Scalable 18F processing conditions for copper-mediated radiofluorination chemistry facilitate DoE optimization studies and afford an improved synthesis of [18F]olaparib

Article abstract of DOI:10.1039/d1ob00903f

A convenient and scalable base-free method for processing [18F]fluoride as [18F]TBAF is reported and applied to copper-mediated radiofluorination radiosyntheses. A central feature of this method is that a single production of [18F]TBAF can be divided into small aliquots that can be used to perform multiple small-scale reactions in DoE optimization studies. The results of these studies can then be reliably translated to full batch tracer productions using automated synthesizers. The processing method was applied to the DoE optimization of [18F]olaparib, affording the tracer in high radiochemical yields via both manual (%RCY = 78 ± 6%, n = 4 (CMRF step only)) and automated (up to 80% (%RCY); 41% activity yield (%AY)) radiosynthesis procedures.

Full text of DOI:10.1039/d1ob00903f

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Biomolecular Chemistry
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1
8
Scalable F processing conditions for copper-
mediated radiofluorination chemistry facilitate
DoE optimization studies and afford an improved
Cite this: Org. Biomol. Chem., 2021,
9, 6995
1
18
Received 7th May 2021,
Accepted 2nd August 2021
synthesis of [ F]olaparib†
DOI: 10.1039/d1ob00903f
a
a
a,b,c
Gregory D. Bowden,
Nantanat Chailanggar, Bernd J. Pichler
and
a,b
rsc.li/obc
Andreas Maurer
*
1
8
5
A convenient and scalable base-free method for processing [ F] expanding tracer production demands. Radiosynthesis optim-
1
8
fluoride as [ F]TBAF is reported and applied to copper-mediated ization is an essential part of this process. A well-optimized
radiofluorination radiosyntheses. A central feature of this method radiosynthesis (in terms of both chemistry and purification) is
18
is that a single production of [ F]TBAF can be divided into small more reliable and ensures maximal activity yields, thus making
aliquots that can be used to perform multiple small-scale reactions radiopharmaceutical production more efficient in light of the
in DoE optimization studies. The results of these studies can then continuously increasing demand for PET radiotracers.
be reliably translated to full batch tracer productions using auto- Additionally, carefully optimizing radiosyntheses can help mini-
mated synthesizers. The processing method was applied to the mize the use of potentially toxic reagents, precursors, solvents,
18
DoE optimization of [ F]olaparib, affording the tracer in high or catalysts. From a GMP perspective, simplified tracer pro-
radiochemical yields via both manual (%RCY = 78 ± 6%, n = 4 duction, purification, and expedited quality control procedures
(
CMRF step only)) and automated (up to 80% (%RCY); 41% activity can make it easier for radiopharmacies to meet the regulatory
yield (%AY)) radiosynthesis procedures.
requirements regarding solvent and impurity content.
Design of Experiments” (DoE) is a statistical toolset that
aims to provide a detailed model of processes’ performance
“
As the use of positron emission tomography (PET) as a mole-
cular imaging tool continues to grow, so will the demand for
novel clinically relevant PET tracers. The development of new
automatable radiochemical methodologies, particularly for
radiochemistry, has become an important area of research to
meet this demand. The copper-mediated radiofluorination
with respect to multiple experimental variables (factors) while
6
minimizing the number of optimization experiments. We
1
8
F
have previously reported that using a DoE approach expedites
the radiosynthesis optimization process in terms of cost and
time and can extract practically useful information in the form
(CMRF) family of aromatic radiofluorinations is a recent
7
of response surface models (RSMs). This information can
example of a “next-generation” radiochemical methodology that
then be used to develop more efficient radiosynthesis proto-
cols with more limited use of harmful substances. This work
laid the basis for a DoE based tracer development pipeline
that increases the rate at which radiopharmacists can estab-
lish, optimize, automate, and deliver CMRF-based tracer pro-
ductions for preclinical study.
has become a highly relevant tool for radiolabeling aromatic
18 1–3
compounds with F.
