β-Configured clickable [18F]FDGs as novel 18F-fluoroglycosylation tools for PET

Article abstract of DOI:10.1039/c7nj00716g

In oncology and neurology the ¹⁸F-radiolabeled glucose analogue 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) is by far the most commonly employed metabolic imaging agent for positron emission tomography (PET). Herein, we report a novel synthetic route to β-configured mannopyranoside precursors and a chemoselective ¹⁸F-fluoroglycosylation method that employ two β-configured [¹⁸F]FDG derivatives equipped with either a terminal azide or alkyne aglycon respectively, for use as a CuAAC clickable tool set for PET. The β-configured precursors provided the corresponding [¹⁸F]FDGs in a radiochemical yield of 77-88%. Further, the clickability of these [¹⁸F]FDGs was investigated by click coupling to the suitably functionalized Fmoc-protected amino acids, Fmoc-N-(propargyl)-glycine and Fmoc-3-azido-l-alanine, which provided the ¹⁸F-fluoroglycosylated amino acid conjugates in radiochemical yields of 75-83%. The ¹⁸F-fluoroglycosylated amino acids presented herein constitute a new and interesting class of metabolic PET radiotracers.

Full text of DOI:10.1039/c7nj00716g

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b-Configured clickable [18F]FDGs as novel
18F-fluoroglycosylation tools for PET†
Cite this:DOI: 10.1039/c7nj00716g
M. Elgland,a P. Nordeman,b T. Fyrner,a G. Antoni,b K. Peter R. Nilsson *a and
P. Konradsson*a
In oncology and neurology the 18F-radiolabeled glucose analogue 2-deoxy-2-[18F]fluoro-D-glucose
([18F]FDG) is by far the most commonly employed metabolic imaging agent for positron emission
tomography (PET). Herein, we report a novel synthetic route to b-configured mannopyranoside precursors
and a chemoselective 18F-fluoroglycosylation method that employ two b-configured [18F]FDG derivatives
equipped with either a terminal azide or alkyne aglycon respectively, for use as a CuAAC clickable tool set for
PET. The b-configured precursors provided the corresponding [18F]FDGs in a radiochemical yield of 77–88%.
Further, the clickability of these [18F]FDGs was investigated by click coupling to the suitably functionalized
Fmoc-protected amino acids, Fmoc-N-(propargyl)-glycine and Fmoc-3-azido-L-alanine, which provided the
18F-fluoroglycosylated amino acid conjugates in radiochemical yields of 75–83%. The 18F-fluoroglycosylated
amino acids presented herein constitute a new and interesting class of metabolic PET radiotracers.
Received 1st March 2017,
Accepted 14th June 2017
DOI: 10.1039/c7nj00716g
rsc.li/njc
from normal tissue.4 Consequently, there is a great need for new
PET tracers that exhibit both high affinity and selectivity
Introduction
2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is often referred to as towards a particular biomolecular target. In recent years, the
the golden standard in the field of positron emission tomo- concept of employing [18F]FDG as a prosthetic group for the
graphy (PET), where approximately 90% of all PET scans are 18F-radiolabeling of ligands with defined molecular targets
performed using [18F]FDG.1 As a glucose derivative, [18F]FDG in vivo has received considerable attention.5 The rationale is
act as a biomarker of glucose metabolism and as such has that glycoconjugates (e.g., glycopeptides, glycoproteins) in general
found widespread use in oncology and neurology, both in clinic exhibit improved pharmacokinetic properties such as increased
and in research.2 When injected into the human body, it in vivo kinetics, higher metabolic stability and faster blood
preferentially accumulates in tissue that exhibit an increase clearance compared to their non-glycosylated counterparts.6
in glycolysis, e.g., cancer cells. Conversely, diminished glucose Furthermore, the relatively long half-life of 18F (t1/2 = 109.8 min)
consumption due to neuronal cell death in the brain inflicted provides a sufficient amount of time to perform multi-step
by neurodegenerative disorders, e.g., Alzheimer’s disease, can radiosynthesis followed by a subsequent PET investigation.
