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Applied Radiation and Isotopes 68 (2010) 329–333

Contents lists available at ScienceDirect

Applied Radiation and Isotopes

0969-80

doi:10.1

� Corr

E-m

journal homepage: www.elsevier.com/locate/apradiso

Evaluation of 4-[18F]fluoro-1-butyne as a radiolabeled synthon for clickchemistry with azido compounds

Dong Hyun Kim, Yearn Seong Choe �, Byung-Tae Kim

Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Center for Molecular and Cellular Imaging, Samsung Biomedical Research

Institute, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Republic of Korea

a r t i c l e i n f o

Article history:

Received 12 August 2009

Received in revised form

5 September 2009

Accepted 3 November 2009

Keywords:

Click chemistry

Radiolabeled acetylene synthon

4-[18F]fluoro-1-butyne

Vinyl acetylene

43/$ - see front matter & 2009 Elsevier Ltd. A

016/j.apradiso.2009.11.003

esponding author. Tel.: +82 2 3410 2623; fax

ail address: ysnm.choe@samsung.com (Y.S. Ch

a b s t r a c t

Click chemistry is a useful approach for the preparation of novel radiopharmaceuticals. In this study, we

evaluated 4-[18F]fluoro-1-butyne as a radiolabeled synthon for click chemistry with azido compounds.

Our results showed that nucleophilic substitution of 4-tosyloxy-1-butyne with K[18F]F produces vinyl

acetylene as well as 4-[18F]fluoro-1-butyne, while the same reaction using 5-tosyloxy-1-pentyne gives

exclusively 5-[18F]fluoro-1-pentyne. Thus, o-[18F]fluoro-1-alkynes with chain lengths longer than four

carbons may be better radiolabeled synthons for use in click chemistry.

& 2009 Elsevier Ltd. All rights reserved.

1. Introduction

The Huisgen 1,3-dipolar cycloaddition of organic azides andalkynes has been used for the synthesis of triazole compounds inmodern organic chemistry; however, the reaction typicallyproduces both 1,4- and 1,5-triazoles (Huisgen, 1963, 1984).Recently, Sharpless et al. found that the regioselectivity of thereaction is dramatically improved when carried out in thepresence of Cu(I) catalyst giving exclusively 1,4-triazole and upto a 107 times increase in reaction rate (Kolb et al., 2001; Bocket al., 2006). Furthermore, Cu(I)-catalyzed click chemistry is mildand efficient, requiring, in many cases, no protecting groups orpurification steps (Rostovtsev et al., 2002; Tornoe et al., 2002;Wang et al., 2003; Link and Tirrell, 2003; Speers et al., 2003;Hotha and Kashyap, 2006). Therefore, click chemistry betweenterminal alkynes and azides has been widely applied to synthesesin various fields, including organic chemistry, medicinal chem-istry, and drug discovery, and has also been shown to be a usefulmethodology for the preparation of novel radiophamaceuticals(Marik and Sutcliffe, 2006; Glaser and Arstad, 2007; Li et al., 2007;Mindt et al., 2008; Ross et al., 2008; Hausner et al., 2008; Kimet al., 2008a, 2009).

In the present study, 4-[18F]fluoro-1-butyne was selected asthe acetylene synthon for click chemistry with an azidocompound. Although the addition of smaller substituents to

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: +82 2 3410 2639.

oe).

biomolecules is desirable to preserve bioactivity, 4-[18F]fluoro-1-butyne is easier to handle than 3-[18F]fluoro-1-propyne (bp:15 1C) (Job and Sheridan, 1962), due to its higher boiling point(bp: 45 1C), and has been also used by our group and others forthe preparation of small molecules and peptides (Marik andSutcliffe, 2006; Kim et al., 2008a, 2009). Therefore, we evaluated4-[18F]fluoro-1-butyne to find whether it is a suitable synthon forclick chemistry.

