Rapid and efficient synthesis of [18F]fluoronicotinamides, [18F]fluoroisonicotinamides and [18F]fluorobenzamides as potential pet radiopharmaceuticals for melanoma imaging

Article abstract of DOI:10.1002/jlcr.1869

In an attempt to simplify nucleophilic radiofluorination reactions to be amenable for automation, a series of [¹⁸F]fluoronicotinamides, [ ¹⁸F]fluoroisonicotinamides and [¹⁸F]fluorobenzamides were synthesized using one-step

Full text of DOI:10.1002/jlcr.1869

Research Article
Received 22 May 2010,
Revised 21 November 2010,
Accepted 22 November 2010
Published online 17 February 2011 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1869
Rapid and efficient synthesis of [18F]fluoro-
nicotinamides, [18F]fluoroisonicotinamides
and [18F]fluorobenzamides as potential pet
radiopharmaceuticals for melanoma imaging
Ã
I. Al Jammaz, B. Al-Otaibi, S. Okarvi, and J. Amartey
In an attempt to simplify nucleophilic radiofluorination reactions to be amenable for automation, a series of
[
18F]fluoronicotinamides, [18F]fluoroisonicotinamides and [18F]fluorobenzamides were synthesized using one-step synthetic
approach involving displacement reactions on trimethylammonium-nicotinamide, trimethylammonium-isonicotinamide
and trimethylammonium-benzamide precursors. Based on starting [18F]-fluoride, radiochemical yields and purities were
found to be greater than 90 and 97%, respectively, within 20 min synthesis time and, without high-performance liquid
chromatography purification. This synthetic approach holds great promise as a rapid and simple method for the automated
radiofluorination of [18F]fluoronicotinamides, [18F]fluoroisonicotinamides and [18F]fluorobenzamides with high radio-
chemical yield and very short preparation time.
Keywords: 18F-fluorination; 18F-fluoronicotinamide; 18F-fluoroisonicotinamide; 18F-fluorobenzamide; melanoma targeting; PET
radiopharmaceuticals
characterization of cancer, molecular assessment of treatment
effects and more fundamental understanding of the disease
process.15 Recently, N-(2-diethylaminoethyl)-4-[18F]fluorobenza-
Introduction
Advancement of scintigraphic tumor imaging is highly deter-
mined by the development of more tumor-specific radiotracers.
Selective high-affinity binding radiotracers have shown promises
in improvement of the specificity and sensitivity of nuclear
medicine imaging procedures. The widespread of melanin
pigmentation in most of melanoma tumor cells has been
targeted with radioiodinated aminoalkyl-iodobenzamides,
-nicotinamides and -isonicotinamides based radiopharmaceuti-
cals for diagnostic purposes. These efforts were initiated by the
synthesis and biological evaluation of N-(2-diethylaminoethyl)-4-
mide was synthesized using a sequence of reactions with more
than 2.5 h overall synthesis time.16 Biodistribution studies of this
compound showed a rapid and high melanotic tumor uptake
and low residual activity in normal tissues signifying the
enhanced imaging potential of this radiotracer. More recently,
series of [18F]fluoronicotinamides were prepared and displayed
high tumor uptake and rapid body clearance predominantly via
renal pathway.17 These radiofluorinated nicotinamides were
prepared in one radiosynthetic step, using [18F]fluoro to
chloronicotinamide exchange reaction under elevated tempera-
ture (1501C), followed by high performance liquid chromato-
graphy (HPLC) purification and the radiochemical yields of these
compounds were ranged between 35 and 55% in 40 min
synthesis time. As part of our on-going research effort to
develop precursors for radiofluorination of bioactive molecules,
we here report the synthesis of series of [18F]fluoronicotina-
mides, [18F]fluoroisonicotinamides and [18F]fluorobenzamides
using a rapid, simple and efficient synthetic approach.
