A Transmetalation Reaction Enables the Synthesis of [18F]5-Fluorouracil from [18F]Fluoride for Human PET Imaging

Article abstract of DOI:10.1021/acs.organomet.6b00059

Translation of new ¹⁸F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for ¹⁸F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful ¹⁸F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [¹⁸F]fluoride of human doses of [¹⁸F]5-fluorouracil, a PET tracer for cancer imaging in humans. The first preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [¹⁸F]5-fluorouracil precursor. Routine production of >10 mCi doses of [¹⁸F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [¹⁸F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated ¹⁸F-fluorination.

Full text of DOI:10.1021/acs.organomet.6b00059

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A Transmetalation Reaction Enables the Synthesis of [18F]5-
Fluorouracil from [18F]Fluoride for Human PET Imaging
Andrew J. Hoover,† Mark Lazari,⊥ Hong Ren,†,‡,§ Maruthi Kumar Narayanam,⊥ Jennifer M. Murphy,⊥
R. Michael van Dam,⊥ Jacob M. Hooker,‡,§ and Tobias Ritter*,†,§,¶
†Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United
States
‡Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown,
Massachusetts 02129, United States
§Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston,
Massachusetts 02114, United States
⊥Department of Molecular and Medical Pharmacology and Crump Institute for Molecular Imaging, David Geffen School of Medicine
at University of California, Los Angeles, 570 Westwood Plaza, Los Angeles, California 90095, United States
¶Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mulheim an der Ruhr, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Translation of new 18F-fluorination reactions to
produce radiotracers for human positron emission tomography
(PET) imaging is rare because the chemistry must have useful
scope and the process for 18F-labeled tracer production must be
robust and simple to execute. The application of transition metal
mediators has enabled impactful 18F-fluorination methods, but to
date none of these reactions have been applied to produce a
human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production
from [18F]fluoride of human doses of [18F]5-fluorouracil, a PET tracer for cancer imaging in humans. The first preparation of
nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the
[18F]5-fluorouracil precursor. Routine production of >10 mCi doses of [18F]5-fluorouracil was accomplished with a new
instrument for azeotrope-free [18F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated
18F-fluorination.
Scheme 1. Strategy for the Synthesis of [18F]5-Fluorouracil
INTRODUCTION
■
Transition-metal-mediated fluorination reactions have in-
creased in scope and application, particularly for the synthesis
of 18F-labeled molecules for positron emission tomography
(PET).1−3 However, no such reaction has yet been translated
to enable human PET imaging. Here we report the cGMP4
production of human doses of [18F]5-fluorouracil ([18F]5-FU),
a PET tracer for clinical research in oncology,5 by nickel-
mediated oxidative fluorination with [18F]fluoride (Scheme
1).2d The synthesis of the [18F]5-FU nickel precursor was
enabled by the first transmetalation reaction from arylboronic
acid derivatives that yields isolated nickel σ-aryl complexes. The
transmetalation reaction was developed because other methods
for nickel σ-aryl preparation were inadequate. All previously
reported syntheses of [18F]5-FU for human use have employed
[18F]F2 gas,6 which is challenging to produce and handle and is
less preferable as a starting material compared to [18F]fluoride.7
Nickel σ-aryl complexes are employed as precatalysts,8
substrates for mechanistic investigation,9 and precursors for
late-stage 18F-fluorination.10 Nickel σ-aryl complexes react with
[18F]fluoride and oxidant in less than 1 min at 23 °C in the
presence of water to afford [18F]aryl fluorides.2d In contrast,
competing methods such as the 18F-fluorination of aryliodine-
(III) precursors2k,3a,b,d−f and copper-mediated fluorination of
arylboronate esters2j utilize extended reaction times at elevated
temperatures with azeotropically dried [18F]fluoride. A draw-
back of nickel σ-aryl complexes is that limited methods exist for
Received: January 22, 2016
© XXXX American Chemical Society
A
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their preparation, which we sought to address with this
investigation. Nickel σ-aryl complexes are commonly prepared
by oxidative addition of Ni(0) to aryl halides11 or by
transmetalation from aryllithium, Grignard, and arylzinc
reagents.12,13 However, the range of accessible nickel σ-aryl
complexes is limited due to the strong reducing activity of
Ni(0) reagents and the basicity and nucleophilicity of
organometallic Li, Mg, and Zn precursors. There are no
general methods for nickel σ-aryl preparation from more
functional-group-tolerant p-block organometallics such as
arylboron, aryltin, or arylsilicon reagents.14−16 The preparation
of other first-row transition metal σ-aryl complexes from such
reagents is rare.17 Development of a versatile nickel(II) σ-aryl
synthesis by transmetalation was further motivated by the
failure of previously reported oxidative addition methodology2d
to afford the desired nickel(II) σ-aryl precursor to [18F]5-FU
(see the Supporting Information).
