Efficient automated syntheses of high specific activity 6-[18F]fluorodopamine using a diaryliodonium salt precursor

Article abstract of DOI:10.1002/jlcr.3367

6-[¹⁸F]Fluorodopamine (6-[¹⁸F]F-DA) is a positron emission tomography radiopharmaceutical used to image sympathetic cardiac innervation and neuroendocrine tumors. Imaging with 6-[¹⁸F]F-DA is constrained, in part, by the bi

Full text of DOI:10.1002/jlcr.3367

Research article
Received 2 September 2015,
Revised 25 November 2015,
Accepted 1 December 2015
Published online 23 December 2015 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3367
Efficient automated syntheses of high specific
1
8
activity 6-[ F]fluorodopamine using a
†
diaryliodonium salt precursor
a
a
b
c
c
Kiel D. Neumann, Linlin Qin, Amy L. Vāvere, Bin Shen, Zheng Miao,
c
b
b
Frederick T. Chin, Barry L. Shulkin, Scott E. Snyder, * and
a
Stephen G. DiMagno *
1
8
18
6
-[ F]Fluorodopamine (6-[ F]F-DA) is a positron emission tomography radiopharmaceutical used to image sympathetic
18
cardiac innervation and neuroendocrine tumors. Imaging with 6-[ F]F-DA is constrained, in part, by the bioactivity and
neurotoxicity of 6-[ F]fluorodopamine. Furthermore, routine access to this radiotracer is limited by the inherent difficulty
of incorporation of [ F]fluoride into electron-rich aromatic substrates. We describe the simple and direct preparation of
high specific activity (SA) 6-[ F]F-DA from no-carrier-added (n.c.a.) [ F]fluoride. Incorporation of n.c.a. [ F]fluoride into a
diaryliodonium salt precursor was achieved in 50–75% radiochemical yields (decay corrected to end of bombardment).
Synthesis of 6-[ F]F-DA on the IBA Synthera® and GE TRACERlab FX-FN automated platforms gave 6-[ F]F-DA in >99%
chemical and radiochemical purities after HPLC purification. The final non-corrected yields of 6-[ F]F-DA were 25 ± 4%
n = 4, 65 min) and 31 ± 6% (n = 3, 75 min) using the Synthera and TRACERlab modules, respectively. Efficient access to high
SA 6-[ F]F-DA from a diaryliodonium salt precursor and n.c.a. [ F]fluoride is provided by a relatively subtle change in
reaction conditions – replacement of a polar aprotic solvent (acetonitrile) with a relatively nonpolar solvent (toluene) during
the critical radiofluorination reaction. Implementation of this process on common radiochemistry platforms should make 6-
1
9
1
8
1
8
18
18
1
8
18
1
8
(
1
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18
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[
F]F-DA readily available to the wider imaging community.
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Keywords: 6-[ F]fluorodopamine; positron emission tomography; emission computed tomography; diaryliodonium salts; fluorine-18
1
8
Introduction
lies in investigating the potential use of [ F]F-DA as an NB
imaging agent.
1
,2
Early work by Kirk and coworkers
demonstrated that
Historically, electrophilic methods provided the most direct
access to 6-[ F]F-DA. Direct electrophilic fluorination methods
rely typically on [ F]F gas as the source of the label to produce
2
Although sufficient
yields for patient studies are attainable using these strategies,
precautions are required to avoid injecting a high mass dose of
dopamine and 6-[ F]fluorodopamine that are present in the
final product. In addition, electrophilic syntheses require a
3
6
-fluorodopamine (6-F-DA) 4is readily converted to 6-
18
fluoronorepinephrine in vivo. 1 The observation of 6-F-DA
18
8
18
metabolism suggested that 6-[ F]fluorodopamine (6-[ F]F-DA)
18
6,24,25
low specific activity (SA) 6-[ F]F-DA.
could be used as a positron emission tomography radiotracer to
5
6,7
image cardiac sympathetic innervation. Imaging studies in dogs,
8–10
11–13
baboons,
and humans
subsequently established the utility
19
1
8
of this radiotracer in cardiac imaging. 6-[ F]F-DA is also taken up
selectively in neuroendocrine tumors, which accumulate and store
catecholamine derivatives recognized by the cell membrane
26
1
4,15
norepinephrine transporter (NET).
