An efficient method for enhancing the reactivity and flexibility of [18F]fluoride towards nucleophilic substitution using tetraethylammonium bicarbonate

Article abstract of DOI:10.1002/ejoc.201402587

The standard method used to generate reactive [¹⁸F]fluoride for [¹⁸F]radiolabelling is to trap it on an anion-exchange cartridge then elute it with a basic aqueous solution, which is then subjected to azeotropic evaporation to remove

Full text of DOI:10.1002/ejoc.201402587

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402587
An Efficient Method for Enhancing the Reactivity and Flexibility of
[18F]Fluoride Towards Nucleophilic Substitution Using Tetraethylammonium
Bicarbonate
Laurent Brichard*[a] and Franklin I. Aigbirhio[a]
Keywords: Imaging agents / Isotopic labelling / Radiolabelling / Radiofluorination / Fluorine / Positron emission
tomography
The standard method used to generate reactive [18F]fluoride
for [18F]radiolabelling is to trap it on an anion-exchange
cartridge then elute it with a basic aqueous solution, which
is then subjected to azeotropic evaporation to remove water.
We have now developed a method through the use of tetra-
ethylammonium hydrogen carbonate in which we can obtain
efficient recovery of [18F]fluoride (up to 99%), remove the
requirement for the time-consuming and inefficient azeo-
tropic evaporation process and produce a reactive [18F]fluor-
ide that can undergo a wide range of aliphatic and aromatic
[
18F]nucleophilic substitutions in up to 93% radiochemical
conversion at end-of-synthesis in the presence or without
water.
neurological system being investigated, high specific activity
[18F]radiopharmaceuticals are required for administration.
Therefore, to achieve a high specific activity that would lead
to a low mass of [19F] compound being co-injected to the
subject, the starting activity formed in the cyclotron is often
required to be the highest practicable. For radioprotection
reasons, the production of [18F]radiopharmaceuticals is car-
ried out in lead-shielded fume hoods using automated de-
vices designed to remotely perform the radiochemical pro-
cedures. Consequently, simplicity in the radiosynthesis pro-
cess and in the conception of these synthesisers is often the
key to obtaining [18F]radiotracers in a reliable and repro-
ducible manner. Typically, the preparation of [18F]radio-
tracers for PET studies involves the following stages: i)
trapping of cyclotron-produced [18F]fluoride on an anion
exchange column by Solid Phase Extraction (SPE) and re-
covery of the expensive [18O]water, ii) elution of the [18F]-
fluoride from the SPE cartridge to a reactor with an aque-
ous solution of a suitable base (e.g.: K2CO3, tBu4NHCO3,
Cs2CO3), iii) azeotropic evaporation with acetonitrile to re-
move the water from the reactor, iv) radiolabelling reaction
with the precursor, in the presence of a phase-transfer agent
[e.g.: Kryptofix® 2.2.2 (K222), tetraalkylammonium salt]
that enhances the reactivity of [18F]fluoride towards nucleo-
philic substitution reactions, in an appropriate organic sol-
vent; usually acetonitrile (MeCN), dimethylformamide
(DMF) or dimethylsulfoxide (DMSO), v) purification via
reversed-phase HPLC and/or SPE methods and formula-
tion of the purified [18F]radiopharmaceutical into a solvent
suitable for intravenous injection (e.g.: saline, phosphate
buffer). Over the years, many different techniques have been
implemented to improve the efficiency of the labelling reac-
Introduction
Positron Emission Tomography (PET)[1] is a powerful
preclinical and clinical molecular imaging technique that
uses short half-life β+ emitters incorporated into small or-
ganic molecules to study various in vivo physiological pro-
cesses (e.g. glucose metabolism,[2] cellular proliferation,[3]
hypoxia[4]). Among the different positron-emitters available
for PET, fluorine-18 is by far the most widely used. It can
be readily produced as [18F]fluoride with a biomedical
cyclotron in high amount of radioactivity (Ͼ100 GBq) and
high specific activity (Ͼ200 GBq/μmol) by irradiating an
[18O]H2O target with protons according to the 18O(p,n)18F
nuclear reaction. F-18 has a convenient half-life of
109.7 min. that makes it suitable for complex synthesis, long
scanning protocol and also allows it to be transported to a
reasonable distance. Furthermore, 97% of F-18 decay
occurs through emission of β+ with a low energy of 634 keV
that limits the distance travelled by the positron into
aqueous tissues to a few millimetres.
