)6.80-6.84(m,2H)6.84-6.98(dt,2H)7.14(d,J＝8.59Hz,2H)7.35(d,J＝3.03Hz,2H)7.37(d,J＝2.78Hz,2H)7.62-7.74(m,3H)8.06-8.11(m,1H)

Radiolabelling on a remote Synthesis Module (Tracerlab FX)_N) The above process is carried out. Precursor 2e (2 mg) in 0.5mL of LDMSO +0.5mL of acetonitrile was treated with anhydrous potassium carbonate/kryptofix/[ F-18]]The fluoride complex was treated at 100 ℃ for 6 min. 1M HCl (1 mL) +10mg ascorbic acid was added and the mixture was heated at 100 ℃ for 4 min. 2M NaOH (0.5 mL), water (6 mL), and ethanol (1 mL) were added, and the crude mixture was captured on a C18 column. The crude product mixture was eluted with acetonitrile and diluted with 0.1M ammonium formate buffer (1 mL) +5mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (fig. 6). After purification by semi-preparative HPLC, the product was diluted with water +5mg ascorbic acid, captured on a C18 column and eluted with 1mL ethanol.

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) -vinyl ] -N-methylaniline yield: 21% (corrected for decay).

EXAMPLE 7 radiolabeling and column-based purification of mesylate 2a

The synthesis was performed on a Tracerlab MX synthesizer. The [ F-18] fluoride (2.0 GBq) was captured on a QMA column (Waters). The activity was eluted into the reactor using a mixture of eluents (22 mg kryptofix, 0.7mL methanol, 0.1mL 0.2M potassium methanesulfonate solution, 0.01mL tetrabutylammonium bicarbonate solution). The mixture was dried (heat, nitrogen flow, vacuum, addition of acetonitrile) and 7.0mg of precursor 2a in 1.5mL of tert-amyl alcohol +0.3mL of acetonitrile was added to the residue. After heating at 120 ℃ for 20min, the solvent was evaporated and a mixture of 2.2mL of 1.5MHCl, 1.1mL of acetonitrile and 30mg of sodium ascorbate was added. The resulting solution was heated at 100 ℃ for 7.5 min. The crude product (910 MBq, 64% corrected for decay) was transferred to a vial and diluted with 1.5mL of 2M NaOH and 0.3mL of 0.1M ammonium formate solution. The samples were analyzed by analytical HPLC (fig. 7). The crude product was loaded onto a Chromabond flash column (RS 4 Nucleodur 100-30C18ec, Macherey-Nagel) and 40% EtOH in phosphate buffer (pH 7.4) was flushed through the column by an HPLC pump at a flow rate of 9 mL/min. Radioactivity and UV detectors were connected to HPLC to monitor purification (fig. 8). After 15min, the solvent was changed to 50% EtOH in phosphate buffer (pH 7.4). The product fractions (25%, corrected for decay) were collected from 17.5-19min and analyzed by analytical HPLC (fig. 9).

EXAMPLE 8 radiolabeling and column-based purification of tosylate 2b

The synthesis was performed on a Tracerlab MX synthesizer. The [ F-18] fluoride (1.6 GBq) was captured on a QMA column (Waters). The activity was eluted into the reactor using a mixture of eluents (22 mg kryptofix, 0.7mL methanol, 0.1mL 0.2M potassium methanesulfonate solution, 0.01mL tetrabutylammonium bicarbonate solution). The mixture was dried (heat, nitrogen flow, vacuum, addition of acetonitrile) and 8.0mg of precursor 2b in 1.5mL of tert-amyl alcohol +0.3mL of acetonitrile was added to the residue. After heating at 120 ℃ for 20min, the solvent was evaporated and a mixture of 2.2mL of 1.5MHCl, 1.1mL of acetonitrile and 30mg of sodium ascorbate was added. The resulting solution was heated at 100 ℃ for 7.5 min. The crude product (775 MBq, 67%, corrected for decay) was transferred to a vial and diluted with 1.5mL of 2M NaOH and 0.3mL of 0.1M ammonium formate solution. The samples were analyzed by analytical HPLC (fig. 10). The crude product was loaded onto a Chromabond flash column (RS 4 Nucleodur 100-30C18ec, Macherey-Nagel) and 40% EtOH in phosphate buffer (pH 7.4) was flushed through the column by an HPLC pump at a flow rate of 9 mL/min. Radioactivity and UV detectors were connected to HPLC to monitor purification (fig. 11). After 15min, the solvent was changed to 50% EtOH in phosphate buffer (pH 7.4). Product fractions (31%, corrected for decay) were collected from 17.5-19min and analyzed by analytical HPLC (fig. 12).

Example 9 radiolabelling and column-based purification on Tracerlab MX Using tosylate 2b

To synthesize and purify 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] -ethoxy } phenyl) vinyl ] -N-methylaniline on Tracerlab MX, a kit was assembled (Table 1).