also indirectly be probed using [18F]FDG. However, despite its
Several methods have been employed for the ligation of
prominent role, one major drawback associated with using [18F]FDG to a diverse set of ligands, for instance (i) via oxime
[18F]FDG is that it suffers from poor tissue selectivity when formation,7 (ii) chemoenzymatic approaches8 as well as using
distinguishing between malignant cells and benign cells that (iii) thiol-selective S-glycosylation.9 More importantly, one of
have a high metabolic rate, such as certain cells associated with the most established methods is by means of the CuAAC click
inflammation or infection.3 Furthermore, since [18F]FDG is a reaction10,11 which allows for a wide substrate scope using mild
metabolic imaging agent it is not sufficiently capable of detecting conditions.12 Accordingly, in 2009, Maschauer et al.,13 reported
tumors found in most prostate cancers, bronchoalveolar-cell the synthesis of a set of 2-O-trifluoromethanesulfonyl-D-manno-
carcinoma or renal-cell carcinoma due to the fact that their pyranosides, i.e., precursors of [18F]FDG analogs, that were
metabolic rate is relatively low and therefore indistinguishable equipped with either a a-1-O-propargyl (10a), a-1-O-(2-azido)ethyl
(6a), a- or b-azido aglycons (16a and 16b respectively, Scheme 1).
In their study, only minor amounts of the a-configured precur-
sors were radiolabeled (r14% radiochemical yield (RCY)) which
a
¨
Linkopings University, IFM – Department of Biology, Chemistry & Physics,
rendered them inapplicable for PET. In contrast, the b-azide pre-
cursor (16b) gave a significantly higher RCY (71%) indicating
that the b-anomeric configuration is a key criterion for a
¨
SE-581 83 LINKOPING, Sweden. E-mail: petko@ifm.liu.se, petni@ifm.liu.se
b Department of Medicinal Chemistry, Uppsala University, Uppsala SE-75123,
Sweden
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7nj00716g successful 18F-radiolabelling.
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Scheme 1 (to the left) Previous work by Maschauer et al. on 18F-radiolabeling of clickable a and b [18F]FDG precursors and (to the right) this work
describing the high-yielding 18F-radiolabeling of b-D-mannopyranoside triflates equipped with both azide- and alkyne spacers.
The propensity of the precursors to undergo the displace- [18F]FDG that can be retrieved in a sufficient radiochemical yield
ment by 18FÀ correlates well with the Richardson–Hough rules is available.
from 1967 that predict the SN2 displacement viability in carbo-
In this work, we report the detailed synthesis of the CuAAC
hydrate sulfonate derivatives with external nucleophiles.14 The clickable b-configured [18F]FDGs (Scheme 1). In order to evaluate
outcome of the reaction is dictated by stereoelectronic effects their clickability, the [18F]FDGs were chemically ligated to the
but also accompanied by steric factors. This theory recently got suitably functionalized Fmoc-protected amino acids Fmoc-N-(pro-
extended by Hale et al. to encompass seemingly disallowed pargyl)-glycine 12 and Fmoc-3-azido-L-alanine 14 by means of the
trifluoromethanesulfonate displacements.15 Briefly, the theory click reaction which successfully provided the expected [18F]FDG
predicts that 2-O-trifluoromethanesulfonyl-b-D-mannopyranosides conjugates, both rapidly and in good radiochemical yield. Due to
experience a significantly lower dipolar repulsion at the transition the increased cell proliferation of most cancers, protein synthesis
state and will therefore readily undergo the SN2 displacement is up-regulated and, as a natural consequence, the amino acid
while the corresponding a-anomer should only give minor uptake is usually significantly increased. The synthesized [18F]FDG
substitution or none at all.
amino acid conjugates will therefore serve as the basis for a new
The b-azide equipped [18F]FDG (17b, Scheme 1) has success- class of highly promising metabolic imaging agents. Further-
fully been utilized as a 18F-fluoroglycosylation tool to provide more, the described 18F-fluoroglycosylation method may well be
[18F]FDG conjugates with a diverse set of ligands, e.g., the RGD extended to encompass the radiolabeling of, not only amino
peptide targeting the integrin receptor,16,17 folic acid targeting acids, but also peptides and proteins.
the folate receptor,18 and a diarylpyrazole targeting the NTS-1
neurotensin receptor.19 However, the first generation of clickable
[18F]FDGs is rather limited in scope. Ideally, a spacer between the
FDG unit and the attached click functional group is desired to
Results and discussion
prevent any potential steric interference between the FDG unit Since the fluorination step required to obtain the b-configured
and the ligand to which it will be attached. In fact, it has been [18F]FDG ([18F]7, [18F]11), is accompanied by an SN2 inversion,
shown that glucose derivatives bearing an anomeric 1,2,3- the triflate precursors (6, 10) are by necessity b-D-mannopyranosides.