[18F]-labelled radiotracers are regularly used to image
and quantify in vivo the activity of biological systems that
are present in low concentrations (e.g. dopaminergic[5] and
serotonergic[6] receptors). However, in order to study these
structures in optimal conditions, avoiding saturation of the
[a] Molecular Imaging Chemistry Laboratory, Wolfson Brain
Imaging Centre, Department of Clinical Neurosciences,
University of Cambridge, Cambridge Biomedical Campus,
Box 65, CB20QQ, Cambridge, UK
E-mail: bl260@wbic.cam.ac.uk
http://www.wbic.cam.ac.uk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejo.201402587.
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Brichard, F. I. Aigbirhio
SHORT COMMUNICATION
Scheme 1. [18F]-labelled compounds synthesised from [18F]Et4NF.
tion (e.g. transition metal catalysis,[7] ionic liquids,[8] (7 mg/ 22 mg) is added to the reaction vessel. Finally, a re-
fluorous SPE,[9] microwaves,[10] microfluidic[11]) but only a cent study shows the ability of [18F]fluoride to react with
few have translated into routine application and while less symmetrical and unsymmetrical diaryliodonium salts to
have dealt with the early key steps of the process which provide [18F]fluoroarenes in good yields even in the pres-
consist of the removal of [18F]fluoride from its [18O]H2O ence of up to 28% water in the reaction mixture.[14] Still,
matrix and the generation of its reactive form. This part of this technique, while not requiring an evaporation step, has
the procedure can be lengthy in the context of F-18 radio- so far only been proven efficient for this type of radiochem-
chemistry (around 10–15 min), commonly leads to losses in istry.
radioactivity and often results, at the end of process, in the
Herein, we describe a new method where tetraethyl-
formation of a slurry in the reactor vessel which does not ammonium hydrogen carbonate dissolved in a polar aprotic
completely dissolve in the reaction solvent, hence leaving a solvent (MeCN, DMF, DMSO) containing up to 5% of
significant amount of unreacted [18F]fluoride at the end of water can be used to efficiently elute [18F]fluoride from an
labelling. Finally, this procedure can also be difficult to anion-exchange cartridge (QMA, carbonate form) to pro-
automate, leading to irreproducible results. Recently, as a duce tetraethylammonium [18F]fluoride. Importantly this
means of improving the process, the use of strong organic can then be applied towards the radiosynthesis of wide
bases in an organic solvent containing low amounts of range [18F]-labelled compounds via aliphatic or aromatic
water or alcohol has been proposed to efficiently elute the nucleophilic substitution (Scheme 1) without the need of
[18F]fluoride from the anion-exchange column (QMA, any azeotropic drying procedures. Giving added flexibility,
carbonate form, Waters), thus avoiding the need for an these reactions can also be performed in presence or with-
evaporation step.[12] This method relies on the use of P2Et out small percentage of water. Et4NHCO3 has previously
{NЈЈЈ-ethyl-N,N,NЈ,NЈ-tetramethyl-NЈЈ-[tris(dimethylamino)- been proposed as an alternative to the K222/K2CO3 system
phosphoranylidene]phosphorimidic triamide, pKa: 32.9} for in the radiolabelling of various molecules. However the
the elution of the QMA and BTMG (2-tert-butyl-1,1,3,3- method still requires the standard process of eluting the
tetramethylguanidine, pKa: 23.56) as an additive for the anion-exchange column with a 10% aqueous solution of
subsequent labelling reaction. However, this restricts the the ammonium salt followed by azeotropic evaporation of
practical application of this process to the labelling of or- the residual water before performing the labelling reaction
ganic molecules with no base-sensitive groups unless they itself.[15]
are appropriately protected. Furthermore, the purification
of the [18F]radiotracer may be rendered more problematic
in the presence of these two compounds. Finally, the study
only reports labelling reactions carried out in MeCN
whereas other polar aprotic solvents such as DMF and
Results and Discussion
For our method [18F]Fluoride is passed through a QMA
DMSO are widely used in nucleophilic substitution reac- cartridge in the carbonate form and extracted from [18O]-
tions with [18F]fluoride. In another report, the use of a H2O. At the end of trapping of the [18F]fluoride, the