[
125I]iodobenzamide two decades ago.1 The high melanotic
tumor uptake of iodobenzamide in melanoma-bearing mice has
led to the development of series of radioiodinated benzamide
compounds as potential melanoma imaging probes.2–8 Owing
to the high affinity of [123/131I]iodobenzamide radiotracers
toward melanocytes and favorable tissue distribution character-
istics, some of these radiotracers were further pursued in
melanoma patients and exhibited selective and sensitive
detection of melanoma and its metastases.9–13 Lately, a series
of [123I]iodonicotinamides were developed and biologically
evaluated as potential imaging and staging of metastatic
melanoma.14 These findings demonstrated that N-(2-diethyla-
minoethyl)-5-[123I]iodonicotinamide exhibits highest melanotic
tumor uptake and the nature of nicotinamide greatly con-
tributed to the rapid clearance from the body. With the
increased use of positron emission tomography in diagnostic
imaging, there has been great interest in the development of
positron-emitting radiopharmaceuticals for early detection and
Cyclotron and Radiopharmaceuticals Department, King Faisal Specialist Hospital
and Research Centre, P.O. Box 3354, Riyadh 11211, Kingdom of Saudi Arabia
*Correspondence to: I. Al Jammaz, Cyclotron and Radiopharmaceuticals
Department, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354,
Riyadh 11211, Kingdom of Saudi Arabia.
E-mail: jammaz@kfshrc.edu.sa
J. Label Compd. Radiopharm 2011, 54 312–317
Copyright r 2011 John Wiley & Sons, Ltd.

I. Al Jammaz et al.
stirred for 5 h then excess of excess thionylchloride and volatile
components were removed under reduced pressure. The
yellowish residue was re-solublilized in dichloromethane (5 mL)
followed by drop-wise addition of a mixture of N,N-diethy-
lethane-1,2-diamine (46 mL, 0.32 mmol) and triethylamine (50 mL,
0.36 mmol). Mixture was then refluxed for 3 h followed by
evaporation till dryness and column chromatography separation
using methanol:ethyl acetate (8:2) solvent system to yield 5a as
an oily yellowish material in 66% yield. The attained ES-MS [M1
Experimental
The chemicals used in the study were all analytical reagent
grade purchased from Aldrich and were used without further
purification unless stated. Acetonitrile (ACN) was kept over
molecular sieves. Sep-Pak cartridges were purchased from
Waters-Millipore. TLC-SG sheets were purchased from Gelman
Sciences Inc. HPLC analysis was carried out on Econosil C-18
reversed phase column (analytical, 250 mm  4.6 mm). The
solvent system used was non-linear gradient (eluant A, water
with 0.1% TFA; eluant B, ACN with 0.1% TFA; gradient, 0–60% B,
60–60% B and 60–0% B over 10 min each at flow rate of 1.0 mL/
min). A Jasco chromatographic system equipped with a variable
wavelength ultraviolet monitor and in tandem with a Canberra
flow through radioactivity detector was used. Ultraviolet
absorption was monitored at 254 nm. Chromatograms were
acquired and analyzed using BORWIN software. Mass spectro-
scopy was run on Quattra electrospray mass spectrometer (ES-
MS). NMR was run on JEOL (400 MHz) Spectrometer with TMS as
the reference.
1
1]1 = 240. H NMR (CDCl3): d 8.56 (d, 1H, H2), 8.42 (s, 1H, H5), d
7.81 (d, 1H, H3), d d 3.48 (q, 2H, H9), d 2.93 (t, 2H, H10), d 2.64 (q,
4H, H12,14), d 1.34 (t, 6H, H13,15).
The same general procedure A was applied to 6-fluoropyr-
idine-3-carboxylic acid 3b to produce (after column chromato-
graphy separation using methanol:ethylacetate (8:2) solvent
system) 5b as an oily yellowish material in 92% yield. The
attained ES-MS [M11]1 = 240. 1H NMR (CDCl3): d 8.73 (s, 1H, H2),
d 8.43 (q, 1H, H5), d 7.18 (d, 1H, H4), d 3.47 (q, 2H, H9), d 3.47 (q,
4H, H12,14), d 3.05 (t, 2H, H10), d 1.34 (t, 6H, H13,15).