2. Experimental section

Chemicals and solvents were obtained from Sigma-Aldrich (St.Louis, MO, USA), and HPLC solvents were obtained from J.T. Baker(Phillipsburg, NJ, USA). 1H NMR spectra were obtained using aVarian UnityInova 500NB (500 MHz) spectrometer (Palo Alto, CA,USA) at the Cooperative Center for Research Facilities, Sung-kyunkwan University (Suwon, Korea). Chemical shifts (d) arereported as ppm downfield of an internal tetramethylsilanestandard. Fast atom bombardment (FAB) mass spectra wereobtained using a JMS-700 Mstation (JEOL Ltd, Tokyo, Japan) atthe Korea Basic Science Institute (Seoul, Korea). HPLC was carriedout using a SpectraSystem (Thermo Scientific, Waltham, MA, USA)equipped with a semi-preparative column (YMC-Pack C18, 5m,10�250 mm). Eluant was simultaneously monitored usingNaI(Tl) radioactivity and UV (218 nm) detectors. [18F]Fluoridewas produced by the 18O(p,n)18F reaction using a GE HealthcarePETtrace cyclotron (Uppsala, Sweden). Radioactivity was

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D.H. Kim et al. / Applied Radiation and Isotopes 68 (2010) 329–333330

measured in a dose calibrator (Biodex Medical Systems, Shirley,NY, USA).

2.1. Synthesis of non-radiolabeled compounds 3 and 4

2.1.1. Use of acetonitrile as the reaction medium

4-Tosyloxy-1-butyne (30 mg, 0.13 mmol) was dissolved inacetonitrile (2 mL), and K2,2,2 (101 mg, 0.27 mmol) and KF (9 mg,0.15 mmol) were added. While the reaction mixture was stirred at90 1C for 3 h, the volatile products were distilled with acetonitrileinto a second vial containing 2,3,4,6-tetra-O-acetyl-b-D-glucopyr-anosyl azide (55 mg, 0.15 mmol), CuI (6 mg, 0.03 mmol), andsodium ascorbate (11 mg, 0.05 mmol) at �30 1C (constanttemperature bath). After completion of the distillation, thereaction mixture was warmed to room temperature and DIEA(10mL, 0.05 mmol) was added. The reaction mixture was thenstirred at room temperature for 1 h. At the end of the reaction,solvent was removed in vacuo, and the residue was extracted withdichloromethane, washed with water, and dried over anhydrousNa2SO4. Flash column chromatography (1:1 hexane-ethyl acetate)gave 3 (5.5 mg, 8.9%) and 4 (33 mg, 58.9%) as white solids.

2.1.2. Use of t-BuOH or t-amyl alcohol as the reaction medium

Nucleophilic fluorination of 4-tosyloxy-1-butyne was carriedout in t-BuOH or t-amyl alcohol medium and the remainder of thesynthesis was identical to that described in Section 2.1.1. In thecase of using t-BuOH as the reaction medium, the second vial wasallowed to stand at room temperature to avoid freezing of thereaction mixture, and 3 (1.7 mg) and 4 (6.4 mg) were obtained in1.7% and 6.7% yields, respectively. In the case of using t-amylalcohol as the reaction medium, 3 (11.8 mg) and 4 (33.6 mg) wereobtained in 8.5% and 26.1% yields.

2.1.3. One-pot synthesis of 3 and 44-Tosyloxy-1-butyne (60 mg, 0.27 mmol) was dissolved in

acetonitrile (2 mL), and K2,2,2 (201 mg, 0.53 mmol) and KF(17 mg, 0.29 mmol) were added. After the reaction mixture wasstirred at 90 1C for 3 h, 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosylazide (109 mg, 0.29 mmol), CuI (10 mg, 0.05 mmol), DIEA (20mL,0.11 mmol), and sodium ascorbate (22 mg, 0.11 mmol) wereadded. The reaction mixture was then stirred at room tempera-ture for 1 h. At the end of the reaction, the reaction mixture wasextracted with dichloromethane, washed with water, and driedover anhydrous Na2SO4. Flash column chromatography (1:1hexane-ethyl acetate) gave 3 (2.2 mg) in 1.9% and 4 (71.6 mg) in62.8% yields. When the reaction was carried out in t-BuOH ort-amyl alcohol, the products 3 and 4 were obtained in 6.7% and25.3% yields (t-BuOH) and in 7.6% and 37.4% yields (t-amylalcohol).