polymeric solid support loaded with a long alkyl chain qua- cartridge is rinsed with either 5 mL hexane (for procedures
ternary ammonium salt instead of a QMA cartridge is de- using MeCN and DMF) or 5 mL DMSO to remove the
scribed for the trapping of [18F]fluoride and its subsequent residual water present on the solid support. The [18F]fluor-
elution in an organic solvent containing low amount of ide is subsequently eluted in the reverse direction with a
water.[13] However, in order to increase the radiochemical solution of Et4NHCO3 in either MeCN, DMF or DMSO
yield in most of the labelling reactions presented in this containing various concentrations of water (Table 1). When
publication, either Et4NHCO3 (50 mg) or K2CO3/K2.2.2 MeCN is used to elute the [18F]fluoride from the anion ex-
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Enhanced Method for the Preparation of [18F]Radiotracers
change cartridge, the efficiency of tetraethylammonium reacted with the corresponding triflate precursor at 115 °C
hydrogen carbonate to release the activity reaches 95% for 10 min. (Table 2, entry 1). A small addition of water to
(Table 1, MeCN, entry 1). By incrementally adding a few the reaction mixture (Table 2, entry 2) results in an increase
percentage of water to the eluent, the effectiveness of the of the RCC to 76%. However, when more water is progress-
process improves to 97% for solutions containing 0.5, 1 and ively added, the RCC starts to decrease to a value of 68–
1.5% (Table 1, MeCN, entries 2–5) aqueous contents and 73% (Table 2, entries 3–6). Similarly, the RCC for the syn-
to 98% when 2% water is present (Table 1, MeCN, entry thesis of [18F]-2 ([18F]fallypride,[17] a dopamine D2/D3 re-
5). Finally, [18F]fluoride can be recovered quantitatively ceptors marker) from the tosylate precursor initially in-
from the QMA cartridge by means of a solution of creases from 53% to 58% when switching from dry DMF
Et4NHCO3 in MeCN containing 5% water (Table 1, to the eluent containing 0.5% water (Table 2, entries 7–8).
MeCN, entry 6). By switching to DMF, a slight decrease in The addition of more water to the reaction mixture leads
the efficacy of Et4NHCO3 for releasing the [18F]fluoride to a steady decrease in RCC with values of 56, 55, 51 and
from the solid support is observed with an elution efficiency 45% when using eluent solution containing respectively 1,
of 88% when no water is added to the eluent solution 1.5, 2 and 5% of water (Table 2, entries 9–12). The synthesis
(Table 1, DMF, entry 1). However, by raising the amount of [18F]-3 ([18F]FEDAA1106,[18] a peripheral benzodiazep-
of water in the solution, a steady increase in the elution ine receptor radioligand) from the tosylate precursor fol-
efficiency is noticed with values of 89, 90, 93, 94 and 99% lows a pattern differing from the previous radiolabelled
for, respectively, 0.5, 1, 1.5, 2 and 5% of water added to the compounds discussed. Indeed, in this case, the RCC is not
solution of Et4NHCO3 in DMF (Table 1, DMF, entries 2– significantly affected by the presence or not of water with
6). In the case of Et4NHCO3 dissolved in DMSO, it should values ranging between 83% and 87% (Table 2, entries 13–
be noted that, for as yet unknown reasons, nearly no elution 18). The next radiochemical that was synthesised is [18F]-
occurs when the QMA cartridge is rinsed with hexane after fluoroethyl tosylate ([18F]-4) which is a frequently employed
the trapping whilst the [18F]fluoride is displaced when the [18F]synthon for the radiosynthesis of various [18F]radio-
solid support is washed with DMSO. Also, contrary to the pharmaceuticals.[19] The reaction proceeds with an excellent
2 previous solvents, the elution of [18F]fluoride from the RCC of 93% when Et4NHCO3 is dissolved in pure aceto-
cartridge is very poor when low amounts of water are added nitrile and the addition of water only causes small varia-
to the tetraethylammonium hydrogen carbonate solutions. tions in yields with RCCs of 94, 90, 90 and 91% with water
Indeed, only 3% of the radioactivity is recovered when the additions of respectively 0.5, 1, 1.5 and 2% (Table 2, entries
dry eluent is used and this value only increases slowly to 19–23). However, the use of an eluent containing 5% water
17, 27, 43 and 56% when quantities of water added are 0.5, leads to a significant drop of the RCC to 82% (Table 2,
1, 1.5 and 2% respectively (Table 1, DMSO, entries 1–5). entry 24).
