Rapid synthesis of maleimide functionalized fluorine-18 labeled prosthetic group using “radio-fluorination on the Sep-Pak” method

Article abstract of DOI:10.1002/jlcr.3623

Following our recently published fluorine-18 labeling method, “Radio-fluorination on the Sep-Pak”, we have successfully synthesized 6-[¹⁸F]fluoronicotinaldehyde by passing a solution (1:4 acetonitrile: t-butanol) of its quaternary ammonium salt

Full text of DOI:10.1002/jlcr.3623

Received: 11 December 2017
DOI: 10.1002/jlcr.3623
Revised: 6 March 2018
Accepted: 9 March 2018
N O T E
Rapid synthesis of maleimide functionalized fluorine‐18
labeled prosthetic group using “radio‐fluorination on the
Sep‐Pak” method
1
1
2
2
1
Falguni Basuli
| Xiang Zhang
| Elaine M. Jagoda | Peter L. Choyke | Rolf E. Swenson
1
Imaging Probe Development Center,
National Heart, Lung, and Blood Institute,
National Institutes of Health, Rockville,
Maryland, USA
Following our recently published fluorine‐18 labeling method, “Radio‐fluorina-
1
8
tion on the Sep‐Pak”, we have successfully synthesized 6‐[ F]
fluoronicotinaldehyde by passing a solution (1:4 acetonitrile: t‐butanol) of its
2
Molecular Imaging Program, National
quaternary
ammonium
salt
precursor,
6‐(N,N,N‐trimethylamino)
Cancer Institute, National Institutes of
Health, Bethesda, Maryland, USA
nicotinaldehyde trifluoromethanesulfonate (2), through a fluorine‐18 contain-
ing anion exchange cartridge (PS‐HCO ). Over 80% radiochemical conversion
3
Correspondence
1
8
was observed using 10 mg of precursor within 1 minute. The [ F]
Falguni Basuli, Imaging Probe
Development Center, National Heart,
Lung, and Blood Institute, National,
Institutes of Health, Rockville, MD, USA.
Email: bhattacharyyaf@mail.nih.gov
18
fluoronicotinaldehyde ([ F]5) was then conjugated with 1‐(6‐(aminooxy)
hexyl)‐1H‐pyrrole‐2,5‐dione to prepare the fluorine‐18 labeled maleimide func-
18
tionalized prosthetic group, 6‐[ F]fluoronicotinaldehyde O‐(6‐(2,5‐dioxo‐2,5‐
18
18
dihydro‐1H‐pyrrol‐1‐yl)hexyl) oxime, 6‐[ F]FPyMHO ([ F]6). The current
Sep‐Pak method not only improves the overall radiochemical yield (50 ± 9%,
decay‐corrected, n = 9) but also significantly reduces the synthesis time (from
Funding information
National Cancer Institute; National Insti-
tutes of Health, Grant/Award Number:
HHSN261200800001E
60‐90 minutes to 30 minutes) when compared with literature methods for the
synthesis of similar prosthetic groups.
KEYWORDS
aldehyde, fluorine‐18, maleimide, Sep‐Pak
5
,6
1
| INTRODUCTION
precursors. Although conversions were comparable, the
reaction was much faster for the trimethylammonium
18
The goal of the present study is to expand the scope of our
triflate precursors. Moreover, purification of 2 or 4‐[ F]
fluorobenzaldehydes from the trimethylammonium triflate
precursors was done simply by using a Sep‐Pak. The same
research group has demonstrated high radiochemical con-
version using the pyridine derivative by halogen (Cl)
exchange. More challenging fluorine‐18 labelings at the
meta‐position to prepare 3‐[ F]fluorobenzaldehydes have
1,2
novel radiolabeling method, “Radiofluorination on the
Sep‐Pak”, to prepare useful fluorine‐18 labeled synthons.