The methodology’s broad scope and
operational simplicity have meant that radiopharmacy research
groups have readily adopted it as a convenient method for
rapidly developing novel tracers for preclinical evaluation. As
these tracers become more utilized by preclinical and clinical
imaging scientists, radiopharmacists must adapt “next-gen”
radiolabeling methods, like CMRF chemistry, to meet the
4
This initial work focused on optimizing reaction conditions
18
and assumed little influence from the F processing method.
18
However, the processing of [ F]fluoride is an essential step in
18
any F-radiosynthesis, and it can indeed have a significant
18
a
influence on the final yield. The purpose of F processing is to
Werner Siemens Imaging Center, Department of Preclinical Imaging and
18
dehydrate the [ F]fluoride ion and provide an appropriate
Radiopharmacy, Eberhard Karls University, Tübingen, Germany.
E-mail: andreas.maurer@med.uni-tuebingen.de
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8
counter ion to maximize the nucleophilicity of the [ F]fluoride
ion before its reaction with a substrate. For practical reasons,
the DoE studies mentioned above were performed using small
b
Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed
Tumor Therapies”, Eberhard Karls University, Tübingen, Germany
c
German Cancer Research Center, German Cancer Consortium DKTK, Partner Site
18
aliquots (80 µl) of a [ F]KF solution eluted from a single QMA
quaternary methylammonium resin) cartridge with a solution
Tubingen, D-72076 Tübingen, Germany
(
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00903f
of potassium triflate and potassium carbonate in water (Fig. 1,
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following requirements: (1) The procedure needed to be opera-
tionally simple, fast, scalable, and automatable using standard
radiosynthesis modules. (2) Given our desire to carefully study
the effect of various reaction components (e.g., pyridine load,
not discussed in this work) on CMRF reactions’ performance,
the QMA eluent should minimize any components that may
affect or interact with either the copper-mediator or the precur-
sor. We thus wanted to avoid the use of eluents that included
the precursor, catalyst, or pyridinium salts (as successfully
12,13
employed by Zhang et al. and Antuganov et al.)
(3) The
method should eliminate the use of strongly basic anions (e.g.,
carbonates) and cryptand PTCs from the QMA preconditioning
and eluent solutions to ensure true scalability from “aliquoted”
DoE reaction studies to full “batch” radiosyntheses.
Several groups have investigated alternative QMA cartridge
eluents that are less basic and better suited to CMRF chemistry
than the classic combination of potassium carbonate and
1
0–18
Kryptofix® 2.2.2 (K222).
Tetraalkylammonium salts and
their alcohol adducts have long been studied as facilitators of
1
9–22
traditional fluorination reactions.
Their use has since
been adapted for various radiofluorination strategies. One of
the more widely adopted methods has been the alcohol-
enhanced CMRF developed by Zischler et al. (Fig. 1, Method
1
8
B), whereby the [ F]fluoride was efficiently eluted from the
QMA using tetraethylammonium bicarbonate (TEAB) in an
1
6
18
alcoholic solvent. This method could provide processed
F
from the QMA cartridge with high elution efficiency and could
be used to synthesize several radiotracers in good to excellent
radiochemical yields. However, the technique suffered a sig-
1
8
nificant drawback: the aqueous F needed to be loaded onto
the cartridge in the reverse direction to ensure maximal
elution efficiency. This “back-flushing” procedure adds oper-
ational complexity and increases the probability of introducing
Fig. 1 Previous (methods A-C) and current (method D) work into the radiochemical impurities from the irradiated cyclotron target
18
development of CMRF specific F processing methods.
water into the reactor vessel.