TABLE 1 composition of kit for the manufacture of 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] -ethoxy } phenyl) vinyl ] -N-methylaniline on Tracerlab MX

The arrangement of the cassette on the MX modules is shown in FIG. 13.

During the synthesis sequence, precursor 2b was dissolved in the "red-capped vial" using about 1.8mL of acetonitrile from the "blue-capped vial". Fluoride (2.4 GBq) was transferred to MX module and captured on QMA column. The activity was eluted into the reactor using a potassium carbonate/kryptofix mixture from an "eluent vial". After azeotropic drying (heating, vacuum, nitrogen flow and addition of acetonitrile from "blue-capped vial"), the solution of 2b in acetonitrile was transferred from "red-capped vial" to the reactor. The resulting mixture was heated at 120 ℃ for 10 min. HCl was transferred from the "green cap vial" into the reactor by syringe. The mixture was heated at 110 ℃ for 5 min. During deprotection, the solvent mixture from "solvent package 1" was flushed through the "purification column" by the left syringe. The crude product mixture was mixed with the sodium hydroxide/buffer mixture from the "2 mL syringe" and diluted with solvent 1 from "solvent bag 1". The diluted crude product mixture was passed through a "purification column". To remove non-radioactive byproducts, solvent 1 from "solvent bag 1" was loaded into the left syringe and flushed through the "purification column" into the waste bottle. This procedure was repeated 6 times. Solvent 2 from "solvent bag 2" was loaded into the right syringe and transferred to the left syringe. Solvent 2 was flushed through the "purification column" by the left syringe. The first fraction was put into a waste bottle, but 7.5mL fractions were automatically collected in the right syringe. Finally, the product fractions were transferred to product vials (pre-loaded with formulation base 1 and formulation base 2). 770MBq (32%, not corrected for decay) of 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] -ethoxy } phenyl) vinyl ] -N-methylaniline was obtained in a total manufacturing time of 58 min. Column-based purification provided a product that was radiochemically and chemically pure, similar to the purity obtained by semi-preparative HPLC (fig. 14, fig. 15).

EXAMPLE 10 unprotected tosylate precursor 2g and Synthesis and radiolabelling

Precursor synthesis

a) 2- {2- [2- (4- { (E) -2- [4- (methylamino) phenyl ] vinyl } phenoxy) ethoxy ] -ethoxy } ethyl 4-methylbenzenesulfonate (2 g-1)

200mg of 2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] phenyl } -vinyl ] phenoxy } ethoxy) ethoxy ] ethyl 4-methylbenzenesulfonate (2 b) were dissolved in 2.5mL of dichloromethane. 250 μ L of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure. The crude product was dissolved in dichloromethane (5 mL) and washed with sodium carbonate solution (10%, 2 × 2 mL). The organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography (silica gel, 12-100% ethyl acetate in hexanes). 84mg of 2g-1 as a pale red solid was obtained.

¹H NMR(300MHz,CDCl₃)δppm 2.42(s,3H),2.87(s,3H),3.61-3.64(m,2H),3.65-3.68(m,2H),3.69-3.72(m,2H),3.81-3.84(m,2H),4.10-4.13(m,2H),4.15-4.17(m,2H),6.63(d,J=8.3Hz,2H),6.84-6.91(m,4H),7.32(d,J=7.9Hz,2H),7.34(d,J=8.7Hz,2H),7.39(d,J=8.7Hz,2H),7.80(d,J=8.3Hz,2H)。

MS(ESIpos)：m/z=512(M+H)⁺

b) 2- {2- [2- (4- { (E) -2- [4- (methylamino) phenyl ] vinyl } phenoxy) ethoxy ] -ethoxy } ethyl 4-methylbenzenesulfonate hydrochloride (2 g-2)

200mg of 2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] phenyl } -vinyl ] phenoxy } ethoxy) ethoxy ] ethyl 4-methylbenzenesulfonate (2 b) were dissolved in a solution of 2M HCl in diethyl ether. The mixture was stirred at room temperature for 72 h. The solvent was removed under reduced pressure. Diethyl ether was added and the precipitate was collected. Washed with diethyl ether and dried under reduced pressure. 160mg of 2g-2 were obtained as a pale yellow solid.