Only with a volume of 5% water can the elution reach a
satisfactory efficiency of 89% (Table 1, DMSO, entry 6).
4-[18F]Fluorobenzonitrile ([18F]-5) was synthesised from
the nitro precursor and was chosen as a model radiochemi-
cal for aromatic nucleophilic substitution reactions. Since
the elution efficiency of Et4NHCO3 is much lower in
DMSO than in acetonitrile or DMF, no reactions were at-
tempted with the eluents containing 0 or 0.5% water (see
Table 1). When 1% water is added to the elution solution,
even though the amount of [18F]Et4NF recovered is poor,
the reaction proceeds with a high RCC of 73% (Table 2,
entry 27). Adding more water in the system leads to a slight
increase in RCCs with values of 75, 79 and again 79% when
the aqueous percentage is at, respectively, 1.5, 2 and 5%
(Table 2, entries 28–30). In the case of compound [18F]-6 (a
potential tau neurofibrillary tangle tracer), the changes in
RCCs with regards to the amount of water follow a dif-
ferent model. With 1% water present in the elution solu-
tion, the reaction proceeds with a high RCC of 85%
(Table 2, entry 33). However, this high yield comes together
Table 1. Efficiency of [18F]fluoride elution with Et4NHCO3 in vari-
ous organic solvents.
Entry Water added in eluent (% v/v) Elution Efficiency (%ϮStD[a] [b]
MeCN DMF DMSO
)
1
2
3
4
5
6
0
0.5
1
1.5
2
95Ϯ4.0 88Ϯ4.6
3[c]
97Ϯ2.3 89Ϯ3.7 17Ϯ3.5[d]
97Ϯ2.1 90Ϯ3.6 27Ϯ0.7[d]
97Ϯ1.9 93Ϯ3.6
98Ϯ1.6 94Ϯ4.6
43Ϯ4.3
56Ϯ4.5
89Ϯ1.3
5
Ͼ99
99Ϯ0.5
[a] StD: Standard deviation. [b] Average of at least 5 experiments
unless otherwise stated. [c] Single experiment. [d] Average of 2 ex-
periment.
The [18F]Et4NF solutions obtained from elution of the with a poor elution efficiency with the E4NHCO3 solution,
QMA cartridges were then applied to the radiosynthesis of which results in an overall yield of only 23%. By increasing
[18F]-labelled compounds (Scheme 1) via aliphatic or aro- the amount of water in the eluent solution, the RCC de-
matic nucleophilic substitution (Table 2). To achieve this, creases gradually with a final value of 67% when 5% water
aliquots of the eluate from the QMAs were mixed with the is present (Table 2, entries 34–36). Nonetheless, this comes
appropriate precursor solutions and heated at a selected along with an improvement of the elution effectiveness and,
temperature for a specific time. [18F]-1 (unhydrolysed [18F]- when taking into account those 2 parts of the process, the
FDG,[16] a glucose metabolism tracer) is synthesised with a overall yield with the eluent containing 5% water reaches
RCC of 65% when the eluate containing no-added-water is 60%.
Eur. J. Org. Chem. 2014, 6145–6149
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6147

L. Brichard, F. I. Aigbirhio
SHORT COMMUNICATION
Table 2. Radiochemical conversion yields for the synthesis of vari-
ous [18F]-labelled compounds using [18F]Et4NF.