4-(2-Fluoroethyl)-1-(20,30,40,60-tetra-O-acetyl-b-D-glucopyrano-

syl)-1,2,3-triazole (3): 1H NMR (CDCl3, 500 MHz) d 7.69 (s, 1H),5.85–5.88 (m, 1H), 5.41–5.47 (m, 2H), 5.24–5.28 (m, 1H), 4.72(dt, 2H, J=52.5, 6.5 Hz), 4.33 (dd, 1H, J=12.5, 5.0 Hz), 4.17 (dd, 1H,J=12.5, 2.0 Hz), 4.01 (ddd, 1H, J=10.0, 5.0, 2.0 Hz), 3.16 (dt, 2H,J=25.5, 5.8 Hz), 2.11 (s, 3H), 2.09 (s, 3H), 2.05 (s, 3H), 1.90 (s, 3H);MS (FAB) m/z 446 (M+ +H); HRMS calcd for C18H25FN3O9

446.1576, found 446.1575.4-Vinyl-(20,30,40,60-tetra-O-acetyl-b-D-glucopyranosyl)-1,2,3-tria-

zole (4): 1H NMR (CDCl3, 500 MHz) d 7.72 (s, 1H), 6.69 (dd, 1H,J=17.7, 11.2 Hz), 5.97 (d, 1H, J=15.1 Hz), 5.87 (d, 1H, J=9.0 Hz),5.47–5.39 (m, 3H), 5.24 (t, 1H, J=9.8 Hz), 4.31 (dd, 1H, J=12.7,5.1 Hz), 4.14 (dd, 1H, J=12.7, 2.0 Hz), 4.01–3.98 (m, 1H), 2.09 (s,3H), 2.07 (s, 3H), 2.03 (s, 3H), 1.89 (s, 3H); MS (FAB) m/z 426(M+ +H); HRMS calcd for C18H24N3O9 426.1513, found 426.1518.

2.2. Synthesis of non-radiolabeled compound 6

Compound 6 was synthesized at a 29% yield using the sameprocedure as described for the synthesis of 3.

4-(3-Fluoropropyl)-1-(20,30,40,60-tetra-O-acetyl-b-D-glucopyrano-

syl)-1,2,3-triazole (6): 1H NMR (CDCl3, 600 MHz) d 7.57 (s, 1H),5.87–5.83 (m, 1H), 5.44–5.40 (m, 2H), 5.26–5.22 (m, 1H), 4.49 (dt,2H, J=47.2, 5.8 Hz), 4.31 (dd, 1H, J=12.6, 4.2 Hz), 4.15 (dd, 1H,J=12.6, 1.9 Hz), 4.01–3.98 (m, 1H), 2.87 (dt, 2H, J=2.3, 1.8 Hz),2.14–2.11 (m, 2H), 2.09 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 1.88 (s,3H); MS (FAB) m/z 460 (M+ +H); HRMS calcd for C19H27FN3O9

460.1732, found 460.1735.