Arylboronic acids/esters were desired as the aryl source for
transmetalation, because they are easily prepared and may
contain functional groups not tolerated in organometallic
reagents of Li, Mg, and Zn.18 As a starting point for the
development of the synthesis of Ni(II) σ-aryl complexes by
transmetalation from arylboronic acids, the reduction of
inorganic LnNiIIX2 precatalysts (for example, (PCy3)2NiCl2)
by boronic acid in Suzuki−Miyaura coupling was considered
(Scheme 2).19 Reduction to low-valent Ni is likely initiated by
transmetalation in order to access the desired precursors for
18F-fluorination.
RESULTS AND DISCUSSION
■
Complex 1 was synthesized as a reagent for preparative
transmetalation (Scheme 3). Consistent with our design for a
transmetalation reagent, complex 1 has a hydroxide ligand to
activate the arylboron reaction partner for transmetalation,
dissolves in organic solvents such as pyridine and DMSO, and
contains the pyridylsulfonamide ligand required for oxidative
arene fluorination. Complex 1 was prepared on a multigram
scale starting from nickel(II) acetate tetrahydrate, potassium
tert-butoxide, and the bidentate pyridylsulfonamide ligand in a
1:2:1 molar ratio in pyridine solvent. After evaporation of
pyridine and dissolving in THF, 1 precipitated by treatment
with just 3% water (by volume), likely by hydrolysis of a more
soluble nickel(II) tert-butoxide intermediate. The use of
pyridine as solvent for the synthesis of 1 is essential. In all
other solvents evaluated, an insoluble orange solid identified as
the square-planar bispyridylsulfonamide nickel(II) complex 2
precipitates after mixing inorganic Ni(II) precursors with a
pyridylsulfonamide ligand. The rapid formation of 2 by
association with two ligands stands in contrast with reactivity
observed for Pd(II), where a complex with a single
pyridylsulfonamide ligand can be isolated in 99% yield by
concentration of a CH2Cl2 solution of Pd(OAc)2, pyridylsulfo-
namide, and 3 equiv of pyridine.20 Complex 1 is a green solid
that appears to be stable when stored in a sealed vial under air
at room temperature for several months. In pyridine-d5
solution, 1 exhibits a set of characteristic proton NMR signals
between −10 and 50 ppm. The structure of 1 was determined
by X-ray crystallography and consists of a tetrameric nickel(II)
hydroxide core, with one hydroxide and one pyridylsulfonamide
ligand per nickel atom. Two of the nickel atoms are bound to
acetate derived from the nickel(II) acetate tetrahydrate
precursor, with almost equivalent Ni−O bond lengths (2.05
and 2.07 Å).