2-fluoro-[N-(2-pyrrolidin-1-yl)ethyl)]isonicotinamide 5c, 6-fluoro-
[N-(2-pyrrolidin-1-yl)ethyl]nicotinamide 5d
N-[2-(diethylamino)ethyl]-2-fluoroisonicotinamide 5a, N-[2-
(diethylamino)ethyl]-6-fluoronicotinamide 5b
The above general procedure A was applied to the reaction of 2-
(pyrrolidin-1-yl)ethanamine (40.6 mL, 0.32 mmol) with com-
pounds 3a (50 mg, 0.35 mmol) and 3b (50 mg, 0.35 mmol),
respectively, followed by column chromatography separation
using methanol:ethyl acetate (8:2) solvent system, to give 5c
and 5d as oily yellowish residues in 70 and 88%, respectively.
Compounds 2, 3, 4, 7, 9, 10 and 14 in Schemes 1 and 2 were
synthesized utilizing the methods reported by AlJammaz et al.,18
Amartey et al.,19 Kilbourn and colleagues20 and Stocklin and
¨
colleagues21. As a general procedure A, 2-fluoropyridine-4-
carboxylic acid 3a, (50 mg, 0.35 mmol) was placed in a 25 mL
flask containing dichloromethane (5 mL) followed by the
addition of thionylchloride (500 mL, 10.25 mmol). Mixture was
1
The attained ES-MS [M11]1 = 238 for both 5c and 5d. H NMR
(CDCl3): d 8.64 (d, 1H, H2), d 8.42 (s, 1H, H5), d 7.71 (d, 1H, H3), d
3.47 (q, 2H, H9), d 3.01 (t, 2H, H10), d 2.77 (t, 4H, H12,15), d 1.34
(q, 4H, H13,14) for 5c and d 8.72 (s, 1H, H2), d 8.40 (d, 1H, H5), d
7.16 (d, 1H, H4), d 3.46 (q, 2H, H9), d 3.02 (t, 2H, H10), d 1.85 (t,
4H, H12,15), d 1.36 (q, 4H, H13,14) for 5d.
CH
CH
COOH
Olah's
reagent
KMnO
N
F
N
NH
N
F
N-[2-(diethylamino)ethyl]-4-fluorobenzamide 8a, 4-fluoro-
[N-(2-pyrrolidin-1-yl)ethyl]benzamide 8b
1
2
3
SOCl
General procedure A was applied to the reaction of 4-fluoro-
benzoic acid 6 (150 mg, 1.07 mmol) with N,N-diethylethane-1,2-
diamine (138 mL, 0.96 mmol) and 2-(pyrrolidin-1-yl)ethanamine
(122 mL, 0.96 mmol), respectively, followed by column chroma-
tography separation using methanol:ethyl acetate (8:2) solvent
system, to furnish 8a and 8b as oily colorless residues in 74 and
79% yields, respectively. The attained ES-MS [M11]1 = 239 for
8a and 237 for 8b. 1H NMR (CDCl3): d 7.84 (dd, 2H, H3,5), d 7.18
(dd, 2H, H2,6), d 3.48 (q, 2H, H9), d 2.65 (m, 6H, H10,12,14), d 1.10
(t, 6H, H13,15) for 8a and d 7.87 (dd, 2H, H3,5), d 7.19 (d, 2H,
H2,6), d 3.54 (q, 2H, H9), d 2.72 (t, 2H, H10), d 2.63 (q, 4H, H12,15),
d 1.82 (t, 4H, H13,14) for 8b.