¹H NMR(300MHz,CDCl₃)δppm 2.43(s,3H),3.03(s,3H),3.62-3.64(m,2H),3.66-3.68(m,2H),3.69-3.72(m,2H),3.82-3.85(m,2H),4.12-4.14(m,2H),4.16-4.18(m,2H),6.88-6.94(m,3H),7.04(d,J=16.2Hz,1H),7.32(d,J=7.9Hz,2H),7.42(d,J=8.7Hz,2H),7.49-7-56(m,4H),7.80(d,J=8.3Hz,2H)。

MS(ESIpos)：m/z=512(M+H)⁺

c) 2- {2- [2- (4- { (E) -2- [4- (methylamino) phenyl ] vinyl } phenoxy) ethoxy ] -ethoxy } ethyl 4-methylbenzenesulfonate trifluoroacetate (2 g-3)

200mg of 2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] phenyl } -vinyl ] phenoxy } ethoxy) ethoxy ] ethyl 4-methylbenzenesulfonate (2 b) were dissolved in 2.5mL of dichloromethane. 252. mu.L of trifluoroacetic acid were added and the mixture was stirred at room temperature for 5 h. The solvent was removed under reduced pressure. The crude product was washed with hexane and diethyl ether and dried under reduced pressure. 84mg of 2g-3 are obtained as a light brown solid.

¹H NMR(300MHz,DMSO d6)δppm 2.40(s,3H),2.72(s,3H),3.46-3.50(m,2H),3.51-3.55(m,2H),3.57-3.61(m,2H),3.69-3.73(m,2H),4.10-4.09(m,2H),4.10-4.13(m,2H),),6.59-6.66(m,2H),6.85-6.97(m,4H),7.34(d,J=8.3Hz,2H),7.43(d,J=8.8Hz,2H),7.46(d,J=8.1Hz,2H),7.76(d,J=8.3Hz,2H)。

MS(ESIpos)：m/z=512(M+H)⁺

Radiolabelling

4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] -ethoxy } phenyl) ethenyl ] -N-methylaniline

Radiolabelling was performed using potassium carbonate/kryptofix or tetrabutylammonium hydroxide or tetrabutylammonium bicarbonate as reagents.

a) Radiolabelling using potassium carbonate/kryptofix

The [ F-18] fluoride is captured on a QMA column. A solution of 7.5mg kryptofix, 1mg potassium carbonate in 1425. mu.L acetonitrile and 75. mu.L water was used to elute the activity. The mixture was dried at 120 ℃ under a gentle stream of nitrogen. Drying was repeated after addition of 1mL of acetonitrile. 1mg of precursor in acetonitrile (5.0 mg of 2g-1 or 5.36mg of 2g-2 or 6.11mg of 2 g-3) was added and the mixture was heated at 120 ℃ for 15 min. Fluoride incorporation was measured by radio-TLC (silica gel, ethyl acetate) and the results are summarized in table 2.

b) Radiolabelling with tetrabutylammonium hydroxide

Will [ F-18]Fluoride was captured on a QMA column. Using 300. mu.L 4% n-Bu₄A mixture of OH and 600. mu.L acetonitrile was used to elute the activity. The mixture was dried at 120 ℃ under a gentle stream of nitrogen. Drying was repeated after addition of 1mL of acetonitrile. 1mg of precursor in acetonitrile (5.0 mg of 2g-1 or 5.36mg of 2g-2 or 6.11mg of 2 g-3) was added and the mixture was heated at 120 ℃ for 15 min. Fluoride incorporation was measured by radio-TLC (silica gel, ethyl acetate) and the results are summarized in table 2.

c) Radiolabelling using tetrabutylammonium bicarbonate

Will [ F-18]Fluoride was captured on a QMA column. Using 300. mu.L 4% (wt) n-Bu₄NHCO₃(4% of n-Bu₄Aqueous OH saturated with carbon dioxide) with 600 μ L acetonitrile. The mixture was dried at 120 ℃ under a gentle stream of nitrogen. Drying was repeated after addition of 1mL of acetonitrile. 1mg of precursor in acetonitrile (5.0 mg of 2g-1 or 5.36mg of 2g-2 or 6.11mg of 2 g-3) was added and the mixture was heated at 120 ℃ for 15 min. Fluoride incorporation was measured by radio-TLC (silica gel, ethyl acetate) and the results are summarized in table 2.

TABLE 22g-1, 2g-2, 2g-3 radiolabels

Drawings

FIG. 12a the crude product mixture after conversion; top: a radioactive channel; bottom: UV channel

FIG. 22 b the crude product mixture after conversion; top: a radioactive channel; bottom: UV channel

FIG. 32 c crude product mixture after conversion; top: a radioactive channel; bottom: UV channel

FIG. 42 d crude product mixture after conversion; top: a radioactive channel; bottom: UV channel

FIG. 52 e crude product mixture after conversion; top: a radioactive channel; bottom: UV channel

FIG. 62 f crude product mixture after conversion; top: a radioactive channel; bottom: UV channel

FIG. 72 a crude product mixture after conversion on Tracerlab MX; a: a radioactive channel; b: UV channel

FIG. 82 a post-conversion column-based purification; top: a radioactive channel; bottom: UV channel