Scheme 2. Plausible Pathway for Reduction of Nickel(II) by
Arylboronic Acid
Transmetalation occurs when 1 is treated with arylboronic
acid (or ester) in pyridine at 70 °C for 1 h, to generate the
desired complexes (Scheme 4). The preparation of complexes
3a−3i represents the first example of preparative nickel(II) σ-
aryl synthesis starting from boronic acids or esters. In addition
to the previously inaccessible [18F]5-fluorouracil precursor 3a,
diverse nickel(II) σ-aryl and heteroaryl complexes 3b−3i were
synthesized. While the previous synthesis of pyridylsulfonamido
nickel(II) σ-aryl complexes by oxidative addition with nickel(0)
biscyclooctadiene required a glovebox,2d synthesis by trans-
metalation with 1 does not and is conveniently set up at the
bench. Purification of the nickel(II) σ-aryl complexes is
accomplished without exclusion of water or oxygen. The
transmetalation reaction likely proceeds by dissociation of 1 in
pyridine solution, so that the oxygen atom of the nickel
hydroxide will be coordinatively unsaturated and, therefore, be
able to bond to boron for transmetalation.
Fluorination of the nickel(II) σ-aryl complexes 3a−3e occurs
rapidly with [18F]fluoride and iodine(III) oxidant2d at 23 °C
(Scheme 5). Incorporation of 18F at the 3-position of a
thiophene ring system was observed in the synthesis of [18F]4c.
Electron-rich O/S-heteroarenes are difficult to fluorinate on the
same ring as the heteroatom with conventional nucleophilic
radiofluorination chemistry.21 Furthermore, oxidative [18F]-
fluorination occurs in the presence of a tertiary amine to afford
[18F]4d, which is notable because of the reactivity of amines
transmetalation from arylboronic acid to LnNiIIX2 to form
LnNiII(Aryl)X, which is relevant because the desired 18F-
fluorination precursors are LnNiII(Aryl)X complexes. However,
to our knowledge, direct observation of a nickel(II) σ-aryl
complex formed by transmetalation from an arylboronic acid or
ester has not been reported. Instability of LnNiII(Aryl)X
compared to LnNiIIX2, in the presence of boronic acid and
base, may prevent the accumulation of LnNiII(Aryl)X. To
develop a preparative synthesis of LnNiII(Aryl)X from
arylboronic acids, a fundamental challenge of relative rates
must be addressed. Transmetalation to form LnNiII(Aryl)X
must be more facile than its destruction by homocoupling or
protiodemetalation.
To maximize the transmetalation rate, an LnNiIIX2 precursor
that contains a basic X-type ligand, such as hydroxide, that
could induce transmetalation from arylboron reagents was
desired. In support of this design, a study has implicated that
transmetalation to a nickel(II) hydroxide is faster than
transmetalation to the analogous nickel(II) halide in the
presence of base.9c Incorporation of the required pyridylsulfo-
namide ligand as the second X-type ligand in the LnNiIIX2
precursor would increase its solubility in organic solvent,
prevent a second transmetalation and hence homocoupling
from occurring due to the weak basicity of the sulfonamide, and
eliminate the need for additional ligand exchange steps after
B
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a
Scheme 3. Synthesis of Nickel Hydroxide Cubane 1, a Reagent for Preparative Transmetalation
a
ORTEP structures of 1 and 2 (50% probability ellipsoids) are displayed. Hydrogen and solvent atoms are omitted for clarity, as are the counterion
and pyridylsulfonamide ligand atoms in 1 (except nitrogens bound to nickel). Ar = 2-nitrophenyl.
toward oxidation with iodine(III) oxidants.22 Formation of
[18F]4d can be rationalized on the basis of oxidative
fluorination being faster than amine oxidation and that product
[18F]4d is spared from oxidation because the starting material
3d is present in slight excess compared to oxidant. Complexes
3g, 3h, and 3i, all of which contain unbound Lewis basic pyridyl
substituents, did not undergo radiofluorination to the desired
products. In contrast, bisalkoxypyrimidine complex 3a under-
went fluorination to form [18F]4a in 15% radiochemical
conversion (RCC). This result served as a starting point for
our synthesis of [18F]5-FU from [18F]fluoride.