O
COCl
RCH CH NH
RCH CH NH / TEA
N
N
F
F
5
4
H
O
O
O
NH
O
Cl
R
N-[2-(diethylamino)ethyl]-2-(dimethylamino)isonicotinamide
11a, N-[2-(diethylamino)ethyl]-6-(dimethylamino)nicotinamide
11b
RCH CH NH / TEA
SOCl
General procedure A was applied to the reaction of 2-(dimethyl-
amino)pyridine-4-carboxylic acid 9a (150 mg, 0.9 mmol) and
F
F
F
6
8
7
6-(dimethylamino)pyridine-3-carboxylic
acid
9b
(150 mg,
0.9mmol) with N,N-diethylethane-1,2-diamine (146 mL, 0.81mmol),
followed by column chromatography separation using methano-
l:ethyl acetate (8:2) solvent system, to furnish 11a and 11b as oily
yellowish residues in 56 and 64% yields, respectively. The attained
R = N(CH CH ) and N
Scheme 1. Synthesis of the reference fluoroisonicotinamide, fluoronicotinamide
(5a-d) and fluorobenzamide (8a,b) compounds.
J. Label Compd. Radiopharm 2011, 54 312–317
Copyright r 2011 John Wiley & Sons, Ltd.
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I. Al Jammaz et al.
COOH
COCl
CONHCH2CH2R
SOCl2
CH3
RCH2CH2NH2/ TEA
CH3
CH3
CH3
N
N
N
N
N
N
CH3
CH3
9
10
11
CONHCH2CH2R
CF3SO3CH3
N+
CH3
CH3
N
H3C
12
O
OH
O
Cl
O
NH
R
SOCl2
RCH2CH2NH2/ TEA
N
N
N
H3C
CH3
H3C
CH3
NH
H3C
CH3
13
14
15
O
R
CF3SO3CH3
R = N(CH2CH3)2 and N
H3C
N+ CH3
CH3
16
Scheme 2. Synthesis of trimethylammonium isonicotinamide, nicotinamide (12a-d) and benzamide (16a,b) triflate precursors.
1
ES-MS [M11]1 = 265 for both 11a and 11b. H NMR (CDCl3): d (s, 6H, H6) for 11c and d 8.94 (s, 1H, H2), d 8.66 (d, 1H, H5), d 7.26
8.65 (d, 1H, H2), d 8.49 (s, 1H, H5), d 8.05 (d, 1H, H3), d 3.77 (d, 1H, H4), d 3.47 (q, 2H, H9), d 2.17 (t, 2H, H10), d 1.95 (t, 4H,
(q, 2H, H9), d 3.36 (m, 6H, H10,12,14), d 1.36 (q, 6H, H13,14), d 1.24 H12,15), d 1.35 (t, 4H, H13,14), d 1.24 (s, 6H, H6), for 11d.
(s, 6H, H6) for 11a and d 8.95 (s, 1H, H2), d 8.35 (d, 1H, H5), d 7.65
(d, 1H, H4), d 3.57 (q, 2H, H9), d 3.18 (t, 2H, H10), d 1.77 (q, 4H,
H12,14), d 1.34 (t, 6H, H13,15), d 1.24 (s, 6H, H6) for 11b.