Using this method, nucleophilic fluorine‐18 labeling can
be done rapidly without azeotropic drying of [ F]fluo-
ride. Due to the versatility of the aldehyde functional
group for radiolabeling of biomolecules, we decided to
apply this method to prepare fluorine‐18 labeled alde-
hyde. A variety of prosthetic groups containing aldehyde
functionalities have been developed. Kugler et al and
Lemaire et al reported labeling of 4‐fluorobenzaldehydes
and 2‐fluorobenzaldehydes and compared the radiolabeling
efficiencies of nitro‐ and trimethylammonium triflate‐
18
5
18
7
also been reported by our and other groups from a variety
8-10
of precursors. Recently, Richarz et al reported fluorine‐18
labeled benzaldehydes according to the “minimalist”
radiolabeling protocol, without base and azeotropic drying
of [ F]fluoride. In this approach, fluorine‐18 was eluted
with a quaternary ammonium triflate precursor in
3,4
18
11
J Label Compd Radiopharm. 2018;1–7.
wileyonlinelibrary.com/journal/jlcr
Published 2018. This article is a U.S.
1
Government work and is in the public domain in the USA

2
BASULI ET AL.
methanol and was evaporated at 70°C to 80°C. The residue
was dissolved in the appropriate solvent, and the resulting
Macherey‐Nagel (Düren, Germany) and the packing mate-
rial was reduced to half (~20 mg). Luna (2) C18 column
(10 × 250 mm, 5 μm) was obtained from Phenomenex
(Torrance, CA, USA). Other columns and all other Sep‐
Pak cartridges used in this synthesis were obtained from
Agilent Technologies (Santa Clara, CA, USA) and Waters
(Milford, MA, USA), respectively. Oasis MCX Plus car-
tridge was conditioned by passing 5‐mL acetonitrile. Sep‐
Pak plus C18 cartridges were conditioned with 5‐mL eth-
anol, 10‐mL air, and 10‐mL water. Low resolution mass
spectra (MS) were recorded on a 6130 Quadrupole LC/
MS, Agilent Technologies instrument equipped with a
18
solution was heated to obtain labeled aldehydes. The [ F]
fluorobenzaldehyde, thus prepared using different methods,
were used for a variety of coupling reactions to radiolabel a
3
,4
wide range of biomolecules.
18
[
F]Fluorobenzaldehydes are also used in the
synthesis of maleimide functionalized fluorine‐18 labeling
agents, another important class of radiolabeling synthons
for site specific labeling of biomolecules via coupling with a
thiol group. A variety of fluorine‐18 labeled maleimide func-
tionalized prosthetic groups have been developed over the
18
1
13
19
last few years, eg, 2‐[ F]fluoronicotinaldehyde O‐(6‐(2,5‐
diode array detector. H, C, and F NMR spectra were
recorded on a 400‐MHz Bruker spectrometer. Chemical
shifts (ppm) are reported relative to the solvent residual
1
8
12
dihydro‐1H‐pyrrol‐1‐yl)hexyl) oxime ([ F]FBAMPy), N‐[2‐
18
18
13,14
(
4‐[ F]fluorobenzamido)ethyl]maleimide ([ F]FBEM),
N‐[6‐ (4‐ [ F]fluorobenzylidene)aminooxyhexyl]maleimide
[ F]FBAM), [ F]FDG‐maleimidehexyloxime ([ F]FDG‐
1‐[3‐(2‐[ F]fluoropyridin‐3‐oxy)propyl]maleimide
and N‐(2‐(2,5‐dioxo‐2,5‐dihydro‐1H‐
pyrrol‐1‐yl)‐ethyl)‐6‐fluoronicotinamide ([ F]FNEM).