2.4 mL [18O]water in which it was produced in a cyclotron
(26% yield of dry [18F]fluoride). To increase the yield, a more
efficient [18F]fluoride concentration process was developed that
afforded 81% yield of [18F]fluoride (Scheme 6, top). This
process is performed with an instrument (see the Supporting
Information for full details) that leverages a miniaturized ion-
exchange cartridge and microfluidic lines in order to elute
[18F]fluoride with a total of 4 μL of water. The [18F]fluoride
was eluted into 1 mL of dry MeCN to afford a 0.4% aqueous
MeCN solution that has sufficiently low water content for
oxidative [18F]fluorination, without the need for evaporation
steps. Because azeotropic drying and fluoride resolubilization
were not necessary, time was saved and radiochemical yield
improved.
Our ultimate goal was to prepare human doses of [18F]5-FU
from [18F]fluoride to enable PET imaging in oncology.
Therefore, an isolated yield of at least 10 mCi was desired.5
Purity to match USP guidelines and production in a cGMP
environment were also required. Oxidative fluorination of 3a
with [18F]fluoride affords [18F]4a, which is protected with
hydrophobic tert-butyl groups that facilitate purification by
conventional reverse-phase chromatographic methods. All
previous preparations of human doses of [18F]5-FU started
from [18F]F2 gas and uracil, and a challenging separation of
[18F]5-FU from uracil and other polar byproducts was
required.6 Purified [18F]4a undergoes rapid and clean
conversion to [18F]5-FU upon mixing with HCl(aq) in ethanol
at room temperature. Neutralization of HCl with NaHCO3
forms a buffered saline solution for in vivo application.
The streamlined [18F]fluoride concentration was incorpo-
rated into a cGMP process for the synthesis of [18F]5-FU
(Scheme 6, bottom). Formulated [18F]5-FU was isolated with a
yield range of 13.5−18.8 mCi (over three runs), starting from
1.4−1.8 Ci of [18F]fluoride, with a synthesis time of about 1.5
h. A specific activity of 34.3 18.0 Ci/μmol was observed for
isolated [18F]5-FU.23 The percent yield of 0.92% 0.18% is
low due to the RCC of [18F]fluoride to [18F]4a (2.9% 0.5%,
n = 3).24 Nearly all of the remaining 18F eluted near the
beginning of reverse-phase HPLC runs and at the baseline of
silica TLC analysis runs, consistent with the presence of
unreacted [18F]fluoride that remains after the rapid fluorination
reaction ceases. The origin of low RCC may involve side
reactions of the water- and base-sensitive biscationic iodine(III)
oxidant or of high-valent nickel intermediates. Application of
PPTS to buffer the [18F]fluoride solution2i did not substantially
improve the RCC (2.96%). Development of robust alternative
oxidants or high-valent nickel σ-aryl fluorination precursors
Preliminary efforts to produce [18F]5-FU on a large scale by
[18F]fluorination of 3a with an established automation
platform2i resulted in the isolation of 2.4 mCi of [18F]5-FU
(0.2% yield, see the Supporting Information). The yield was
prohibitively low for human dose production and was
diminished by inefficient separation of [18F]fluoride from the
C
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Scheme 4. Synthesis of Nickel(II) σ-Aryl Complexes by
Transmetalation from Boronic Acids and Esters
Scheme 5. Oxidative Fluorination of Nickel(II) σ-Aryl
a
a
Complexes
a
Conditions: 0.5 mL of 18F− solution (0.50 mL of MeCN, 5.0 mg of
18-crown-6, 1.0 μL of 0.56 M K3PO4(aq.), 1.5 μL of 18F−(aq)), 1.0 mg of
Ni complex, 1.0 mg of PhI(4-OMe-pyridine)2(OTf)2.
complex 3a. Oxidative fluorination of 3a allowed for the first
synthesis of [18F]5-fluorouracil from [18F]fluoride that affords
doses suitable for in vivo use in humans. The nickel-mediated
synthesis of [18F]5-fluorouracil represents the first clinical
translation of transition-metal-mediated fluorination to enable
PET imaging in humans. We aim to advance oncology clinical
research by routinely supplying human doses of [18F]5-
fluorouracil.