4-[2-(diethylamino)ethylaminocarbonyl]pyrid-2-yltrimethyl-
ammonium triflate 12a, 3-[2-(diethylamino)ethylaminocar-
bonyl]pyrid-6-yltrimethylammonium triflate 12b
2-(dimethylamino)-N-[2-(pyrrolidin-1-yl)ethyl]isonicotinamide
11c, 6-(dimethylamino)-N-[2-(pyrrolidin-1-yl)ethyl]nicotinamide
11d
As a general procedure B, compounds 11a (120 mg, 0.45 mmol)
and 11b (120 mg, 0.45 mmol) were dissolved in dry dichloro-
methane (3 mL) in separate flasks and were purged with
General procedure A was applied to the reaction of compounds nitrogen for 5 min. Methyl trifluoromethanesulfonate (52 mL,
9a (150 mg, 0.9 mmol) and 9b (150 mg, 0.9 mmol) with 2- 0.45 mmol) was added to both solutions through rubber
(pyrrolidin-1-yl)ethanamine (103 mL, 0.96 mmol) followed by septum. The mixtures were stirred at ambient temperature for
column chromatography separation using methanol:ethyl acet- overnight. Reaction mixtures were then concentrated under
ate (8:2) solvent system to furnish 11c and 11d as oily yellowish reduced pressure to obtain a yellowish paste. Upon treatment
residues in 56 and 66%, respectively. The attained ES-MS [M11] with cold ether, yellowish oily residues were formed, separated
1 = 263 for both 11c and 11d. 1H NMR (CDCl3): d 8.65 (d, 1H, H2), out and dried in a desiccator to give 12a and 12b in 85 and 94%
d 8.24 (s, 1H, H5), d 7.55 (d, 1H, H3), d 3.73 (q, 2H, H9), d 2.17 yields, respectively. The attained ES-MS [M11]1 = 280 for both
1
(t, 2H, H10), d 2.09 (t, 4H, H12,15), d 1.37 (q, 4H, H13,14), d 1.24 12a and 12b. H NMR (CDCl3): d 8.65 (d, 1H, H2), d 8.50 (s, 1H,
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I. Al Jammaz et al.
H5), d 8.06 (d, 1H, H3), d 3.77 (q, 2H, H9), d 3.37 (m, 6H, (5 mg) and potassium carbonate (1 mg) in ACN:H2O solution
H10,12,14), d 1.38 (q, 6H, H13,14), d 1.24 (s, 9H, H6) for 12a and d (950 mL:50 mL), followed by azeotropic evaporation to dryness
8.97 (s, 1H, H2), d 8.36 (d, 1H, H5), d 7.56 (d, 1H, H4), d 3.54 (q, 2H, with aliquots of ACN. The solid residue was resolubilized in ACN
H9), d 3.19 (t, 2H, H10), d 1.77 (q, 4H, H12,14), d 1.36 (t, 6H, (0.2 mL) containing one of the aryltrimethylammonium triflate
H13,15), d 1.24 (s, 9H, H6), for 12b.
precursors 12a–d (2 mg). The reaction mixture was heated in
capped 2 mL reaction-vial at 901C for 5 min. The [18F]-5a–d
4-[2-(pyrrolidin-1-yl)ethylaminocarbonyl] pyrid-2-yltrimethyl- products were taken up in ether (2 Â 1 mL) and passed through
ammonium triflate 12c, 3-[2-(pyrrolidin-1-yl)ethylaminocar-
bonyl] pyrid-6-yltrimethylammonium triflate 12d
Sep-Pak silica cartridge. The ether solution was evaporated to
dryness under gentle stream of nitrogen, then residues were
resolubilized in saline and passed through 0.22 mm pore mem-
brane filter for further studies. Radiochemical yields for [18F]-5a-d
were 9271.2, 9372.2, 9272.1 and 9371.8%, respectively.
General procedure B was applied to the reaction of compounds
11a (120 mg, 0.45 mmol) and 11b (120 mg, 0.45 mmol) with
methyl trifluoromethanesulfonate (52 mL, 0.45 mmol) to furnish
12c and 12d as oily yellowish residues in 75 and 70% yields,
respectively. The attained ES-MS [M11]1 = 278 for both 11c and
11d. 1H NMR (CDCl3): d 8.65 (d, 1H, H2), d 8.25 (s, 1H, H5), d 7.54
(d, 1H, H3), d 3.72 (q, 2H, H9), d 2.15 (t, 2H, H10), d 2.09 (t, 4H,
H12,15), d 1.37 (q, 4H, H13,14), d 1.24 (s, 9H, H6) for 11c and d
8.95 (s, 1H, H2), d 8.65 (d, 1H, H5), d 7.25 (d, 1H, H4), d 3.48 (q, 2H,
H9), d 2.15 (t, 2H, H10), d 1.96 (t, 4H, H12,15), d 1.35 (t, 4H,
H13,14), d 1.24 (s, 9H, H6) for 11d.