18
1
13
peaks of acetonitrile (δ H, 2.50 ppm; C 118.26, 1.79),
1
8
15 18
18
1
1
(
methanol (δ H, 3.34 ppm), and chloroform (δ H,
7.26 ppm). F NMR spectra are reported with reference
to the trifluoroacetic acid (δ F, −76.72 ppm). High perfor-
16
18
19
MHO),
1
8
17,18
19
(
[ F]FPyME),
18
19
mance liquid chromatography (HPLC) purification and
analytical HPLC analyses for radiochemical work were per-
formed on an Agilent 1200 Series instrument equipped with
multi‐wavelength detectors along with a flow count
radiodetector (Eckert & Ziegler, B‐FC‐3500 diode).
HPLC conditions:
Preparation of any of these compounds requires a 2‐
step or 3‐step synthesis with overall preparation times
ranging from 60 to 90 minutes. The objective of this work
is to improve the radiosynthesis of a maleimide
functionalized radiolabeling agents by using our newly
developed “Radiofluorination on the Sep‐Pak” method.
18
Herein, we report rapid synthesis of 6‐[ F]
Method A; Column: Phenomenex Luna (2) C18 column
(10 × 250 mm, 5 μm). Mobile phase: A: water (0.1%
TFA); B: acetonitrile (0.1% TFA). Isocratic: 45% B;
flow rate of 4 mL/min.
18
fluoropyridinealdehyde ([ F]5) and its coupling with a
maleimide functionalized amino‐oxy ligand to produce a
18
useful synthon ([ F]6) for site‐specific radiolabeling of
biomolecules in 30 minutes of total synthesis time.
Method B; Column: Agilent XDB C18 column
(
4.6 × 150 mm, 5 μm). Mobile phase: A: water (0.1%
TFA); B: acetonitrile (0.1% TFA). Gradient: 20% to
40% B in 10 minutes; flow rate of 1 mL/min.
Method C; Column: Agilent XDB C18 column
(4.6 × 150 mm, 5 μm). Mobile phase: A: water (0.1%
TFA); B: acetonitrile (0.1% TFA). Isocratic: 60% B;
flow rate of 1 mL/min.
2
| MATERIALS AND METHODS
The precursor 4‐formyl‐N,N,N‐trimethylanilinium trifluoro-
methanesulfonate (1) was purchased from ABX advanced
biochemical compounds (Radeberg, Germany). The non‐
radioactive cold standard 6‐fluoropyridinealdehyde was
obtained from Sigma Aldrich (St. Louis, MO, USA).
The precursor 6‐(N,N,N‐trimethylamino)nicotinaldehyde
2.1 | Precursors and cold standard
2
.1.1 | 6‐(N,N,N‐trimethylamino)
nicotinaldehyde trifluoromethanesulfonate
Scheme 1, 2)
19
trifluoromethanesulfonate (2),
1‐(6‐(aminooxy)hexyl)‐
and non‐radioactive cold stan-
dard of fluorine‐18 labeled maleimide derivative,
fluoronicotinaldehyde O‐(6‐(2,5‐dioxo‐2,5‐dihydro‐1H‐
13,20
1
H‐pyrrole‐2,5‐dione
(
The precursor was synthesized according to the literature
13
pyrrol‐1‐yl)hexyl) oxime, FPyMHO (6), were synthesized
by literature methods. All other chemicals and solvents
were received from Sigma Aldrich (St. Louis, MO, USA)
and used without further purification. Anhydrous solvents
were used for all radiolabeling reactions. Fluorine‐18 was
received from National Institutes of Health cyclotron facil-
method using 6‐chloronicotinaldehyde instead of 2,3,5,6‐
19
tetrafluorophenyl 6‐chloronicotinate.
Briefly, to a
tetrahydrofuran (THF, 2 mL) solution of 6‐chloro-
nicotinaldehyde (1.4 g, 9.9 mmol) under nitrogen was
added 1 M THF solution of trimethylamine (11 mL,
11 mmol), and the reaction was stirred at room tempera-
ture for 24 hours. The off‐white precipitate thus obtained
was collected and washed with cold (4°C) THF. The solid
ity (Bethesda, MD, USA). Chromafix 30‐PS‐HCO anion‐
exchange Sep‐Pak cartridges were purchased from
3

BASULI ET AL.