Orlovskaya et al. showed that tetrabutylammonium tosylate
18
(
TBAOTs) in an alcoholic solvent was able to efficiently elute [ F]
3
Method A), as initially described by Makaravage et al. These ali- fluoride from a QMA-bicarbonate cartridge (QMA-HCO , QMA
3
18
23
quots of [ F]KF solution were then transferred into 5–6 reaction cartridge with bicarbonate counter ion) (Fig. 1, Method C).
vessels and were individually azeotropically dried with three TBAOTs was also found to be suitable as a stable and inert PTC
additions of acetonitrile (1.5 ml) by the standard method. for traditional S 2 radiofluorinations. The authors were able to
N
18
While laborious and time-consuming, this method ensured a show that TBAOTs in ethanol could elute F from a QMA-HCO3
relatively even distribution of [ F]fluoride and QMA eluent salts cartridge with a high elution efficiency (>90%) without needing
between the reaction vessels, reducing experimental variability to load the F onto the QMA cartridge in the reverse direction.
in the DoE studies. It also allowed multiple experiments to be The authors later reported the CMRF compatibility of similar
conducted from one delivery of cyclotron produced [ F]fluor- processing chemistry (using the “back-flushing” protocol dis-
ide, making the use of multi-experiment DoE studies a practical cussed above) when applied to the CMRF synthesis of 6-L-[ F]
1
8
18
1
8
F
18
18
24
possibility. However, in many instances, the results obtained FDOPA.
from these DoE studies did not scale up when performed with approach, we aimed to develop an F processing method that
batch” quantities of QMA eluents. The deleterious effects of entirely eliminates the presence of carbonate base from a CMRF
larger amounts of carbonate bases and phase transfer catalysts reaction mixture by preconditioning the QMA cartridge with an
Inspired by this fast and operationally simple
18
“
(
PTCs) present in QMA eluent solutions on CMRF reactions organic sulfonate anion (Fig. 1, Method D).
8–11
have been well documented.
A series of experiments were performed to evaluate and
1
8
To further our work in establishing a rapid tracer develop- compare different F processing protocols, each featuring an
1
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ment and radiosynthesis optimization pipeline around the DoE
approach, we required an F processing method that met the solvent evaporation under a stream of argon (Table 1). Each
F processing step, followed by either azeotropic drying or
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Scheme 1 Model reaction to test F processing parameters.
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run was performed using a batch F elution from a single
QMA cartridge. An unoptimized model CMRF reaction using
4-biphenylboronic acid pinacol ester (15 µmol), copper(II) tri-
flate (5 µmol), and pyridine (25 µmol), in DMA (700 µl) was
then carried out at 120 °C for 20 minutes under an atmosphere
of air (Scheme 1). Each reaction was quenched with 0.2 M HCl
1
8
(
1 ml) to ensure the dissolution of all [ F]fluoride from the
reaction vessel walls. The radiochemical yield (%RCY) was
evaluated using radioTLC to measure reaction performance,
and selected experiments were evaluated with radioHLPC to
confirm compound identity.
Using standard published QMA processing methods
1
8
(
Table 1, entries 1 and 2) yielded good recoveries of [ F]fluor-
ide; however, as expected, the model CMRF reactions did not
tolerate the presence of Kryptofix and potassium carbonate.
The elimination of Kryptofix using conditions similar to those
published by Makaravage et al. (and those used in our previous
work) improved CMRF reaction performance (Table 1, entries
3
and 4). These experiments also demonstrated the importance
of the QMA cartridge preconditioning anion, as reaction per-
formance again increased when the QMA cartridges were con-
ditioned with potassium triflate (0.5 M, 10 ml) instead of
sodium bicarbonate (1 M, 10 ml).
Entries 5–7 showed that TBAOTf in water possessed
1
8
sufficient eluting power to quantitatively recover [ F]fluoride
from the QMA cartridge without the need for an additional
1
8
carbonate base. We then attempted to elute the F with
methanol via a protocol similar to that of the minimalist
approach employed by Zischler and coworkers (Table 1, entries
1
8
8
and 9). The F was loaded onto the QMA cartridge in the
reverse direction (back-flushing) and then washed with metha-
nol in the forward direction to remove any residual water, after
1
8
which the F could be recovered by eluting with TBAOTf in
methanol (1 ml, 5–10 mg ml− ). However, much of the F was
1
18
lost during the methanol wash step. This was possibly due to a
1
8
combination of the F being loaded on the front end of the
cartridge and the use of a triflate QMA counterion over the
standard bicarbonate ion used in previous works.