N-[2-(diethylamino)ethyl][18F]-4-fluorobenzamide [18F]-8a, [18F]-4-
fluoro-[N-(2-pyrrolidin-1-yl)ethyl]benzamide [18F]-8b
The desired compounds [18F]-8a,b were radiofluorinated using the
arylmethylammonium triflate precursors 16a,b (5 mg) and follow-
ing the radiofluorination procedure mentioned above. Final
products [18F]-8a,b were resolubilized in saline and passed through
0.22 mm pore membrane filter for further studies. Radiochemical
yields for [18F]-8a,b were 9172.2 and 92.71.9%, respectively.
N-[2-(diethylamino)ethyl]-4-(dimethylamino) benzamide 15a,
4-(dimethylamino)-N-[(2-pyrrolidin-1-yl)ethyl] benzamide 15b
Partition coefficient
General procedure A was applied to the reaction of 4-
(dimethylamino)benzoic acid 13a (150 mg, 0.91 mmol) with
N,N-diethylethane-1,2-diamine (118 mL, 0.82 mmol) and 2-(pyrro-
lidin-1-yl)ethanamine (104 mL, 0.82 mmol), respectively, followed
by column chromatography separation using methanol:ethyl
acetate (8:2) solvent system, to furnish 15a and 15b as oily
colorless residues in 52 and 55% yields, respectively. The
attained ES-MS [M11]1 = 263 for 15a and 261 for 15b. 1H
NMR (CDCl3): d 7.79 (dd, 2H, H3,5), d 6.90 (dd, 2H, H2,6), d 3.25 (q,
2H, H9), d 2.60 (m, 6H, H10,12,14), d 1.22 (s, 6H, H4), d 1.12 (t, 6H,
H13,15) for 15a and d 7.95 (dd, 2H, H3,5), d 7.29 (d, 2H, H2,6), d
3.56 (q, 2H, H9), d 2.52 (t, 2H, H10), d 2.31 (q, 4H, H12,15), d 1.89
(t, 4H, H13,14), d 1.21 (s, 6H, H4) for 15b.
100 mL of the final solution of any of the radiofluorinated
compounds ([18F]-5a-d or [18F]-8a,b), were added into a test
tube each containing 1 mL of n-octanol and 0.9 mL of buffered
water (pH = 7.3). The tubes were shaken for 1 min. After partial
separation of the phases by gravity, 0.7 mL of each phase was
transferred to separate tubes and centrifuged at 5000 rpm for
5 min. Duplicate 0.2 mL aliquots of each phase were taken for
g-radioactivity measurement and the partition coefficient was
determined by the function: Partition coefficient = Log10 (counts
in n-octanol layer/counts in aqueous layer).