3
2
.1.3 | 6‐Fluoronicotinaldehyde O‐(6‐(2,5‐
dioxo‐2,5‐dihydro‐1H‐pyrrol‐1‐yl)hexyl)
oxime, FPyMHO, (Scheme 2, 6)
The compound was prepared according to the literature
13
method for a similar compound.
Briefly, to a solution of 1‐(6‐(aminooxy)hexyl)‐1H‐pyr-
role‐2,5‐dione. HCl (0.025 g, 0.10 mmol) in
dimethylformamide
(10
mL)
was
added
6‐
fluoronicotinealdehyde (0.018 g, 0.14 mmol). The mixture
was stirred for 30 minutes at room temperature. The solu-
tion was diluted with water and extracted with diethyl
ether. The diethyl ether extract was washed with brine
and dried (Na SO ). The solvent was removed under vac-
1
8
18
SCHEME 1 Synthesis of [ F]fluoroaryl aldehydes [ F]4 and
1
8
[
F]5
2
4
uum, and the residue was purified by flash column chro-
matography (silica gel, hexane/EtOAc = 70/30) to afford
0
.027 g (0.084 mmol, 84%) as a white powder.
1
H NMR (400 MHz, Chloroform‐d) δ 8.38 to 8.28 (m,
1
6
2
H), 8.17 to 8.05 (m, 2H), 6.97 (dd, J = 8.6, 2.9 Hz, 1H),
.70 (s, 2H), 4.18 (t, J = 6.6 Hz, 2H), 3.54 (t, J = 7.3 Hz,
1
3
H), 1.80 to 1.56 (m, 4H), 1.52 to 1.30 (m, 4H).
C
NMR (101 MHz, CDCl3)
δ
170.84, 163.94 (d,
J = 242.2 Hz), 146.77 (d, J = 15.3 Hz), 143.89, 138.46 (d,
1
8
SCHEME 2 Synthesis of 6‐[ F]fluoronicotinaldehyde O‐(6‐(2,5‐
J = 8.3 Hz), 134.04, 126.78 (d, J = 4.7 Hz), 109.95 (d,
1
8
dioxo‐2,5‐dihydro‐1H‐pyrrol‐1‐yl)hexyl) oxime, 6‐[ F]PyMHO,
19
J = 37.9 Hz), 74.50, 37.76, 28.86, 28.45, 26.49, 25.40.
F
1
8
(
[ F]6)
NMR (376 MHz, Chloroform‐d) δ ‐65.89. HRMS (ESI) cal-
culated mass for the parent C H FN O Na [M + Na],
16
18
3 3
342.1224, found 342.1228.
was suspended in anhydrous dichloromethane (50 mL), and
trimethylsilyl trifluoromethanesulfonate (2 mL) was added
over 10 minutes, followed by stirring at room temperature for
2
2
.2 | Radiosynthesis
18
2
0 minutes. The solvent was evaporated under reduced
pressure and washed with diethyl ether to afford compound
as an off‐white solid (1.7 g, 5.4 mmol, 55% yield) and was
.2.1 | 4‐[ F]fluorobenzaldehyde
2
18
(Scheme 1, [ F]4)
used without further purification.
1
Fluorine‐18 labeled target water (370 ‐ 1850 MBq) was
diluted with 2 mL water and passed through an anion‐
exchange cartridge (Chromafix 30‐PS‐HCO ). The car-
H NMR (400 MHz, Acetonitrile‐d ) δ 10.21 (s, 1H),
3
9
8
.10 (d, J = 2.1 Hz, 1H), 8.58 (dd, J = 8.6, 2.2 Hz, 1H),
13
.08 (d, J = 8.6 Hz, 1H), 3.61 (s, 9H); C NMR (101 MHz,
3
tridge was washed with anhydrous acetonitrile (6 mL)
CD CN) δ 190.08, 150.42, 141.31, 133.25, 117.35, 115.66,
3
18
19
and dried for 1 minute. The [ F]fluoride from the Sep‐
Pak was eluted (0.5 mL/min) with its quaternary ammo-
nium triflate salt (1, 10 mg) in 0.5 mL 1:4 acetonitrile:t‐
5
5.11; F NMR (376 MHz, CD CN) δ −79.32.