2.3. Radiochemical synthesis of 4-[18F]fluoro-1-butyne ð½18F�1Þ and

5-[18F]fluoro-1-pentyne ð½18F�5Þ

2.3.1. Use of acetonitrile as the reaction medium

After loading a QMA cartridge with [18F]F� , radioactivity waseluted using a 1:1 mixture of water and CH3CN (600mL) contain-ing K2,2,2 (13 mg, 0.03 mmol) and K2CO3 (3 mg, 0.02 mmol).Solvents were removed under N2 at 90 1C and the remainingwater was removed by two azeotropic distillations using100–200mL aliquots of CH3CN at 90 1C under a gentle stream ofN2. The resulting K[18F]F was dissolved in CH3CN (1 mL) andtransferred to a vial containing 4-tosyloxy-1-butyne (8 mg,0.036 mmol), which was connected to a second vial via ETFEtubing (1/16 in I.D., 25 cm length). This reaction mixture was thenstirred at 95 1C for 15 min, during which the volatile productsdistilled with acetonitrile into the second empty vial, vented usinga needle and placed �30 1C. An aliquot of the distillate wasanalyzed by reverse phase HPLC with a 40 min, 3.5 mL/min lineargradient from 95:5 to 0:100 mixture of water containing TFA(0.1%) and acetonitrile containing TFA (0.1%). [18F]1 and vinylacetylene (2) eluted at retention times of 16 and 20 min,respectively. [18F]5 was prepared using the same proceduredescribed for the synthesis of [18F]1 (HPLC tR=21 min).

2.3.2. Use of t-BuOH or t-amyl alcohol as the reaction medium

Nucleophilic [18F]fluorination of 4-tosyloxy-1-butyne wascarried out in t-BuOH or t-amyl alcohol medium and theremainder of the synthesis was identical to that described inSection 2.3.1. HPLC analysis showed the formation of [18F]1 and 2.

2.4. Click reaction of o-[18F]fluoro-1-alkynes with azido compound

The reaction mixture containing [18F]1 and 2, obtained fromthe procedure described in Section 2.3, was distilled withacetonitrile into a second vial containing 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl azide (15 mg, 0.039 mmol), CuI (3.1 mg,0.02 mmol), and sodium ascorbate (21 mg, 0.11 mmol) in a dryice/acetone bath. After completing the distillation, [18F]1 wasobtained at a 4573% (n=6) decay-corrected radiochemical yieldbased on [18F]fluoride ion. The reaction mixture was then warmedto room temperature, and DIEA (14mL, 0.12 mmol) and water(250mL) were added to the mixture. The reaction mixture wasthen stirred at 90 1C for 15 min, concentrated under N2 at 50 1C(water bath) to remove acetonitrile, diluted with water (500mL),and analyzed by reverse phase HPLC under the same conditions asdescribed for analyses of [18F]1. [18F]3 and 4 eluted at 21 and22.5 min, respectively. The decay-corrected radiochemical yield of[18F]3 from [18F]fluoride ion was 2776% (n=6). [18F]5 and [18F]6were obtained in 5976% (n=4) (HPLC tR=21 min) and in 5275%(n=4) (HPLC tR=23 min) decay-corrected radiochemical yields,respectively from [18F]fluoride ion using the same proceduresdescribed for the synthesis of [18F]1 and [18F]3.

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OAcOAcO

OAcN

OAc

NN

18F

OTs

18F

[18F]1 [18F]3a

b

D.H. Kim et al. / Applied Radiation and Isotopes 68 (2010) 329–333 331

2.5. One-pot synthesis of ½18F�3 and 4

One-pot synthesis of [18F]3 was carried out using the sameprocedure described in Section 2.1.3. HPLC analysis showed theformation of [18F]3 and 4.

OAcOAcO

OAcN

OAc

NN

42

b

Scheme 1. Nucleophilic substitution of 4-tosyloxy-1-butyne with K[18F]F fol-

lowed by click reaction with an azido compound. Reagents and conditions: (a)

K[18F]F/K2,2,2, CH3CN, 95 1C, 15 min; (b) 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl

azide, CuI, sodium ascorbate, DIEA, CH3CN, H2O, 90 1C, 15 min.