EXPERIMENTAL SECTION
■
Synthesis of Nickel Hydroxide Cubane 1. To a 1 L round-
bottomed flask were added nickel(II) acetate tetrahydrate (2.80 g, 11.3
mmol, 1.00 equiv) and a Teflon-coated stirbar. The flask was fitted
with a septum, and the headspace was filled with nitrogen. Anhydrous
pyridine (114 mL) was added, and a blue solution was observed after
mixing. To this solution was added 2-nitro-N-(2-(pyridin-2-yl)-
phenyl)benzenesulfonamide2d (4.00 g, 11.3 mmol, 1.00 equiv, as a
solution in 166 mL of anhydrous pyridine) by cannula over 3 min, and
a green-blue solution was observed. To this solution was added
potassium tert-butoxide (2.53 g, 22.5 mmol, 2.00 equiv, as a solution in
80 mL of anhydrous pyridine) by cannula over 5 min. A yellow-green
solution with a colorless precipitate was observed, which was stirred at
23 °C for 45 min, before being concentrated in vacuo (by rotary
evaporation at 60 °C until all liquid pyridine was removed and then
under high vacuum at 23 °C) to give a mixture of green and orange
solids. These solid residues were ground with a spatula under
anhydrous THF (130 mL) in order to dissolve the green solid. The
mixture was filtered through Celite on a glass frit, which was then
rinsed with anhydrous THF (2 × 20 mL). The THF filtrates were
combined to give a dark green solution, which was treated dropwise
with H2O (5.0 mL) over 30 min, with magnetic stirring, which caused
a light green solid to precipitate. The solid was collected by filtration
on a glass frit, rinsed with THF (2 × 20 mL), and dried in vacuo (0.2
Torr, 50 °C, 40 min; then 0.2 Torr, 150 °C, 2 h) to afford 2.66 g of the
title compound (as a solvate with 4 water molecules) as a green solid
(50% yield). NMR spectroscopy: 1H NMR (600 MHz, pyridine-d5, 23
°C, δ): 46.1, 45.2, 44.8, 44.5, 43.0, 41.8, 40.9, 40.7, 39.6, 39.4, 39.2,
37.4, 36.1, 33.6, 33.1, 32.2, 30.4, 29.4, 24.4, 22.0−19.0, 20.3, 19.9, 19.6,
a
b
Yields of isolated products are given. Synthesized from arylboronic
c
acid. Synthesized from the arylboronic ester of 2,2-dimethyl-1,3-
propanediol.
may lead to a more efficient fluorination reaction. Nevertheless,
at this stage the yield of [18F]5-FU is sufficient for human PET
imaging because only 5−10 mCi is needed for a human dose.5
[18F]5-FU is obtained as a sterile, colorless saline solution, with
>99% radiochemical purity, <10 μg of impurities not arising
from USP formulation ingredients, and <0.1 ppm of Ni. The
doses of [18F]5-FU pass quality control protocols for
radiopharmaceuticals for human use and are validated for
human in vivo application. No other preparation from
[18F]fluoride of [18F]5-FU for human use has been reported.
CONCLUSIONS
■
The first preparative synthesis of nickel(II) σ-aryl complexes by
transmetalation from arylboronic acids and esters was
developed and enabled the synthesis of previously inaccessible
D
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a
Scheme 6. cGMP Synthesis of [18F]5-Fluorouracil (>10 mCi) for Use in Human PET Imaging
a
b
Based on decay-corrected measurement of trapped activity on a microcartridge, relative to initial [18F]fluoride in [18O]water. Three elutions were
c
applied, with 0.5 μmol of K3PO4 and 3.0 μmol of 18-crown-6 ([18c6]) in 6.2 μL of MeCN/H2O (4/1, v/v) per elution. Based on decay-corrected
d
measurement of eluted activity relative to trapped activity. Yield (not decay corrected) based on [18F]fluoride (range: 7−14 mCi) in 2.4 mL of
e
water at the start of synthesis. Starting from 1.7 Ci of [18F]fluoride, the yield (not decay corrected) was 79%. SPE: solid phase extraction; see
f
Supporting Information for full purification details. Isolated yield (not decay corrected) is based on activity of [18F]fluoride (range: 1.4−1.8 Ci) in
[18O]water at the start of synthesis.