3
MS (ESI) calculated mass for the parent
C H F NO S, 313.06, found 165 [M − OTf].
11
14
3
4
18
butanol to produce compound [ F]3. The Sep‐Pak was
further eluted with 1‐mL acetonitrile, and eluent was col-
lected in the same vial. The reaction mixture was heated
2
2
.1.2 | 1‐(6‐(Aminooxy)hexyl)‐1H‐pyrrole‐
,5‐dione
1
8
at 120°C for 2 minutes to produce compound [ F]4. No
attempts were made to purify this product.
The compound was prepared according to the literature
13,20
method.
1
H NMR (400 MHz, Methanol‐d ) δ 6.82 (s, 2H), 4.04
18
4
2
.2.2 | 6‐[ F]fluoronicotinaldehyde
(
(
t, J = 6.4 Hz, 2H), 3.52 (t, J = 7.1 Hz, 2H), 1.76 to 1.65
m, 2H), 1.65 to 1.55 (m, 2H), 1.53 to 1.41 (m, 2H), 1.41
18
(
Scheme 1, [ F]5)
to 1.30 (m, 2H).
Fluorine‐18 labeled target water (370‐3700 MBq) was
diluted with 2‐mL water and passed through an anion‐
exchange cartridge (Chromafix 30‐PS‐HCO3). The
MS (ESI) calculated mass for the parent C H N O ,
10
16 2 3
+
2
12, found 213 [M + H] .

4
BASULI ET AL.
1
8
18
cartridge was washed with anhydrous acetonitrile (6 mL)
trapped product [ F]PyMHO, ([ F]6) was eluted from
the Sep‐Pak cartridge with 1.5‐mL acetonitrile. The iden-
tity and purity of the product were confirmed by analyti-
cal HPLC.
18
and dried under vacuum for 1 minute. The trapped [ F]
fluoride from the Sep‐Pak was eluted with the quaternary
ammonium triflate (2, 7‐10 mg) either in 0.5 mL 1:4 ace-
tonitrile:t‐butanol or in 0.5‐mL acetonitrile (0.5 mL/min)
through an activated Oasis MCX Plus cartridge to pro-
18
18
3 | RESULTS AND DISCUSSION
duce 6‐[ F]fluoronicotinaldehyde ([ F]5). The cartridge
was flushed with 1‐mL acetonitrile, which was collected
in the same vial for the next coupling reaction.
19
The precursor 2 (Scheme 1), 1‐(6‐(aminooxy)hexyl)‐1H‐
1
3,20
pyrrole‐2,5‐dione,
and the non‐radioactive cold stan-
13
dard (Scheme 2, 6) of fluorine‐18 maleimide derivative
were synthesized by literature methods. In this study,
packing material of the anion‐exchange cartridge
1
8
2
(
.2.3 | 6‐[ F]fluoronicotinaldehyde O‐(6‐
2,5‐dioxo‐2,5‐dihydro‐1H‐pyrrol‐1‐yl)hexyl)
1
8
18
(Chromafix 30‐PS‐HCO ) was reduced to half (~20 mg),
3
oxime, 6‐[ F]PyMHO, (Scheme 2, [ F]6)
which is capable of effectively trapping all the fluorine‐
18 from the target water. The elution efficiency was
slightly better (10%‐15%) compared with the unmodified
anion‐exchange cartridge. We wanted to test the [ F]
fluoride elution efficiency using a quaternary ammonium
triflate precursor (Scheme 1, 1) of benzaldehyde in differ-
ent solvents with the intention to directly incorporate the
fluoride in the product. Attempts to elute [ F]fluoride
from the Sep‐Pak with 1 in acetonitrile were unsuccessful
(Table 1); however, a solution of 1 in a mixture of aceto-
18
To the above solution of [ F]5 was added a solution of 1‐
6‐(aminooxy)hexyl)‐1H‐pyrrole‐2,5‐dione in (15 mg,
17 mM) in 1:1 methanol:1 N aqueous HCl (400 μL),
and the resulting mixture was heated at 80°C for
minutes. The product was purified by either Sep‐Pak
(
1
1
8
5
or HPLC using semi‐prep column. For Sep‐Pak purifica-
tion, the mixture was diluted with 8 mL of water and
passed through an activated Sep‐Pak plus C18 cartridge.