Pacek and coworkers
a
1
8
Department of Chemistry, University of Nebraska–Lincoln, Lincoln, NE, USA
demonstrated that 6-[ F]F-DA is more sensitive and effective at
localizing pheochromocytomas and paragangliomas than either
b
Division of Nuclear Medicine, Department of Radiological Sciences, St. Jude
131
131
123
Children’s Research Hospital, Memphis, TN, USA
meta-[ I]iodobenzyl guanidine ([ I]MIBG) or [ I]MIBG, the
16–21
clinically used NET-mediated radiopharmaceuticals.
Given
c
Department of Radiology, Stanford University School of Medicine, Stanford, CA,
18
these observations and the inherent advantages of F compared
USA
123 124 131
with
I/ I/ I-radionuclides (decay purity, tissue penetration
18
*
Correspondence to: Stephen G. DiMagno, Department of Chemistry, University
of Nebraska–Lincoln, 818 Hamilton Hall, Lincoln, NE 68588-0304, USA.
E-mail: sdimagno1@unl.edu
Scott E. Snyder, Department of Radiological Sciences, Division of Nuclear
Medicine, St Jude Children’s Research Hospital, Memphis, TN 38105, USA.
E-mail: Scott.snyder@stjude.org
range, half-life), 6-[ F]F-DA may prove to be superior compared
with MIBG for imaging neuroendocrine tumors and micrometastases.
Neuroblastoma (NB) is a neuroendocrine tumor of neural crest
2
2
origin and, as such, possesses sympathetic neuronal behavior.
1
23
Currently, functional imaging of NB, is performed with [ I]
1
8
23
†
MIBG and/or [ F]FDG. However, owing to the limitations of
Additional supporting information may be found in the online version of this
these imaging agents for the specific staging of NB, our interest article at the publisher’s web-site.
J. Label Compd. Radiopharm 2016, 59 30–34
Copyright © 2015 John Wiley & Sons, Ltd.

K. D. Neumann et al.
dedicated F
2
cyclotron target and the appropriate equipment for Experimental
handling corrosive fluorine gas in the facility. Classical
electrophilic methods provide the advantage of a single-step,
regioselective radiolabeling, but these methods often employ
All commercial reagents were purchased from Sigma-Aldrich (St. Louis,
MO, USA) or TCI America (Portland, OR, USA) and used as received, unless
otherwise specified. Diaryliodonium salt 1 was prepared as previously
2
7
28,29
heavy-metal reagents (e.g., mercury and tin
) that must be
37–40
reported.
All reagents used were of >95% purity. All aqueous solutions
removed from the final product, and they afford final product
with relatively low SA (<370 MBq/μmol). More recently, Eskola
were prepared using distilled, deionized water (Milli-Q Integral Water
Purification System, Millipore Corp., Billerica, MA, USA; 18.2 ΜΩ cm resistivity).
and coworkers reported that fluorodestannylation with high SA Radioactive samples were analyzed in a CRC-15R Dose Calibrator
1
8
30
[
F]F
2
could be used to prepare relatively high SA (13 GBq/μmol) (Capintec, Inc., Ramsey, NJ, USA). Thin-layer chromatography (TLC)
-[ F]F-DA in small-scale syntheses (660 MBq); however, this sample analysis was performed on an AR-2000 radio-TLC Imaging Scanner
1
8
6
(
Bioscan, Hopkinton, MA, USA) usingWinScan 3. Analytical HPLC was performed
methodology still requires sophisticated equipment, which is not
18
on an Agilent 1200 Series LC System (Agilent Technologies, Cedar Creek, TX, USA)
using both diode array detection and a Bioscan Flow-Count radioisotope
detector.