3. Results and discussion

4-[18F]Fluoro-1-butyne was synthesized by nucleophilic sub-stitution of 4-tosyloxy-1-butyne with K[18F]F. During this reac-tion, the volatile products were co-distilled, along with theacetonitrile solvent used for the reaction, into a second vial.When an aliquot of the distilled fraction was analyzed by reversephase HPLC, an unknown non-radiolabeled compound and aradiolabeled compound were detected at retention times of 20and 16 min (Fig. 1A). The non-radiolabeled compound was notanalyzed by LC-MS because of its low molecular weight andprobable low boiling point. Therefore, click chemistry betweenthe distillate and 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl azidewas carried out in the presence of CuI, DIEA, and sodiumascorbate (Scheme 1). HPLC analysis showed a radiolabeledpeak at a retention time of 21 min and two non-radiolabeledpeaks at 22.5 and 24 min, the latter being identified as theunreacted azido compound (Fig. 1B). The radiolabeled and non-

Fig. 1. HPLC analysis of the distillate obtained from the nucleophilic substitution

of 4-tosyloxy-1-butyne with K[18F]F (A) and of the reaction mixture obtained from

the click reaction of the distillate with 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl

azide (B). HPLC eluant was monitored simultaneously using NaI(Tl) radioactivity

and UV (218 nm) detectors (black and gray solid lines).

radiolabeled compounds eluting at 21 and 22.5 min wereidentified by co-injection with the products obtained from anon-radiolabeling reaction. The non-radiolabeling reaction wascarried out using 4-tosyloxy-1-butyne and KF with acetonitrilesolvent; the fraction distilling at 90 1C was reacted with 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl azide. The two resultingcompounds, obtained in a ratio of 13:87, were analyzed by 1HNMR spectroscopy and FAB mass spectrometry. The productswere identified as 4-(2-fluoroethyl)-1-(20,30,40,60-tetra-O-acetyl-b-D-glucopyranosyl)-1,2,3-triazole (3) and 4-vinyl-(20,30,40,60-tetra-O-acetyl-b-D-glucopyranosyl)-1,2,3-triazole (4), respectively, andco-eluted in HPLC with the products obtained from theradiolabeling reaction.

This result clearly indicates that nucleophilic substitution of 4-tosyloxy-1-butyne with K[18F]F produced not only 4-[18F]fluoro-1-butyne but also the elimination product, vinyl acetylene (2).Due to their low boiling points (45 1C vs. 0–6 1C) (Hennion et al.,1954), these compounds were not separable by distillation at95 1C. Although distillation of the reaction mixture at 50 1C undera gentle stream of N2 followed by an additional distillation of theprimary distillate at 0 1C to remove 2 results in mostly 4-[18F]fluoro-1-butyne product, this is a cumbersome process thatalso results in loss of the desired product. Recently, Kim et al.(2008 b) demonstrated that nucleophilic fluorination of 1-(2-mesyloxyethyl)naphthalene using tetrabutylammonium fluoridein t-BuOH medium gives the corresponding fluoroalkane as themajor product (87%) and alkene by-product (9%), while theidentical reaction in acetonitrile medium produces more alkeneby-product (61%) than fluoroalkane (33%). They also reported thatfluorination of 2-(2-mesyloxyethyl)naphthalene using CsF in t-amyl alcohol medium gives 2-(2-fluoroethyl)naphthalene in 92%with trace amounts of alkene by-product (Kim et al., 2006).

Therefore, we carried out the nucleophilic fluorination of 4-tosyloxy-1-butyne with KF in t-BuOH or t-amyl alcohol. However,in our case, these reactions gave the same products as inacetonitrile, although the ratio of 3 and 4 obtained using t-BuOH(21:79) or t-amyl alcohol (25:75) was slightly shifted toward theformation of 3 than that obtained using acetonitrile medium(13:87). Low yields of the products were obtained in all solventmediums, probably due to their unavoidable evaporation duringdistillation of 1 and 2. This trend was profound when t-BuOH wasused, because its high melting point (25–26 1C) caused frequentclogging of the transfer tubing connected to a second vial even atroom temperature. Therefore, we carried out an one-pot synthesisof 3 and 4 without distillation of 1 and 2, which gave the identicalproducts, 3 and 4, in higher yields. Radiolabeling reaction alsogave the alkene by-product (2) in addition to the desired product([18F]1) in all solvent mediums upon HPLC analyses. This resultmay be explained by the presence of highly acidic proton at the C3of 4-[18F]fluoro-1-butyne.