We then attempted an alternative procedure, loading the
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F onto the QMA cartridge in the forward direction, followed
1
8
by washing with methanol and eluting the F with the same
TBAOTf solution as before (Table 1, entry 15). To our delight,
1
8
this afforded [ F]TBAF in methanol with acceptable relative
1
8
F recoveries (93 ± 2.2%). The methanol could then be
removed via evaporation at 85 °C under a stream of argon to
1
8
afford dry and carbonate-free [ F]TBAF. The model CMRF
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reaction showed excellent reaction performance with both a further 15 minutes to afford [ F]olaparib after HPLC purifi-
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8
25,27
single batch and aliquoted [ F]TBAF prepared in this manner. cation (activity yield: 6 ± 5%, automated process).
Additionally, the reaction showed tolerance to TBAOTf loads Having synthesized the arylboronate precursor via the pub-
between 5–10 mg (Table 1, entries 14 and 15). Lower TBAOTf lished route (see ESI 1.2†), we used the DoE software MODDE
loads (1 mg) in the QMA eluent solution often failed to com- Go (Sartorious, Germany) to design a response surface optim-
1
8
pletely elute the F from the QMA cartridge and negatively ization study of the CMRF step using an orthogonal central
influenced reaction performance (Table 1, entry 16). Finally, composite design (CCO) (see ESI 3.2.4†). The resulting study
we evaluated the importance of the methanol wash step to consisted of 17 experiments (14 experimental points, 3 center-
remove residual water from the QMA cartridge (Table 1, entry points) to evaluate the effects of the precursor load (Pre,
1
8
1
7). Skipping this step resulting in marginally higher %
F
5–25 µmol), copper mediator load (CuC, 5–25 µmol), and
recoveries and, unexpectedly, had no significantly deleterious solvent volume (SoV, 300–600 µl) on the reaction’s perform-
effects on reaction performance. Furthermore, the elimination ance (ESI Table 1†). The DoE study was conducted using three
1
8
of the methanol wash increased the method’s operational sim-
F cyclotron target washes (over three days), each trapped and
1
8
plicity so that it can be used directly on most F automated eluted from a single QMA cartridge. The resulting methanolic
1
8
synthesizers, a further advantage when considering prospec- [ F]TBAF solution was then aliquoted (150 µl) into single-use
tive large-scale routine radiotracer productions. glass reaction tubes (6 runs per target wash), and the methanol
We also evaluated both acetonitrile and ethanol as alternative was evaporated from each reaction vessel at 90 °C under a
elution solvents, with ethanol being more suited to clinical radio- stream of argon. Finally, the reaction mixture required by the
1
8
tracer production due to its lower toxicity compared to aceto- DoE study was added to the dry [ F]TBAF, and the reaction
nitrile or methanol (Table 1, entries 10–13). TBAOTf in aceto- was allowed to stir for 120 °C for 20 minutes. After quenching
18
nitrile was unable to elute any F from the QMA, suggesting that with 0.1 M HCl, the reaction performance (%RCY) of the
protic solvents are required for this method to work. TBAOTf in CMRF step was measured by radioTLC, and selected runs were
18
ethanol successfully eluted the F, albeit with slightly weaker analyzed via radioHPLC to verify product identity against a
elution efficiency and lower reaction performance.
non-radioactive standard.
1
8
To evaluate our F processing method’s performance and
After acquiring the %RCY data, the resulting data set was
scalability, we applied it to a DoE optimization and sub- found to be skewed and was thus transformed (−log Y) to
1
0
1
8
18
sequent radiosynthesis automation of [ F]olaparib. [ F] ensure a normal distribution. Multiple linear regression (MLR)
Olaparib is a tracer of potential clinical importance as a was used to construct a response surface model from the trans-
1
8
“
second-generation” variant of [ F]PARPi, a radiotracer that is formed data set; the summary of fit statistics suggested the
2
currently in clinical trials for the imaging of the DNA repair resulting model to be valid and predictive (R = 0.972 (goodness
2
5,26
2
enzyme PARP-1.