2
readily available, to generate the high SA [ F]F .
1
8
Nucleophilic F-labeling of aromatic compounds that do not
feature strong electron-withdrawing groups (such as in F-DA)
remains a significant chemistry challenge. As a testament
18
18
to the difficulty of no-carrier-added (n.c.a.) [ F]fluoride Preliminary testing of n.c.a. F incorporation using a
radiopharmaceutical preparation, several methodologies have microfluidic reactor
3
1
32
recently been reported utilizing nickel,
palladium , and
3
3
34
Investigation of the radiolabeling step was performed using the Nanotek®
18
copper -mediated catalysis, and iodonium ylides. A multistep
n.c.a. synthesis of 6-[ F]F-DA was pioneered by Ding and
coworkers to yield high SA 6-[ F]F-DA (74–185 GBq/μmol). This
tour de force, manual radiochemical synthesis required 105 min,
included several synthetic and intermediate purification steps,
18
Microfluidic Synthesis System (Advion Biosciences, Ithaca, NY). [ F]Fluoride
18
was separated from [ O]H
2
O using a QMA anion exchange resin
8
18
(
ORTG, Inc., Oakdale, TN, USA) cartridge that was pretreated with 1 M sodium
18
bicarbonate and rinsed with water. The trapped [ F]fluoride was eluted
from the QMA cartridge into the concentrator vial with 450 μL of an
and proceeded in 9% radiochemical yield (RCY; end of synthesis). acetonitrile : water solution (90:10) containing potassium carbonate
Routine synthesis of n.c.a. 6-[ F]F-DA by this multistep route (0.5 mg) and Kryptofix® [2.2.2.] (K2.2.2) (3.5 mg). The K2.2.2.-[ F]fluoride
18
18
remains a challenge.
Despite 20years of human imaging with 6-[ F]F-DA, there is no
complex was dried azeotropically (105 °C, 3 × 100 μL dry acetonitrile), and
the concentrator vial was cooled to 35 °C. A freshly prepared precursor
solution (34.2 mg of 1 in 450 μL acetonitrile) was added. For experiments
in which solvent composition was varied, this mixture was transferred to
the precursor storage loop. For reactions performed in benzene alone, the
solvent was removed under reduced pressure, benzene (250 μL) was added,
and the reconstituted solution was transferred to the precursor storage
loop. Dry benzene was loaded into a second reagent loop. The separate
volumes were mixed by passing through a microreactor containing a
18
18
direct synthesis that uses n.c.a. [ F]fluoride, avoids heavy-metal
18
reagents, and provides high SA 6-[ F]F-DA in good yield and
quantity. The thermal decomposition of diaryliodonium salt
18
precursors to produce [ F]fluoroarenes, an approach pioneered
3
5–37
by Pike,
[
is a promising alternative method to introduce n.c.a.
1
8
F]fluoride into electron-rich aromatic substrates. In mechanistic
studies over several years, the DiMagno laboratory optimized the 15.7-μL loop at a flow rate of 30 μL/min and a reactor temperature of
important experimental parameters required to perform high-yield 180 °C. Fluorinated intermediate (2) product samples were removed and
1
9
[
F]fluorination reactions with diaryliodonium salt substrates. The spotted onto silica TLC plates which were developed in an ethyl acetate :
hexanes (20:80) mixture and analyzed for radioactivity by comparison to a
key observation from this work was that the use of relatively
nonpolar solvents suppressed a number of troublesome side
reactions of diaryliodonium salts, including internal electron
transfer and disproportionation. Finally, the syntheses of
diaryliodonium salt precursors were refined so that fairly densely
functionalized precursors could be prepared without using
19
19
f
protected 6-[ F]F-DA ( F-2) standard (R (product) = 0.3). Once effective
radiofluorination conditions were identified, the same general synthesis
protocol was performed on both the Synthera® (V1, Ion Beam Application
(
IBA), Louvain-la-Neuve, Belgium) and TRACERlab FX-FN (GE Healthcare,
Waukesha, WI, USA) automated radiosynthesizers.