triazole, generated from the corresponding glucosyl azide, lack Unfortunately, b-D-mannopyranosides are well-known to be
two key properties of [18F]FDG, i.e., trapping via O-6 phosphoryla- challenging to synthesize due to the inherently strong preference
tion and cell uptake via GLUT-1 transporters.20 This effect is most of conventional mannosyl donors to form a-D-mannopyranosides.
likely caused by the close proximity of the triazole. Moreover, This is a result of the simultaneous occurrence of both the
ideally, in order to be able to radiolabel the full set of available a-directing anomeric effect and repulsion between the axial C-2
click-enabled ligands, both azide- and alkyne equipped [18F]FDGs substituent and the approaching nucleophile.21 Moreover,
should be accessible. However, to date no alkyne equipped neighboring group participation of a 2-acyl mannosyl donor
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Scheme 2 General conditions and reagents: (i) oxone, acetone, TBAHSO4, DCM, satd. aq. NaHCO3, 0 1C to rt. (ii) Cl(CH2)2OH, ZnCl2, DCM, 0 1C to rt.
(iii) Propargyl alcohol, ZnCl2, DCM, 0 1C to rt. (iv) NaI, acetone, 70 1C (v) NaN3, DMF, rt. (vi) Tf2O, py, DCM, À15 to 10 1C. (vii) TBANO2, toluene, 50 1C.
(viii) DAST, diglyme, 100 1C, 10 min. (ix) TBANO2, toluene, rt.
also leads to a-mannopyranosides. Fortunately, several ingenious consistently resulted in a complex mixture of products due to
synthetic approaches to circumvent these obstacles have already acetate migration to the unprotected 2-OH, whereas no reaction
been devised.
occurred at ambient temperature. We therefore reasoned that
A particularly elegant approach was developed by the Danishefsky installing a better leaving group might make the reaction
group during the 1990’s, where epoxidation of per-benzylated proceed more smoothly and thus avoid the accompanying
D-glucal using DMDO, conveniently provided the corresponding acetate migration. This was realized by converting the 2-chloro
1,2-a-anhydrosugar that subsequently during glycosylation compound 3 to the corresponding iodo compound by means of
stereoselectively produced the corresponding b-D-glucoside – the classical Finkelstein reaction utilizing NaI (2 eq.) in acetone
and simultaneously generated an unprotected hydroxyl group at 70 1C for 48 h. The azidation of the iodoethyl glucoside using
in the 2-position. Subsequent epimerization of this site, following NaN3 in DMF now proceeded cleanly at ambient temperature to
an oxidation–reduction sequence generated the b-D-mannopyrano- afford the azidoethyl glucoside 4 in good yield (77%) over two
side.22 In this report we employ a similar synthetic approach which steps. Next, we decided to use the nitrite-mediated Lattrell–Dax
is depicted in Scheme 2. The choosen route requires access to inversion for the pending epimerization. The Lattrell–Dax inversion
26
¨
multi-gram quantities of 1,2-anhydrosugar 2a from tri-acetyl-D- has been extensively studied by the Ramstrom group who
glucal 1. While this transformation is commonly achieved using concluded that the inversion proceeds reliably – and even
a dilute solution of DMDO in acetone,23 performing this reaction stereospecifically – if and only if a vicinal equatorial ester is
on a large scale poses several practical issues. For instance, the present. This criterion is suitably met for the glucosides 4 and 8.
DMDO solution has to be kept rigorously dry, only dilute solutions Standard triflation of glucoside 4 using triflic anhydride followed
can be produced (ca. 0.1 M) and furthermore, the scale-up of by inversion using TBANO2 in toluene at ambient temperature
organic peroxy compounds is potentially hazardous.