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OAcOAcO

OAcN

OAc

NN18F

[18F]6

OTs 18F

[18F]5

ba

Scheme 2. Nucleophilic substitution of 5-tosyloxy-1-pentyne with K[18F]F followed by a click reaction with an azido compound. Reagents and conditions: (a) K[18F]F/K2,2,2,

CH3CN, 95 1C, 15 min; (b) 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl azide, CuI, sodium ascorbate, DIEA, CH3CN, H2O, 90 1C, 15 min.

Fig. 2. HPLC analysis of the distillate obtained from the nucleophilic substitution

of 5-tosyloxy-1-pentyne with K[18F]F (A) and of the reaction mixture obtained

from the click reaction of the distillate with 2,3,4,6-tetra-O-acetyl-b-D-glucopyr-

anosyl azide (B). HPLC eluant was monitored simultaneously using NaI(Tl)

radioactivity and UV (218 nm) detectors (black and gray solid lines).

OTsH

OTs

2

Scheme 3. A proposed mechanism for vinyl acetylene formation via b-elimina-

tion.

D.H. Kim et al. / Applied Radiation and Isotopes 68 (2010) 329–333332

In order to prevent the elimination reaction, 5-tosyloxy-1-pentyne was used in place of 4-tosyloxy-1-butyne for the samereaction (Scheme 2). Nucleophilic substitution of 5-tosyloxy-1-pentyne with K[18F]F and the simultaneous distillation gave asingle radiolabeled product with an HPLC retention time of 21 min(Fig. 2A). The subsequent click reaction with 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl azide followed by HPLC analysis gave aradiolabeled product at 23 min, identified by co-elution with 4-(3-fluoropropyl)-1-(20,30,40,60-tetra-O-acetyl-b-D-glucopyranosyl)-1,2,3-triazole (6), and the unreacted azide at 24 min (Fig. 2B). Theseresults indicate that the nucleophilic substitution of 4-tosyloxy-1-butyne with K[18F]F leads to the formation of by-product 2, aswell as the desired product, [18F]1 (Scheme 1), while substitutionof 5-tosyloxy-1-pentyne under the same conditions producesexclusively [18F]5 (bp: 76 1C) with no alkene by-product (Scheme2). This is not surprising given that the formation of 2 may occur

via a b-elimination process initiated by abstraction of the protonfrom the b carbon, leading to the cleavage of the tosyloxy group toproduce more stable, conjugated vinyl acetylene (Scheme 3). Thisresult is also supported by finding that 4-tosyloxy-1-butyne isconverted into vinyl acetylene in high yield upon treatment withalcoholic potassium hydroxide (Eglinton and Whiting, 1950).Thus, nucleophilic substitution and b-elimination are competitivein the case of 4-tosyloxy-1-butyne, whereas only nucleophilicsubstitution occurs in the case of 5-tosyloxy-1-pentyne.

4. Conclusion

4-[18F]Fluoro-1-butyne may not be suitable for click chemistrywith azido compounds because its synthesis is accompanied by analkene elimination product. Therefore, o-[18F]fluoro-1-alkyneswith chain lengths longer than four carbons may serve as betterradiolabeled acetylene synthons for click chemistry.

Acknowledgments

This work was supported by the Nuclear Research & Develop-ment Program of the Korea Science and Engineering Foundation(KOSEF) grant funded by the Korean government (MEST) (Grantcode: 20090067239).

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