38–40
heavy-metal reagents.
Taken together, these preliminary data
1
9
18
18
from [ F]fluorination reactions indicated that F-labeled electron- Synthesis of 6-[ F]fluorodopamine using the IBA Synthera®
rich aromatic compounds should be readily accessible from module
diaryliodonium salt precursors.
Here, we demonstrate that a modest change in reaction
conditions dramatically improves the yield of 6-[ F]F-DA
obtained from a diaryliodonium salt precursor (Figure 1). The
The Synthera® platform utilizes a sterile, single-use Integrated Fluidic
Processor (IFP, ABX Advanced Biochemical Compounds, Radeberg,
Germany) that is mounted on the synthesis module for chemical
manipulations. For this synthesis, two Synthera® modules were
™
18
result is a new method for providing a reliable, high-yielding, connected in series. An external compressed air line was directed toward
18
and scalable radiosynthesis of high SA 6-[ F]F-DA.
the reactor vial on each synthesizer to provide manual cooling.
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8
Figure 1. Synthetic scheme for 6-[ F]F-DA (3) from the diaryliodonium precursor 1. Initial ion exchange at the hypervalent iodine center of 1 is conducted in acetonitrile
1
8
to afford the diaryliodonium–[ F]fluoride complex. Solvent is removed and thermolysis is conducted in toluene to produce 2. Deprotection of the radiolabeled
intermediate 2 in HI produces 3.
J. Label Compd. Radiopharm 2016, 59 30–34
Copyright © 2015 John Wiley & Sons, Ltd.
www.jlcr.org

K. D. Neumann et al.
18
Preliminary experiments demonstrated that significant (40–55%)
radioactivity adhered to the reactor vial upon addition of toluene. To
cartridge (Waters), and the protected 6-[ F]F-DA intermediate was eluted
using ethyl acetate (3.5 mL) and transferred to a secondary reactor in the
minimize radioactivity loss to the reactor vial, each reactor was pretreated adjacent customized module. The solvent was removed under reduced
for at least 15 min with a base wash (saturated potassium hydroxide in
ethanol). The solution was removed, and the reactor and lines were
thoroughly rinsed with 4 × 4 mL aliquots each of water, ethanol, and
pressure using helium and vacuum, and 47% aqueous HI (250 μL) was
added to the dry residue. The resulting solution was heated at 155 °C for
5 min, cooled, and neutralized with 2 M sodium citrate (800 μL). The crude
finally acetonitrile. The lines and reactor were dried by flushing with product was purified by semi-preparative HPLC (Luna C18(2), (5 μm, 10
nitrogen and heating the reactor vial to 80 °C for 10 min. IFP reactor vials mm × 250 mm) 0.1% acetic acid and 0.02% ascorbic acid in water; flow
prepared in this manner retained significantly less [ F]fluoride (15–20%). rate = 2.0 mL/min, product retention time ~ 10.5 min), and the isolated
18
1
8
[
F]Fluoride was trapped on a QMA cartridge and eluted into the
product was confirmed by analytical HPLC and formulated as described
reactor vial with 600 μL of an acetonitrile : water solution (90:10) of
Kryptofix® [2.2.2] (3.0 mg) and potassium carbonate (0.5 mg). The solvent
was removed at 90 °C under reduced pressure over 90 s, and the reactor
vial was cooled to room temperature. Anhydrous acetonitrile (600 μL)
containing 10–12 mg of the diaryliodonium precursor 1 was introduced
to the reactor. Acetonitrile was removed under reduced pressure
earlier.