The cartridge was washed with water (10 mL) followed
by 15% acetonitrile in water (10 mL). The product was
eluted with 1.5‐mL acetonitrile to obtain the final com-
18
1
8
nitrile and t‐butanol (1:4) eluted fluorine‐18 as [ F]fluo-
18
ride salt [ F]3 (Scheme 1, Table 1). Quantitative
1
8
18
18
18
pound 6‐[ F]PyMHO ([ F]6). For HPLC purification,
the crude reaction mixture was diluted with 3‐mL water
and injected on the HPLC (conditions: method A). To
the collected HPLC fraction was added 10‐mL water and
passed through an activated Sep‐Pak plus C18 cartridge,
and the cartridge was washed with 5 mL of water. The
conversion of [ F]3 to the desired product, 6‐[ F]
18
fluorobenzaldehyde ([ F]4), was observed when the
1
8
eluted solution of [ F]3 (1:4 acetonitrile: t‐butanol) was
heated directly at 120°C for 2 minutes (Scheme 1). How-
ever, over 80% of activity was incorporated into the prod-
uct within 1 minute by passing 10 mg of quaternary
3
TABLE 1 Elution conditions from the Sep‐Pak (Chromafix 30‐PS‐HCO )
a
Precursor
1
Amount, mg
Solvent, 1 mL
Product
Eluted from the Sep‐Pak, %
1
8
b
5
Acetonitrile
[ F]3
0
1
8
1:4, acetonitrile: t‐butanol
[ F]3
88
99
1
8
c 11
Methanol
[ F]3
1
8
1
1
2
1
1:4, acetonitrile: t‐butanol
DMSO
[ F]3
18
65
c
5, 6
10
[ F]4
66‐77
1
8
15
10
5
Acetonitrile
[ F]5
89
91
1
8
1
:4, acetonitrile: t‐butanol
Acetonitrile
:4, acetonitrile: t‐butanol
[ F]5
1
8
b,d
2
2
2
[ F]5
80 ± 5
85 ± 3
1
8
b,d
1
[ F]5
1
8
1:4, acetonitrile: t‐butanol
[ F]5
63
c
18
5
10
DMSO
[ F]5
80 ± 6
a
Radiolabeling was performed with 370 to 740 MBq of fluorine‐18, precursor in 0.5‐mL solvent, then flush the cartridge with 1‐mL acetonitrile.
b
c
n ≥ 3.
Literature method (radiochemical yield).
d
71 ± 3% isolated yield.

BASULI ET AL.
5
ammonium triflate precursor (2) in acetonitrile through
the Sep‐Pak containing [ F]fluoride. Fluoride elution
(Figure 1B). The fluorine‐18 incorporation of current
method is comparable with literature method but in
18
5
efficiency was tested using different conditions
shorter times.
1
(Table 1). As previously observed for another product,
The synthesis of the maleimide functionalized labeled
18
Sep‐Pak elution of the labeled‐product was slightly better
with mixed solvents (1:4 acetonitrile: t‐butanol) and an
increased amount of precursor. The current Sep‐Pak
method of fluorination is at room temperature in absence
of any base; therefore, as expected no other major by‐
product (Figure 1A) was observed by analytical HPLC.