over night yielded the b-D-mannopyranosides 5 and 9 cleanly
To circumvent these drawbacks, the Dondoni group, in albeit in a moderate yield of 46% and 48% respectively. The
2006, developed an epoxidation method for glycals where DMDO b-anomeric configuration was confirmed by evaluating the JC-1,H-1
is formed in situ from a biphasic buffered solution containing coupling constant in a coupled 1H–13C NMR experiment and was
oxone, acetone, satd. NaHCO3 and DCM.24 This protocol was found to be 157.6 Hz and 159.0 Hz respectively for b-D-manno-
further elaborated on by Lafont et al. in 2011 by the addition of pyranosides 5 and 9.27 With the desired b-D-mannopyranosides at
the phase transfer catalyst, tetrabutylammonium hydrogen hand, standard triflation afforded the b-D-mannosyl triflates, i.e.,
sulphate (TBAHSO4) that significantly increased the reaction the [18F]FDG precursors 6 and 10 in 48% and 60%, respectively
speed as well as the reproducibility.25 By employing the oxone- after silica gel chromatography. Subsequently, to afford the FDG
acetone-TBAHSO4 epoxidation protocol, we conveniently prepared analogs as a non-radioactive reference, a typical fluorination
the 1,2-anhydrosugar 2a which was then directly used in the protocol using potassium fluoride and the cryptand kryptofix
subsequent glycosylation. The glycosylation of 2-chloroethanol or (K[2.2.2]) in MeCN at 85 1C was attempted. Unfortunately, only
propargyl alcohol, promoted by ZnCl2 in DCM, provided the trace amount of the expected fluorosugar could be observed,
corresponding b-D-glucosides 3 and 8 in 39% and 29%, respec- most likely as a result of the known poor nucleophilicity of
tively over two steps. The predominant by-product formed was the fluoride ion. Instead, we choose to directly fluorinate the
the corresponding 1,2-diol hydrolysis product. Converting the b-D-mannopyranosides bearing a free hydroxyl-group in the
2-chloroethyl glucoside 3 to the corresponding 2-azidoethyl second position, 5 and 9, using the common fluorination agent,
glucoside 4 proved to be a major challenge. Standard conditions DAST.28 At first, the reaction was run in DCM at À25 1C to rt
for azidation, i.e., NaN3 in DMF at elevated temperatures (80 1C over night to give the fluorosugars 7 and 11 in 31% and 19%
or 110 1C), with or without the additives TBAI or TBAB, respectively. The poor yield rendered us to instead perform the
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Scheme 3 General conditions and reagents: (i) oxone, acetone, TBAHSO4, DCM, satd. aq. NaHCO3, 0 1C to rt. (ii) Cl(CH2)2OH, ZnCl2, DCM, 0 1C to rt.
(iii) Propargyl alcohol, ZnCl2, DCM, 0 1C to rt. (iv) NaI, acetone, 70 1C. (v) NaN3, DMF, rt. (vi) Tf2O, py, DCM, À15 to 10 1C. (vii) DAST, diglyme, 100 1C, 10 min.
Table 1 18F-Radiolabeling of a- and b-D-mannopyranoside precursors
reaction in diglyme at 100 1C for 10 min which afforded the
fluorosugars 7 and 11 in a significantly increased yield of 66%
(0.2 mmol) to yield the corresponding [18F]FDGs
and 35% respectively. The fluorination proceeded as expected
with inversion of configuration, as proven by the characteristic
JH-1,H-2 coupling constant of 7.6 Hz for 7 and 7.7 Hz for 11,
confirming the gluco-configuration. Furthermore, 1D 19F-NMR
revealed a characteristic FDG signal for fluorosugar 7 at À199.7 ppm
Entry
1
Precursor
Product
RCY (%)
(ddd, 2JH-2 F-2 = 50.5 Hz, 3JH-3 F-2 = 14.3 Hz, 3JH-1 F-2
, , = 2.7 Hz), and a
,
similar signal for 11 (ESI,† page 35 and 50 respectively).
To test our hypothesis that a b-configured FDG precursor is
radiolabeled to a greater extent than its a-anomeric counter-
part, we decided to synthesize the a-FDGs reported by Maschauer
et al. to make a direct side-by-side comparison using the same
18F-fluorination set-up. On closer inspection of our devised syn-
thetic route to the b-FDGs we realized that since the epoxidation
step is only moderately stereoselective on acetylated glycals (a/b
approx., 7 : 1),24 as a consequence, the minor b-1,2-anhydrosugar
(2b) would then upon glycosylation stereoselectively be ring-
opened to give the sought a-D-mannopyranosides, 4a and 8a,
with the second hydroxyl group exposed.
6
77 Æ 2
2
3
6a
0
10
88 Æ 5
As predicted, the glycosylations outlined in Scheme 3 resulted in
a diastereomeric mixture of the glycosides 4 and 4a, and 8 and 8a,
(dr B 9:1 gluco/manno in both cases) that were separated using
preparative HPLC. Spectroscopic data for the a-mannopyranosides
was in good agreement with the data reported by Maschauer et al.29
Triflation or fluorination (vide supra) of the isolated a-manno-
pyranosides then furnished the required precursors (6a and 10a)
and the a-configured FDGs (7a and 11a) respectively.