Results and discussion
18
This study demonstrates the feasibility of using n.c.a. [ F]
fluoride and a diaryliodonium salt precursor to prepare high SA
(30 kPa) with argon flow at 50 °C. Dry toluene (900 μL) was added to
18
6
-[ F]F-DA rapidly, efficiently, and at a scale that is sufficient
the reactor vial, and the solution was heated to 150 °C for 4 min. The
reactor was cooled to room temperature, and the contents were
transferred from the reactor vial onto a silica Sep-Pak® Plus cartridge
for preclinical and clinical work. Preliminary radiochemical
experiments performed using the general approach depicted
(
Waters Corp, Milford, MA). Toluene was purged from the cartridge using in Figure 1 demonstrated that radiofluorination of the catechol
18
argon (200 kPa), and protected 6-[ F]F-DA (2) was eluted with ethyl acetate ring could be performed rapidly (30-s reaction time) at 180 °C
18
(
2.7 mL) and transferred to the second Synthera® reactor vial. Ethyl acetate in benzene and with good incorporation of [ F]fluoride (~40–
was removed under argon flow and reduced pressure at 90 °C followed by
addition of 57% hydroiodic acid (600 μL). The sealed reactor vial was heated
at 155 °C for 4 min. The solution was cooled to room temperature and
neutralized to pH 3 with 4 mL of a 0.32 M potassium phosphate buffer
5
0%). Owing to the high toxicity of benzene as compared with
toluene, toluene was later used for developing the radiochemical
syntheses on the automated platforms that had intended in vivo
use, and benzene was not considered further. However, for
purposes of chemistry, the aromatic solvents may be used
interchangeably.
(pH 12). The solution was transferred from the reactor vial to the HPLC
injector loop (5 mL) connected to an Agilent 1100 series HPLC pump
equipped with a Zorbax Eclipse XDB-C18 semi-prep (9.4 × 250 mm, 5 μm)
column. Eluent: 20% ethanol, 55 mM citric acid, pH 3 at 2 mL/min. The
18
radioactive peak corresponding to 6-[ F]F-DA (retention time 8.5 min)
was collected and neutralized with 0.1 M ammonium acetate (pH 8.2).
18
Preliminary testing of n.c.a. F incorporation using
microfluidics
1
8
A sample of 6-[ F]F-DA final product was analyzed for radiochemical
identity, purity, and SA by analytical HPLC using an Agilent Zorbax SB-
Aq (3.5 μm, 4.6 mm × 100 mm) chromatography column with a mobile
phase of 10% acetonitrile and 90% aqueous buffer (0.1 M monosodium
phosphate, 0.27 mM disodium EDTA, 0.92 mM octanesulfonic acid,
pH 3.5). The flow rate was 1.0 mL/min, and UV (220 nm) and radioactivity
detectors were used for the analysis. For determination of radiochemical
Like many prior reports of the use of diaryliodonium salts as
radiofluorination precursors, the overall process incorporates a
high-temperature thermolysis reaction and a deprotection step.
The key variable that distinguishes this new methodology from
previously reported methods is that the ion exchange and
thermolysis reactions (Figure 2 and Figures S1 and S2) are
performed in a relatively nonpolar solvent. Investigation of these
labeling conditions was performed using the Advion Nanotek®
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identity, purity, and SA, the HPLC retention time and peak area of 6-[ F]
1
9
F-DA were compared with those for a standard solution of 6-[ F]F-DA
ABX) of known concentration.
An aliquot of the final product, 6-[ F]F-DA, was analyzed for residual system.