Most of the unreacted precursor was removed by passing
the crude reaction mixture through an activated Oasis
MCX plus cartridge. In a patent application, Olberg and
Svadberg reported 33% elution of radioactivity as a prod-
synthon ([ F]6) as well as the nonradioactive cold stan-
dard (6) is outlined in Scheme 2. The progress of the
radiolabeling reaction was monitored by analytical
HPLC, and >90% radiochemical conversion was observed
1
8
at 80°C in 5 minutes. The product ([ F]6) was purified
by using either Sep‐Pak or HPLC. The compound puri-
fied by Sep‐Pak was 90% radiochemically pure (Figure 2
A). The overall isolated radiochemical yield was 50 ± 9%
18
uct ([ F]5) using 20.3 mg of quaternary ammonium
triflate precursor (2) in 1:1 acetonitrile and t‐butanol
21
mixture.
18
The elution efficiency using 2 to produce [ F]5 was
5 ± 3% (uncorrected, n = 6) in a <5‐minute synthesis
8
time with a radiochemical purity of >98% by analytical
18
HPLC. The identity of the product ([ F]5) was confirmed
by comparing its HPLC retention time with co‐injected,
authentic
nonradioactive
6‐fluoronicotinaldehyde
1
8
18
18
FIGURE 1 HPLC analysis of ([ F]5). A, Crude reaction mixture;
B, Sep‐Pak purified product co‐injected with the non‐radioactive
standard. Method A, solid line, in‐line radiodetector; dotted line,
UV detector at 254 nm
FIGURE 2 HPLC analysis of 6‐[ F]PyMHO ([ F]6), A, purified
by Sep‐Pak method; B, purified by HPLC method; C, co‐injected
with the non‐radioactive standard. Method C, solid line, in‐line
radiodetector; dotted line, UV detector at 254 nm

6
BASULI ET AL.
(
decay‐corrected, n = 9) in a 30‐minute synthesis time
2. Basuli F, Zhang X, Woodroofe CC, Jagoda EM, Choyke PL,
Swenson RE. Fast indirect fluorine‐18 labeling of protein/peptide
using the useful 6‐fluoronicotinic acid‐2,3,5,6‐tetrafluorophenyl
prosthetic group: a method comparable to direct fluorination.
J Label Compd Radiopharm. 2017;60(3):168‐175. https://doi.org/
with a molar activity of 259 to 370 GBq/μmol. In a typical
18
radiosynthesis starting from 3626 MBq of [ F]fluoride,
443 MBq of product was obtained. The product was stable
1
in solution up to 2 hours of post‐synthesis. The crude prod-
uct was also purified by HPLC to remove the impurity
peaks (Figure 2B). The overall isolated radiochemical yield
was 43 ± 3% (decay‐corrected, n = 3) in a 45‐minute syn-
thesis time with a comparable molar activity. The identity
of the product [ F]6 (Scheme 2) was confirmed by com-
paring its HPLC retention time with co‐injected, authentic
nonradioactive standard (Figure 2C). T. M. Moore et al
reported another derivative of this thiol‐reactive prosthetic
10.1002/jlcr.3487
1
8
3
4
5
6
. Preshlock S, Tredwell M, Gouverneur V. F‐labeling of arenes
and heteroarenes for applications in positron emission tomogra-
phy. Chem Rev. 2016;116(2):719‐766. https://doi.org/10.1021/acs.
chemrev.5b00493
18
. van der Born D, Pees A, Poot AJ, Orru RVA, Windhorst AD,
Vugts DJ. Fluorine‐18 labelled building blocks for PET tracer
synthesis. Chem Soc Rev. 2017;46(15):4709‐4773. https://doi.
org/10.1039/C6CS00492J
18
group, 2‐[ F]FBAMPy, with a decay corrected yield of
3
. Kügler F, Ermert J, Coenen HH. Labeling of benzodioxin piper-
azines with fluorine‐18 as prospective radioligands for selective
imaging of dopamine D4 receptors. J Label Compd Radiopharm.