18.3, 17.9, 17.7, 17.5, 16.7, 16.0. 14.8, 14.7, 14.4, 14.1, 13.8, 13.5, 13.1,
12.6, 11.9, 11.4, 10.9, 10.7, 10.6, 10.2, 9.9, 8.3, 8.1, 7.5, 6.9, 6.6, 6.3, 6.2,
6.1, 6.0, 5.8, 5.4, 1.9, 1.0, 0.5, 0.2, −0.2, −0.4, −0.7, −1.0, −1.9, −2.0,
−2.6, −3.6, −4.0, −4.6, −5.0, −5.5, −6.5. Due to gradual
decomposition in solution, 13C NMR analysis was not performed.
Anal. Calcd for C70H55N12S4O22KNi4(H2O)4: C, 44.47; H, 3.36; N,
8.89. Found: C, 44.63; H, 3.07; N, 8.77. IR (neat, ν, cm−1): 1594 (w),
1575 (w), 1535 (s), 1489 (m), 1476 (w), 1428 (m), 1367 (m), 1275
(m), 1234 (m), 1147 (s), 1129 (s), 1117 (s), 1061 (m), 972 (s), 852
(w), 824 (m), 753 (s), 730 (s), 651 (m), 630 (w), 593 (s), 562 (s),
528 (m), 434 (m).
General Procedure for Preparation of Complexes 3a−3i by
Transmetalation. Complex 1 (142 mg, 75.0 μmol, 0.250 equiv) and
arylboron reagent (1.0 equiv) were dissolved in dry pyridine (12 mL)
under N2. The mixture was heated with stirring at 70 °C for 1 h. After
cooling to 23 °C, hexanes (120 mL) was added, and the precipitated
product was collected by filtration on Celite, dissolved in dichloro-
methane/pyridine (95:5, v/v), and then passed through the Celite.
The filtrate was concentrated in vacuo to afford a residue, which was
purified by chromatography on SiO2/K2CO3 (9:1 w/w), eluting with
dichloromethane/pyridine (95:5, v/v). The collected fractions were
concentrated in vacuo to remove dichloromethane, and hexanes was
added. The supernatant was decanted after centrifugation, and the
remaining residue was triturated with hexanes. The title compound
was obtained after centrifugation and decantation of the supernatant
and drying of the remaining solid in vacuo. For some complexes, the
solvents used in the workup procedure were varied (see the
Supporting Information for full details).
quickly, and the vial was sealed and mixed until all 18-crown-6 had
dissolved. The vial was opened, aqueous potassium phosphate (0.561
M K3PO4 in water, 2.0 μL per 10.0 mg of 18-crown-6) was added
quickly, and the vial was sealed, shaken, and then vortexed for 10 s.
The vial was opened, aqueous [18F]fluoride from the cyclotron (3.0 μL
per 10.0 mg of 18-crown-6) was added quickly, and the vial was sealed,
shaken, and then vortexed for 10 s. A portion of the resulting solution
(0.50 mL) was added as rapidly as possible, with a 1 mL plastic syringe
with an 18 G disposable metal needle, to the vial containing nickel(II)
aryl complex and oxidant through the septum. After 1 min at 23 °C,
the radiochemical conversion was then measured by radioTLC, and
HPLC analysis was performed to confirm the formation of the title
compound.
cGMP Synthesis of [18F]5-Fluorouracil from [18F]Fluoride. All
chemicals, equipment, facilities, staff, procedures, and documentation
were controlled in accordance with cGMP guidelines. All operations
were conducted behind lead shielding and were remote-controlled.