(
18
solvents by gas chromatography (GC) using an Agilent Technologies
While the thermolysis yielded negligible amounts of 2 in 100%
acetonitrile (data not shown), Figure 2 shows that a modest yield
~10%) of 2 was produced when 50% of the acetonitrile was
7890A GC System, Carbowax column (J&W; 30 m × 250 μm × 0.25 μm),
inlet and detector temperatures of 250 and 300 °C, respectively, oven
temperature of 80 °C, and flow of 1.5 mL/min. The GC peak retention
times and areas were compared with standards of acetone (0.1%, v/v),
ethyl acetate (0.1%), ethanol (0.1%), acetonitrile (0.01%), and toluene
(
(0.01%). The amount of each volatile solvent was calculated based on
the ratio of peak areas for the samples versus the standard.
1
8
Synthesis of 6-[ F]fluorodopamine on the GE TRACERlab FX-
FN
For this method, the automated radiochemistry setup with a GE TRACERlab
4
1
FX-FN and an adjacent customized module has been previously described.
18
As significant F-radioactivity adhered to a borosilicate glass reactor vial, a
glassy carbon reactor vessel was used instead of the glass vial. [ F]Fluoride
n.c.a.) in [ O]water was added directly to the reactor, which was previously
18
18
(
charged with Kryptofix® [2.2.2] (3 mg) and K CO (0.5 mg) in 95:5
2
3
acetonitrile : water (2 mL). Residual water was removed by azeotropic
distillation with an additional aliquot of acetonitrile (2 mL). An acetonitrile
solution containing diaryliodonium precursor 1 (10 mg in 0.5 mL) was added
to the reactor. Acetonitrile was removed under vacuum and heat (50 °C),
toluene (1 mL) was added, and the vial was heated at 150 °C for 5 min.
The crude reaction mixture was passed through a silica Sep-pak® Plus
Figure 2. Optimization of thermal decomposition of 1 conducted at various
temperatures for 30 s in 1:1 acetonitrile : benzene (black bars) and 100% benzene
(gray bars) (n = 3 for each condition) (precursor (1) (5 mg/mL); reactor loop
15.7 μL; flow rate = 31.4 μL/min).
www.jlcr.org
Copyright © 2015 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2016, 59 30–34

K. D. Neumann et al.
replaced with benzene. Figure 2 also demonstrates the marked resulted in a yield of 51 ± 6% (n = 3), uncorrected (75 ± 9%
18
improvement in RCY of the fluoroarene when the thermolysis corrected to EOB). The final yield of purified 6-[ F]F-DA was
reaction is performed in 100% benzene. These data are 31 ± 6% (n = 3), uncorrected (72 ± 10% corrected), and was
19
consistent with previous work performed with [ F]fluoride that achieved in an average of 130 min from EOB. Using a lower
18
showed that the use of polar aprotic solvents in the thermal starting F activity of 11.1–14.8 GBq (300–400 mCi), the specific
decomposition reaction of diaryliodonium fluorides led to very radioactivity of final product was 11.1–7.4 GBq/μmol (0.3 ±
40
poor yields of fluorinated arenes.
Yields of 2 were evaluated with respect to thermolysis time in
0.2 Ci/μmol).
The use of toluene and ethyl acetate in the synthesis limits the
benzene at 180 °C (Figure S1). Maximum yields of 2 were observed number of radiosynthesis platforms that can use this methodology
after only 30 s of heating, and prolonged heating times showed currently. Cassettes that employ relatively robust polymers such as
no increase in labeling; the yield of 2 plateaued at approximately polyethylene, polypropylene, or fluoroelastomers are compatible.
1
8
4
0–45%. These results obtained with n.c.a. [ F]fluoride were at Cassettes constructed from other materials need to be tested on
19
odds with experiments conducted with [ F]fluoride under nearly a case-by-case basis. Purification methods involving widely
19
identical conditions, which produced [ F]2 in 80% yield; the cassette-compatible solvents are currently being optimized.