FIG. 9 column based purified 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) ethenyl ] -N-methylaniline; a: a radioactive channel; b: a UV channel; c: co-elution (UV) with the non-radioactive reference 4- [ (E) -2- (4- {2- [2- (2-fluoroethoxy) ethoxy ] ethoxy } phenyl) ethenyl ] -N-methylaniline

FIG. 102 b crude product mixture after conversion on Tracerlab MX; a: a radioactive channel; b: UV channel

FIG. 112 b post-conversion column-based purification; a: a radioactive channel; b: UV channel

FIG. 12 column based purified 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] ethoxy } phenyl) ethenyl ] -N-methylaniline; a: a radioactive channel; b: a UV channel; c: co-elution (UV) with the non-radioactive reference 4- [ (E) -2- (4- {2- [2- (2-fluoroethoxy) ethoxy ] ethoxy } phenyl) ethenyl ] -N-methylaniline

FIG. 13 arrangement of Tracerlab MX

FIG. 14 analytical HPLC of the crude MX-synthesized product (sample taken from the reactor) before passing through the "purification column"; a: radioactivity; b: UV Signal 320nm

FIG. 15 analytical HPLC of synthesized MX and purified 4- [ (E) -2- (4- {2- [2- (2- [ F-18] fluoroethoxy) ethoxy ] -ethoxy } phenyl) vinyl ] -N-methylaniline on a column; a: radioactivity; b: UV signal 320 nm; c: co-elution (UV) with the non-radioactive reference 4- [ (E) -2- (4- {2- [2- (2-fluoroethoxy) ethoxy ] ethoxy } phenyl) ethenyl ] -N-methylaniline

Claims (11)

1. A compound of formula II

Wherein:

r is selected from

a）H，

b）PG，

PG is an "amine protecting group",

and is

LG is "arylsulfonyloxy".

2. The compound of claim 1, wherein PG is selected from:

a）Boc，

b) trityl, and

c) 4-methoxytrityl.

3. The compound of claim 1 or 2, wherein arylsulfonyloxy is selected from the group consisting of:

p-toluenesulfonyloxy, 4-cyanophenylsulfonyloxy, 4-bromophenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 2-nitrophenylsulfonyloxy, 4-isopropyl-phenylsulfonyloxy, 2,4, 6-triisopropyl-phenylsulfonyloxy, 2,4, 6-trimethylphenylsulfonyloxy, 4-tert-butyl-phenylsulfonyloxy, 4-adamantylphenylsulfonyloxy and 4-methoxyphenylsulfonyloxy.

4. A compound selected from

2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] phenyl } ethenyl ] phenoxy } -ethoxy) ethoxy ] ethyl-4-bromobenzenesulfonate

2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] phenyl } ethenyl ] phenoxy } -ethoxy) ethoxy ] ethyl-4- (adamantan-1-yl) benzenesulfonate

2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] phenyl } ethenyl ] phenoxy } -ethoxy) ethoxy ] ethyl-4-cyanobenzenesulfonate

2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] phenyl } ethenyl ] phenoxy } -ethoxy) ethoxy ] ethyl-2-nitrobenzenesulfonate

2- [2- (2- {4- [ (E) -2- {4- [ (tert-butoxycarbonyl) (methyl) amino ] phenyl } ethenyl ] phenoxy } -ethoxy) ethoxy ] ethyl-4-methylbenzenesulfonate

5. A process for the production of a compound of formula I by reacting a compound of formula II,

the method comprises the following steps:

step l: radiolabelling a compound of formula II with an F-18 fluorinating agent to obtain a compound of formula I if R = H or a compound of formula III if R = PG,

step 2: if R = PG, the protecting group PG is cleaved to obtain the compound of formula I,

and step 3: the purification and preparation of the compounds of formula I,

wherein the compound of formula II is as described in claim 1,2 or 3.

6. The method of claim 5, wherein the compound of claim 4 is used in step 1.

7. The method of claims 5 and 6, wherein the method is a fully automated method.

8. A kit comprising at least one sealed container containing a compound of formula II,

wherein:

r is selected from

a）H，

b）PG，

PG is an "amine protecting group",

and is

LG is "arylsulfonyloxy".

9. The kit of claim 8, wherein PG is selected from the group consisting of:

a）Boc，

b) trityl, and

c) 4-methoxytrityl.

10. The kit of claim 8, wherein the arylsulfonyloxy group is selected from the group consisting of:

a) a p-toluenesulfonyloxy group,

b) (2-nitrophenyl) sulfonyloxy group,

c) (4-cyanophenyl) sulfonyloxy group,

d) (4-bromophenyl) sulfonyloxy group,

e) (4-adamantylphenyl) sulfonyloxy.

11. A kit comprising at least one sealed container containing a compound of claim 4.