The recently reported copper-mediated of model fit); Q = 0.900 (goodness of model prediction); ESI
1
8
18
radiosynthesis of [ F]olaparib reacts azeotropically dried [ F] Fig. 5)†. The results of the DoE study showed all main factors
KF (eluted from a QMA cartridge using Kryptofix, potassium (precursor load, copper mediator load, and solvent volume) to
carbonate, and potassium oxalate (Table 1, entry 1)) with a tri- have significant effects %RCY (ESI Fig. 6†). The copper
methylsilylethoxymethyl (SEM) protected pinacol boronate pre- mediator load, precursor load, and solvent volume terms were
2 4
cursor OLA-BPin, in the presence of [Cu(OTf) (Impy) ] as the found to possess significant quadratic behaviors (they contrib-
2
7
copper mediator (Scheme 2). The reaction is carried out ute to curvature in the response surface). Moreover, factor inter-
under air in 1,3-dimethyl-2-imidazolidinone (DMI) at 120 °C actions (where one setting affects the behavior of another)
for 20 minutes, after which the SEM protecting group is between the precursor and copper mediator loads and between
removed by stirring the reaction mixture with TFA at 120 °C for the copper mediator load and the solvent volume (copper
mediator concentration) were detected. Plotting the response
surface over the investigated ranges revealed that the CMRF syn-
18
thesis of [ F]olaparib performed better at lower reaction con-
centrations (higher solvent volume) and that the optimal
amounts of the precursor and copper mediator were approxi-
mately 10 µmol and 22 µmol, respectively (Fig. 2).
1
8
To verify the DoE study results and the scalability of the
F
1
8
processing method, the radiolabeling of [ F]olaparib was per-
formed manually in triplicate using two sets of optimal con-
ditions from the response surface model. A full batch prepa-
ration of [ F]TBAF was used for each replicate experiment
instead of aliquots of [ F]TBAF from a single QMA cartridge
1
8
1
8
elution. Performing the synthesis with 10.5 µmol OLA-BPin
(
2 4
7 mg), 22 µmol [Cu(OTf) (Impy) ] (18 mg), and 600 µl DMI
18
(total solvent volume) afforded the SEM protected radiolabeled
intermediate [ F]olaparib-SEM in good radiochemical yields
Scheme 2 Radiosynthesis of [ F]olaparib via the CMRF of the precur-
sor OLA-BPin.
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activity is lost elsewhere in the process when using the FX N
Pro. Further investigation found that this most likely occurs
during the first HLB trapping of the product before HPLC puri-
fication. The FX N pro is limited to a dilution volume of ca.
14 ml, while a larger dilution reservoir (25–100 ml) can be
fitted between cassettes one and two of the Elixys. The larger
dilution volume makes Elixys HLB “pre-purification” more
efficient, resulting in an overall %RCY that is more in line with
the results predicted by the DoE response surface. More work
is thus needed to improve the overall process performance on
Fig. 2 4D-plot of the response surface model generated from the DoE the FX N Pro. These results highlight that the optimization of
18
optimization study of the CMRF synthesis of [ F] olaparib.
a radiochemical process is as important as the optimization of
the radiochemistry. However, detailed DoE optimization of the
radiolabeling chemistry can provide a greater margin of error
in line with those predicted by the response surface model (78 when designing automated radiosynthetic processes.
6%RCY, n = 4, DoE Response surface predicted 84%, ESI
±
Fig. 13: Validation Set A).† The validity of the model was again
tested by performing the same synthesis using 15.6 µmol Conclusions
2 4
OLA-BPin (10.5 mg) and 26 µmol [Cu(OTf) (Impy) ] (22 mg), in
1
8
1
8
In conclusion, we have implemented an
F processing
6
00 µl DMI. These conditions again afforded [ F]olaparib-
method that is compatible with CMRF reaction conditions on
both small (experiments using aliquots of QMA eluted [ F]
TBAF) and large scale (single batch) radiosyntheses. Moreover,
SEM in good radiochemical yields (85 ± 3%RCY, n = 3, DoE
Response surface predicted 83%, ESI Fig. 13: Validation Set
B).† These conditions proved slightly better but used more of
the expensive copper-mediator and precursor; therefore, the
previous conditions were favored for further development.