salient difference between the non-radioactive control and the The conditions required for removal of the methyl ether
radioactive synthesis was the presence of solubilized K CO in protective groups are somewhat aggressive, which is a minor
2
3
the acetonitrile solution used to perform the ion exchange drawback for this synthesis, as HI is a very corrosive reagent. A
reaction. It appeared likely that carbonate ions competed with diaryliodonium precursor containing more labile protecting
18
[
F]fluoride for the iodine(III) center and that this problem might groups, which require milder hydrolysis conditions, is currently
be solved by an increase in the concentration of the being developed.
diaryliodonium salt precursor. This simple change allowed the The diaryliodonium salt (1) showed excellent long-term
yields of 2 to approach those of the [ F]fluorinated arene stability when stored at room temperature under dry argon. No
19
18
observed previously at precursor concentrations above 10 mg in decline in yield of 6-[ F]F-DA from a single batch of 1 was noted
9
00 μL of 100% benzene (Figure S2).
in runs conducted over the course of 18 months.
The easy implementation and efficiency of the overall method
1
8
1
8
means that amounts of 6-[ F]F-DA adequate for a single human
Synthesis of 6-[ F]fluorodopamine on the IBA Synthera®
dose (180–370 MBq) may be readily prepared from modest
amounts of [ F]fluoride (0.75–1.2 GBq). Importantly, the yield
The radiosynthesis of 6-[ F]F-DA was performed on two of 6-[ F]F-DA did not decline with increasing amounts of
commercially available automated radiochemical synthesizers, radioactivity; more than 3.7 GBq of pure, high SA 6-[ F]F-DA
the Synthera® (IBA) and the TRACERlab FX-FN (GE). RCYs were was obtained from 9.3 GBq of [ F]fluoride.
measured after the fluorination and thermolysis of 1 to produce Both automated synthesis platforms used in this work
and the GE TRACERlab FX-FN
18
18
18
18
18
18
2
and also after the purification of the final product (3).
provided 6-[ F]F-DA in sufficient quantity, SA, and purity for
Production of the fluorinated intermediate (2) on the IBA use in clinical studies. Method automation is simple, and overall
1
8
Synthera® using the optimized conditions resulted in a yield of
3
F-radiosynthesis times are comparably short. While the overall
18
5 ± 4% (n = 9), uncorrected (46 ± 7% corrected to end of yield of 6-[ F]F-DA was higher on the GE system, the single-use
bombardment (EOB)). Thermal decomposition was performed cassette capabilities of the Synthera® make regulatory
at 150 °C rather than optimal 180 °C determined in preliminary compliance less cumbersome. In our hands, the ability to add a
18
experiments as the optimized conditions on the flow system second azeotropic evaporation of the Kryptofix/[ F]fluoride
Nanotek) do not correlate directly with conventional heating complex with anhydrous acetonitrile generally resulted in higher
(
18
conditions of the Synthera. The final yield of 6-[ F]F-DA (3) after overall RCYs. The GE system is able to accommodate this extra
deprotection and purification by HPLC was 25 ± 4% (n = 4), aliquot of acetonitrile and, thus, provided higher yields of 6-
18
uncorrected (36 ± 4% corrected to EOB), and was achieved in [ F]F-DA. The GE system is also able to accommodate a more
an average of 65 min from EOB. SA was calculated at >74 detailed intermediate solid phase extraction purification of the
GBq/μmol (2 Ci/μmol) (n = 8) for this system from a starting fluorinated intermediate (2). Taken together, these additional
activity of 18.5 GBq (500 mCi).
steps extend the synthesis time on the GE system, as compared
The semi-prep HPLC purification provided a simple separation with the IBA system. Nevertheless, this study demonstrates that
1
8
of 6-[ F]F-DA from radiochemical impurities (Figure S3). Different these methods are easily adaptable for use on synthesis
semi-prep HPLC conditions were used on the Synthera and platforms that are stable to the use of organic solvents.
1
8
TRACERlab FX-FN to demonstrate the versatility of the method.