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0 ± 4% in 80 minutes of synthesis time.
2
013;56(12):609‐618. https://doi.org/10.1002/jlcr.3074
. Lemaire C, Libert L, Plenevaux A, Aerts J, Franci X, Luxen A.
4
| CONCLUSION
Fast and reliable method for the preparation of ortho‐ and
1
8
1
8
para‐[ F]fluorobenzyl halide derivatives: key intermediates for
the preparation of no‐carrier‐added PET aromatic radiopharma-
ceuticals. Journal of Fluorine Chemistry. 2012;138:48‐55. https://
doi.org/10.1016/j.jfluchem.2012.03.015
We
have
successfully
prepared
6‐[ F]
18
fluoronicotinaldehyde ([ F]5) on the Sep‐Pak within a
very short synthesis time (<5 minutes). Using [ F]5,
another useful thiol reactive prosthetic group, [ F]
FPyMHO ([ F]6), was synthesized with an decay‐
corrected radiochemical yield of 50 ± 9% in 30‐minute
synthesis time. This simple and fast radiolabeling proce-
dure at room temperature without azeotropic drying of
fluorine‐18 has potential applications in the preparation
of other useful fluorine‐18 labeled synthons.
18
18
1
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7
. Basuli F, Wu H, Griffiths GL. Syntheses of meta‐[ F]
18
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8
fluorobenzaldehyde and meta‐[ F]fluorobenzylbromide from
phenyl(3‐Formylphenyl) iodonium salt precursors. J Label
Compd Radiopharm. 2011;54(4):224‐228. https://doi.org/10.
1002/jlcr.1853
8
. Ichiishi N, Brooks AF, Topczewski JJ, Rodnick ME, Sanford MS,
Scott PJH. Copper‐catalyzed [ F]fluorination of (mesityl)(aryl)
18
iodonium salts. Org Lett. 2014;16(12):3224‐3227. https://doi.
org/10.1021/ol501243g
ACKNOWLEDGEMENTS
9
. Tredwell M, Preshlock SM, Taylor NJ, et al. A general copper‐
mediated nucleophilic F fluorination of arenes. Angew Chem
Int Ed. 2014;53(30):7751‐7755. https://doi.org/10.1002/anie.
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This project has been funded in whole or in part with fed-
eral funds from the National Cancer Institute, National
201404436
Institutes
of
Health,
under
contract
no.
HHSN261200800001E. The content of this publication
does not necessarily reflect the views or policies of the
Department of Health and Human Services, nor does
mention of trade names, commercial products, or organi-
zations imply endorsement by the U.S. Government.
10. Chun J‐H, Pike VW. Single‐step syntheses of no‐carrier‐added
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functionalized [ F]fluoroarenes as labeling synthons from
diaryliodonium salts. Org Biomol Chem. 2013;11(37):6300‐6306.
https://doi.org/10.1039/c3ob41353e
11. Richarz R, Krapf P, Zarrad F, Urusova EA, Neumaier B,
Zlatopolskiy BD. Neither azeotropic drying, nor base nor other
1
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additives: a minimalist approach to F‐labeling. Org Biomol
Chem. 2014;12(40):8094‐8099. https://doi.org/10.1039/C4OB0
ORCID
1
336K
Falguni Basuli http://orcid.org/0000-0001-7454-9002
Xiang Zhang http://orcid.org/0000-0002-5234-9410
1
1
2. Moore TM, Akula MR, Kabalka GW. Fluorine‐18 radiochemis-
try: a novel thiol‐reactive prosthetic group, [ F]FBAMPy.
Natural Science. 2016;8(01):1‐7.
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