– It does not require the use of any additional, poten-
tially toxic, reagents to enhance the reaction efficiency.
– It is a cheaper and convenient alternative to the use of
the classical K222 as a phase transfer agent.
Entry [18F] compound Solvent Water content
RCC[b]
[%][a]
(%ϮStD)[c]
1
2
3
4
5
6
7
8
1[d]
2[e]
3[f]
4[g]
5[h]
6[i]
MeCN
DMF
0
0.5
1
1.5
2
5
0
0.5
1
1.5
2
5
0
0.5
1
1.5
2
5
0
0.5
1
1.5
2
5
0
0.5
1
1.5
2
5
0
0.5
1
1.5
2
65Ϯ2.6
76Ϯ5.3
73Ϯ5.3
72Ϯ5.1
68Ϯ5.1
70Ϯ2.8
53Ϯ1.0
58Ϯ1.5
56Ϯ0.6
55Ϯ2.3
51Ϯ2.1
45Ϯ5.5
86Ϯ4.6
85Ϯ4.6
87Ϯ1.5
85Ϯ3.5
85Ϯ1.7
83Ϯ4.3
93Ϯ1.4
94Ϯ0.9
90Ϯ0.6
90Ϯ3.0
91Ϯ0.6
82Ϯ1.5
not done
not done
73Ϯ1.1
75Ϯ3.2
79Ϯ3.8
79Ϯ5.3
not done
not done
85Ϯ1.5
81Ϯ2.6
77Ϯ0.6
67Ϯ1.5
– It has the flexibility to be applied to a range of syn-
thetic pathway for [18F]-labelled compounds.
In essence, due to its simplicity, versatility and high ra-
diochemical yields, this is a method that can be readily
applied in all radiochemical laboratories and translated on
automated radiosynthesis systems to become a standard
approach for [18F]fluorination.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
Experimental Section
DMF
In a typical procedure, [18F]fluoride is extracted from its water ma-
trix by passing it through a preconditioned QMA cartridge (carb-
onate form, Waters). At the end of the trapping, the solid support
is rinsed with 5 mL of a dry solvent (hexane or DMSO) in order
to remove excess water. The [18F]fluoride is then eluted with 1 mL
of a solution of Et4NHCO3 (15 mg) in a polar aprotic solvent
(MeCN, DMF or DMSO) either dry or containing additional
water (0.5, 1, 1.5, 2 or 5% in volume). Aliquots of these eluted
solutions (50–100 μL) are subsequently mixed in a 1 mL v-vial with
aliquots (70–100 μL) of the appropriate precursor (0.42–8 mg) in
solution in the same solvent as the eluent used. The reactor is then
capped and heated for a selected time (5–20 min) at various tem-
peratures (95–175 °C). At the end of the labelling reaction, the reac-
tor is cooled and a sample (20 μL) is taken for analysis by High
Performance Liquid Chromatography to determine the radiochem-
ical conversion.
MeCN
DMSO
DMSO
Supporting Information (see footnote on the first page of this arti-
cle): Details of experimental procedures for the synthesis of all
[18F]-labelled compounds including radioHPLC profiles.
5
[a] Water content in the eluate from Table 1. [b] RCC: Radiochemi-
cal conversion determined by radioHPLC based on [18F]com-
pounds dissolved in the reaction mixture (a maximum of 5% of
the radioactivity is lost on the wall of the reaction vessel). [c]
Average of 3 experiments. [d] Precursor: OTf, 115 °C, 10 min. [e]
Precursor: OTs, 175 °C, 5 min. [f] Precursor: OTs, 135 °C, 20 min.
[g] Precursor: OTs, 95 °C, 15 min. [h] Precursor: NO2, 150 °C,
15 min. [i] Precursor: NO2, 150 °C, 15 min.
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Enhanced Method for the Preparation of [18F]Radiotracers
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the cartridge with a solution of Et4NHCO3.
Received: May 19, 2014
Published Online: August 29, 2014
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6149