Results and discussion
Chemistry
4-[2-(diethylamino)ethylaminocarbonyl]phenyltrimethylam-
monium triflate 16a, 4-[2-(pyrrolidin-1-yl)ethylaminocarbo-
nyl]phenyltrimethylammonium triflate 16b
Scheme 1 outlines the synthesis of reference compounds
N-[2-(diethylamino)ethyl]-2-fluoroisonicotinamide 5a, N-[2-(diethyla-
mino)ethyl]-6-fluoronicotinamide 5b, 2-fluoro-[N-(2-pyrrolidin-1-yl)-
ethyl)]isonicotinamide 5c, 6-fluoro-[N-(2-pyrrolidin-1-yl)ethyl]nicoti-
namide 5d, N-[2-(diethylamino)ethyl]-4-fluorobenzamide 8a and
4-fluoro-[N-(2-pyrrolidin-1-yl)ethyl]benzamide 8b using the general
procedure A. These compounds were characterized by physical,
chromatographic and spectral data and were in agreement with
the anticipated structures (see the experimental part). The desired
reference compounds 5a–d and 8a,b were obtained in reasonably
good to excellent chemical yield (66–92%) and in greater than 95%
chemical purity after column chromatography as colorless oil for
the latter and yellowish oily material for the former. All 5a–d and
8a,b compounds were eluted at ꢀ9.4 and ꢀ10.5 min, respectively,
using analytical HPLC column. Scheme 2 entails several reaction
sequences for the preparation of intermediates, N-[2-(diethylamino)
ethyl]-2-(dimethylamino)isonicotinamide 11a, N-[2-(diethylamino)
ethyl]-6-(dimethylamino)nicotinamide 11b, 2-(dimethylamino)-N-
[2-(pyrrolidin-1-yl)ethyl]isonicotinamide 11c, 6-(dimethylamino)-N-
[2-(pyrrolidin-1-yl)ethyl]nicotinamide 11d, N-[2-(diethylamino)ethyl]-
General procedure B was applied to the reaction of compounds
15a (125 mg, 0.47 mmol) and 15b (125 mg, 0.47 mmol) with
methyl trifluoromethanesulfonate (54 mL, 0.47 mmol) to provide
16a and 16b as oily yellowish residues in 54 and 65% yields,
respectively. The attained ES-MS [M11]1 = 278 for 16a and 276
1
for 16b. H NMR (CDCl3): d 7.79 (dd, 2H, H3,5), d 6.94 (dd, 2H,
H2,6), d 3.21 (q, 2H, H9), d 2.65 (m, 6H, H10,12,14), d 1.22 (s, 9H,
H4), d 1.19 (t, 6H, H13,15) for 16a and d 7.77 (dd, 2H, H3,5), d
6.92 (d, 2H, H2,6), d 3.31 (q, 2H, H9), d 2.52 (t, 2H, H10), d 2.06 (q,
4H, H12,15), d 1.86 (t, 4H, H13,14), d 1.22 (s, 9H, H4) for 16b.
Radiosynthesis
N-[2-(diethylamino)ethyl][18F]-2-fluoroisonicotinamide
[18F]-5a,
N-[2-(diethylamino)ethyl][18F]-6-fluoronicotinamide [18F]-5b, [18F]-
2-fluoro-[N-(2-pyrrolidin-1-yl)ethyl)]isonicotinamide [18F]-5c, [18F]-
6-fluoro-[N-(2-pyrrolidin-1-yl)ethyl]nicotinamide [18F]-5d
Aqueous [18F]-fluoride was produced by the 18O (p,n) 18F 4-(dimethylamino)benzamide 15a, 4-(dimethylamino)-N-[(2-pyrroli-
reaction. The fluoride activity (2–10 mCi, 74–370 MBq) was din-1-yl)ethyl]benzamide 15b and their corresponding aryltrimethy-
trapped on ion exchange cartridge, eluted with Kryptofix 2.2.2 lammonium triflate precursors 12a–d and 16a,b. The intermediates
J. Label Compd. Radiopharm 2011, 54 312–317
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I. Al Jammaz et al.
11a–d and 15a,b were obtained using general procedure A, as step. The key precursors aryltrimethylammonium triflates 12a–d
colorless oil for the latter and yellowish oily material for the former and 16a,b were treated using classical catalyzed nucleophlic
in good chemical yield (52–66%) and high purity (97%) after substitution on an ammonium-leaving group with no-carrier-
column chromatography. Methyl trifluoromethanesulfonate was added radiofluoride as described by Al Jammaz et al.18 and
used to convert intermediates 11a–d and 15a,b to their 12a–d, Kilbourn and colleagues20. The final radiofluorinated com-
and 16a,b triflate precursors using the general procedure B (see the pounds [18F]-5a-d and [18F]-8a,b were taken up by ether, which
experimental part). The ammonium triflate precursors were was followed by passing through Sep-Pak silica cartridge to
obtained in good to excellent chemical yield (54–94%) and in remove polar impurities before evaporation to dryness and then
greater than 97% chemical purity as yellowish oil material for 12a–d dilution with saline for further studies. The overall radiochemical
and colorless oily substance for 16a,b. These precursors were yields for all these radiotracers were constantly greater than 90%
characterized by physical, chromatographic and spectral data and (based on starting [18F]-fluoride) and radiochemical purities
were in agreement with the anticipated structures (see the were always greater than 97% as determined by HPLC
experimental part).