Analytical validation (Figure S4) against a 6-[ F]F-DA standard fluoride have been reported in the past few years,
While several other methods for incorporation of n.c.a [ F]
19
31–34
many of
(ABX) confirmed the final product to be >99% radiochemically these methods utilize heavy-metal catalysts, necessitating
pure and >95% chemically pure 3. Analysis of the UV signal additional quality control analyses for human use to verify that
shows a small amount of dopamine (calculated to be 7.7 μg/mL residual metal concentrations are below allowable injection
in this case) but no detectable fluorodopamine. Peaks earlier than limits. Our diaryliodonium method does not use heavy metals
2
min are due to the purification eluent (citric acid).
for either radiolabeling or precursor synthesis. Only the
Residual solvent analysis of the final product showed no spirocyclic iodonium ylides are comparable in this regard. The
42
detectable amount of the class II solvents acetonitrile or toluene. main advantage of the ylide chemistry appears to be the stability
As determined by standard curve comparison, residual ethanol of the precursor; however, we have demonstrated that the
18
was routinely detected at a 1–2% concentration (Figure S5).
diaryliodonium 6-[ F]F-DA precursor (1) is completely stable
Production of fluorinated intermediate (2) on the GE for at least 18 months at room temperature under argon
TRACERlab FX-FN using the same conditions described earlier atmosphere.
J. Label Compd. Radiopharm 2016, 59 30–34
Copyright © 2015 John Wiley & Sons, Ltd.
www.jlcr.org

K. D. Neumann et al.
[
[
[
11] D. S. Goldstein, G. Eisenhofer, B. B. Dunn et al., J. Am. Coll. Cardiol.
Conclusions
1
993, 22, 1961.
12] D. S. Goldstein, C. Holmes, J. E. Stuhlmuller, J. W. Lenders, I. J. Kopin,
Clin. Auton. Res. 1997, 7, 17.
13] S. T. Li, C. Holmes, I. J. Kopin, D. S. Goldstein, J. Nucl. Med. 2003, 44,
We have demonstrated production of the clinically relevant
radiopharmaceutical 6-[ F]F-DA in >25% RCY (end of synthesis)
with an SA of >74 GBq/μmol and a total synthesis time of
18
1
599.
approximately 1–2 h, including HPLC purification. The methodology [14] K. Pacak, G. Eisenhofer, D. S. Goldstein, Endocr. Rev. 2004, 25, 568.
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conducted successfully in multiple laboratories. This adaptability
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18
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regulatory requirements for single-center or multi-center clinical
research. The generality and scope of the [ F]fluoride chemistry
suggest that the methodology may have significant breadth of
19
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Conflict of interest
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24] G. Coates, R. Chirakal, E. L. Fallen et al., Heart 1996, 75, 29.
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Dr. Neumann is currently a consultant for and shareholder of
Ground Fluor Pharmaceuticals (GFP), Inc., Lincoln, NE, who now
produces the diaryliodonium salt precursor material for 6-[ F]-
[
18
fluorodopamine. Dr. DiMagno holds a patent for the nucleophilic [27] T. Chaly, J. R. Dahl, R. Matacchieri et al., Appl. Radiat. Isot. 1993, 44,
fluorination of aromatic ring systems (US Patent 8,604,213 B2, 10
December 2013), which includes the chemistry described herein,
and is a shareholder in GFP, Inc. Other authors declare no conflict
of interest.
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The authors would like to thank Lee Collier and Advion, Inc., for [33] M. Tredwell, S. M. Preshlock, N. J. Taylor, S. Gruber, M. Huiban, J.
Passchler, J. Mercier, C. Génicot, V. Gouverneur, Angew. Chem. Int.
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access to the Nanotek® system. Research funding was provided
by NIH R01EB015536 and American Lebanese Syrian Associated
Charities – St. Jude Children’s Research Hospital. This work was
also supported, in part, by Stanford University Department of
Radiology internal funds (FTC) and National Cancer Institute
ICMIC grant P50 CA114747 (SSG).
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