[18F]Fluoride (1.4−1.8 Ci) in [18O]water (2.4 mL) was passed
through a miniature ion-exchange cartridge, which was then dried with
MeCN (1.0 mL). The trapped [18F]fluoride was released with three
elutions of 0.5 μmol of K3PO4 and 3.0 μmol of 18-crown-6 in 6.2 μL of
MeCN/H2O (4:1, v/v) per elution. The eluted [18F]fluoride was
diluted in a vial containing 1.0 mL of dry MeCN and 10.0 mg of 18-
crown-6, and the resulting solution was rapidly added to a solid
mixture of complex 3a (10.0 mg) and PhI(4-OMe-pyridine)2(OTf)2
(10.0 mg). After 1 min at 23 °C, the reaction solution was diluted with
4.0 mL of water and purified by semipreparative HPLC. The collected
fractions were passed through two C18 silica cartridges, which were
washed with water and then eluted with ethanol into a vial with
concentrated HCl(aq). After 2 min at 23 °C, the reaction solution was
neutralized with NaHCO3(aq) and filtered through solid-phase
extraction cartridges. The resulting solution was transferred to a
clean room, where it was passed through a sterilizing filter to afford
[18F]5-fluorouracil for human injection (13.5−18.8 mCi) as a 23 mL
saline solution with <10% ethanol.
General Procedure for Preparation of [18F]Aryl Fluorides
[18F]4a−[18F]4e. In a nitrogen-filled glovebox, to an oven-dried 1-
dram (4 mL) glass vial were added nickel(II) aryl complex 3 and
PhI(4-OMe-pyridine)2(OTf)22d in a 1:1 mass ratio, and the two solids
were mixed gently with a metal spatula to give a homogeneous
admixture. To an oven-dried 1-dram glass vial was added 2.0 mg of this
admixture, and the vial was sealed with a screw cap with a Teflon-lined
septum insert under nitrogen and removed from the glovebox. An
[18F]fluoride solution with 18-crown-6 and potassium phosphate
tribasic was prepared as follows. To an oven-dried 1-dram (4 mL)
glass vial was added dry 18-crown-6 (20.0−44.0 mg) under nitrogen,
and this vial was sealed with a Teflon-lined cap. The vial was opened
under air, dry MeCN (1.0 mL per 10.0 mg of 18-crown-6) was added
E
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W.; Hooker, J. M.; Groves, J. T. Angew. Chem., Int. Ed. 2015, 54,
5241−5245.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.6b00059.
■
S
(3) For recent advances in arene fluorination (not transition-metal-
mediated) with [18F]fluoride, see: (a) Pike, V. W.; Aigbirhio, F. I. J.
Chem. Soc., Chem. Commun. 1995, 2215−2216. (b) Ross, T. L.;
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Detailed experimental procedures and spectroscopic data
for all new compounds (PDF)
Crystallographic data for 1 (CIF)
Crystallographic data for 2 (CIF)
Crystallographic data for 3a (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: ritter@chemistry.harvard.edu.
Notes
■
(4) FDA Center for Drug Evaluation and Research, Guidance, PET
Drugs−Current Good Manufacturing Practice (CGMP), August 2011.
U R L : h t t p : / / w w w . f d a . g o v / d o w n l o a d s / D m g s /
GuidanceComplianceRegulatoryInformation/Guidances/
UCM266640.pdf (retrieved July 13, 2015).
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Funding provided by NIH-NIGMS (GM088237), NIH-NIBIB
(EB013042), the Blavatnik Biomedical Accelerator, DOE BER
(DE-SC0001249), the Harvard/MGH Nuclear Medicine
Training Program from the Department of Energy (DE-
SC0008430, in support of H.R.), National Center for Research
Resources (1S10RR017208-01A1), and the DOE SCGF
(graduate fellowship to A.J.H.) is gratefully acknowledged.
Acknowledgment is given to Dr. Shao-Liang Zheng, Dr.
Michael Campbell, and Heejun Lee (Harvard University) for
assistance with X-ray crystallographic analysis, Judit Sore, Kari
Phan, and Garima Gautham (Massachusetts General Hospital)
for assistance with cGMP validation, Dr. Nickeisha Stephenson
(Vasdev Lab, Harvard Medical School and Massachusetts
General Hospital) for the aryl bromide precursor to 3i, and
Martin G. Strebl for attempted synthesis of a nickel complex by
oxidative addition.
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G
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