(Figures. 1 and 2) and confirmed by TLC-SG. By avoiding
multi-step radiosynthesis and HPLC purification step for the
preparation of [18F]fluoronicotinamides and [18F]fluorobenz-
amides reported recently16,17, the total synthesis time for these
radiotracers was reduced to less than 20 min. In addition, the
measured specific activity for radiofluorinated compounds [18F]-
5a–d and [18F]-8a,b were always 41000 mCi/mmol. Hence,
these radiofluorinated compounds would be suitable for
biochemical studies such as radioligand binding assays. This
synthetic approach in comparison with the other methods16,17
appears to be advantageous and holds considerable promise in
the synthesis of [18F]-fluoroisonicotinamides, [18F]-fluoronicoti-
namides and [18F]-fluorobenzamides in high radiochemical yield
(490%, based on starting [18F]-fluoride), in a shorter synthesis
time (o20 min), using a less laborious procedure and being
amenable for automation.
Radiochemistry
The rapid and efficient synthetic approach for the preparation of
[18F]-5a, [18F]-5b, [18F]-5c, [18F]-5d, [18F]-8a and [18F]-8b
(Scheme 3) was performed with only one simple radiosynthetic
CONHCH2CH2R
CONHCH2CH2R
18
N+
CH3
CH3
N
N
F
H3C
[
18F]-5a-d
12
Kryptofix 222/K CO
F/CH
O
NH
H
Moreover, the calculated partition coefficient for radiofluori-
nated compounds [18F]-5a–d and [18F]-8a,b were found around
À0.7 and 10.8, respectively, representing a low degree of
lipophilicity for the former and moderate degree of lipophilicity
for the latter compounds.
O
NH
R
R
Conclusion
H3C
N+ CH3
CH3
18F
We have developed synthetic schemes leading to the procure-
ment of key precursors needed for rapid and one-step radio-
fluorination method for the production of series of
[18F]fluoroisonicotinamides and -nicotinamides 5a–d and
[18F]fluorobenzamides 8a,b. The overall radiochemical yields
for both [18F]-5a–d and [18F]-8a,b radiotracers were greater than
[
18F]-8a,b
16
R = N(CH2CH3)2 and N
Scheme 3. Radiosynthesis of [18F]fluoroisonicotinamides, [18F]fluoronicotinamides
([18F]-5a-d) and [18F]fluorobenzamides ([18F]-8a,b) compounds.
Figure 1. HPLC radiochromatograms of [18F]fluoroisonicotinamides 5a (A) and [18F]fluoronicotinamides 5b (B).
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J. Label Compd. Radiopharm 2011, 54 312–317

I. Al Jammaz et al.
Figure 2. HPLC radiochromatograms of [18F]fluorobenzamides 8a,b (A and B).
90% (based on starting [18F]-fluoride) with total synthesis time of
less then 20 min. Radiochemical purities of these radiotracers
were always greater than 97% without the need of HPLC
purification, which makes this method a simple and amenable
for automation.
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Acknowledgements
The authors wish to thank Mr. Mohamed Al-Amoudi for the MS
analysis. This project was supported by the International Atomic
Energy Agency (SAU ]15331) and Research Center of the King
Faisal Specialist Hospital & Research Center (RAC ]2040027).
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