Beyond these “optimal” validation experiments, we performed
a series of “batch” experiments that aimed to test the validity
of the model under non-optimal reaction conditions (ESI
Fig. 13: Alternative Set).† Overall, there seems to be a reason-
able correlation (r = 0.9386) between the results obtained in
1
8
1
8
through the synthesis of [ F]olaparib, we could demonstrate
1
8
that [ F]TBAF produced in this way can be conveniently used
for small scale CMRF optimization studies using DoE, and
importantly, that these results can then be scaled up to full
batch tracer productions which can be performed using auto-
mated radiosynthesizers. We have shown that this F proces-
sing method can unlock the potential of the DoE approach to
aid in the establishment of efficient radiotracer production
processes using the CMRF methodology. This will further
expedite both the preclinical tracer development process and
the translation of the CMRF methodology to routine clinical
tracer productions.
18
1
8
validation experiments conducted with batches of [ F]TBAF
and the results predicted by the DoE study (generated with ali-
1
8
quots of [ F]TBAF.)
Deprotection with TFA (700 µl) at 120 °C for 15 minutes
was found to remove the SEM protecting group with >95%
1
8
efficiency to afford [ F]olaparib.
1
8
The optimized [ F]olaparib radiosynthesis was translated
onto both a Tracerlab FX N Pro (GE, Uppsala, Sweden) and an
Elixys FLEX/CHEM radiosynthesizer to measure the total radio-
synthesis performance (activity yield, %AY) and to prepare the
tracer for preclinical imaging experiments (see ESI 3.3†). The
synthesis was performed via a modified version of the process
Author contributions
Gregory Bowden (G.B.) and Nantanat Chailangger designed and
performed the radiochemical experiments. G.B. performed the
organic synthesis and chemically characterized the compounds.
G.B. designed the DoE study and analyzed the data. G.B. estab-
lished the automated radiosyntheses on both the Elixys FLEX/
CHEM and GE FX N Pro. The manuscript was written and
reviewed by G.B., Andreas Maurer, and Bernd Pichler.
2
7
described in the literature. When performed using an Elixys
FLEX/CHEM coupled to a PURE/FORM synthesis module
(
Sofie Bioscience, USA), the optimized synthesis was able to
1
8
afford [ F]olaparib with a non-decay corrected activity yield
%AY) up to 41% (80% RCY (decay corrected), 25–58 GBq
(
−
1
µmol , (ESI Table 3)),† a significant improvement over the
synthesis described by Guibbal et al.
2
7
Conflicts of interest
The performance of the synthesis using an FX N Pro was
initially found to be significantly lower than expected (5.4 ±
There are no conflicts to declare.
1
.6%AY; 9.3 ± 3.3%RCY, n = 4, ESI Table 5).† However,
sampling of the reaction product mixture before deprotection
and purification revealed the CMRF step to perform within the
Acknowledgements
range predicted by the response surface (59%RCY, n = 1). This We would like to thank the Adolf Leuze Foundation and the
strongly suggests that a large percentage of the product radio- Werner Siemens Stiftung for their financial contributions
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toward this work. Funding for this work was also provided by 13 D. Antuganov, M. Zykov, V. Timofeev, K. Timofeeva,
the Deutsche Forschungsgemeinschaft (DFG, German
Y. Antuganova, V. Orlovskaya, O. Fedorova and
Research Foundation) under Germany’s Excellence Strategy –
R. Krasikova, Eur. J. Org. Chem., 2019, 2019, 918–922.
EXC 2180–390900677. We would also like to thank Dr Gerald 14 R. Richarz, P. Krapf, F. Zarrad, E. A. Urusova, B. Neumaier
Reischl, Marko Matijevic, and other colleagues in the radio-
pharmacy at the Werner Siemens Imaging Center for the deliv-
ery of [ F]fluoride and for technical support.
and B. D. Zlatopolskiy, Org. Biomol. Chem., 2014, 12, 8094–
8099.
15 F. Zarrad, B. Zlatopolskiy, P. Krapf, J. Zischler and
B. Neumaier, Molecules, 2017, 22, 2231.
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16 J. Zischler, N. Kolks, D. Modemann, B. Neumaier and
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