4
10a
0
RCY of the reaction (Table 1). Both b-mannopyranosides 6 and 10
performed well under these conditions and gave RCY of 77 Æ 2%
and 88 Æ 5% for [18F]7 and [18F]11, respectively (n = 2 for both
compounds) (Scheme 4). Unfortunately the a-precursors
gave no results (0% RCY) using these conditions as only unreacted
18FÀ could be identified using analytical radio-HPLC.‡
18F-Radiolabeling
18F was produced using the 18O(p,n)18F reaction using a scan-
ditronix MC-17 cyclotron. The water was transported to the hot
cell and trapped on a QMA which was flushed with MeCN.
[18F]Fluoride was eluted using a kryptofix 2.2.2/K2CO3 solution.
After azeotropic distillation with MeCN the precursor (6, 6a, 10 or
10a) in dry MeCN was added to the vial which was heated to 85 1C
for 30 minutes. After the reaction was finished, an aliquot was
‡ In the original radiolabelling procedure by Maschauer et al. an optimized
kryptofix 2.2.2 buffer (K2CO3/KH2PO4) was necessary in order to keep the
precursors intact and obtain a RCY. In addition, the precursor load was 15 mM
compared to
2 mM used herein. These differences may explain the failed
taken and analysed by radio-HPLC to determine the non-isolated radiolabelling of the a-precursors in our hands.
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[18F]FDGs was demonstrated by click coupling to the suitably
functionalized Fmoc-protected amino acids, Fmoc-N-(propargyl)-
glycine (12) and Fmoc-3-azido-L-alanine (14) in near quantitative
RCY, using a simple two-step one-pot protocol. The 18F-fluoro-
glycosylated amino acids, [18F]13, [18F]15, constitute a new and
interesting class of metabolic oncological PET radiotracers. We
also recognize that while 18F is excellently suited for PET imaging,
the natural isotope, 19F, has almost optimal properties for
19F-NMR, a technique that in recent years has received consider-
able attention as a means to probe biological mechanisms.30 The
developed 18F-fluoroglycosylation method at hand may thus equally
well serve as a means to provide novel 19F-NMR probes. Our lab is
currently engaged in synthesizing [18F]FDG conjugates targeting
cancer and disease associated protein aggregates that will be
reported in due course.
Scheme 4 18F-Fluoroglycosylation of amino acids 12 and 14. General
conditions and reagents: (i) amino acid (0.25 mmol) aq., CuSO4 (50 mL,
0.20 M), aq., (+)-sodium L-ascorbate (50 mL, 0.60 M), 60 1C, 20 min, DMF.
Having established
a synthetic protocol to acquire the
[18F]FDGs we then turned to investigate their performance in
the click reaction. We choose to use the appropriately functio-
nalized Fmoc-protected amino acids, Fmoc-N-(propargyl)-
glycine (12) and Fmoc-3-azido-L-alanine (14) as a model system
to show the proof of concept. The click reaction was performed
in a one pot, two-step process starting from 18FÀ and 6 or 10.
After the reaction, the MeCN was evaporated with a stream of
helium after which the protected [18F]7 or [18F]11 was subse-
quently dissolved in dry DMF, whereto the Cu(I) catalyst,
prepared in situ by the addition of aq. CuSO4 (50 mL, 0.20 M)
and aq. (+)-L-sodium ascorbate (50 mL, 0.60 M) along with
amino acid 12 or 14 (2.5 mmol) were added. The reaction was
then heated to 60 1C for 20 min. The RCY of [18F]13 was 75 Æ
2% and for [18F]15 83 Æ 2% as deducted by analytical-HPLC
(n = 2 for each compound). In preparative runs starting with
3 GBq (81 mCi) of fluoride, 820 MBq (22 mCi) of [18F]13
(55% RCY) and 990 MBq (27 mCi) of [18F]15 (66%) was obtained,
respectively. Both compounds were pure (RCP > 99%) as deducted
by HPLC. The RCY was decay corrected to end of bombardment
(EOB) and the total synthesis time was 2 hours. The corresponding
non-radioactive FDG amino acid conjugates was synthesized using
microwave irradiation at 80 1C for 5 min (ESI,† Scheme S2,
page 3). The click reaction between FDG 7 (1.2 eq.) and amino
acid 12 (1.0 eq.) and between FDG 11 (1.2 eq.) and amino
acid 14 (1.0 eq.) yielded FDG conjugates 13 and 15 in 64% and
86% respectively.
Acknowledgements
Our work is supported by the Swedish Foundation for Strategic
Research and the Swedish Research Council.
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