Efficient methods for the synthesis of 5-(4-[18F]fluorophenyl)- 10,15,20-tris(3-methoxyphenyl)porphyrin as a potential imaging agent for tumor

Article abstract of DOI:10.1002/jlcr.992

F-18-labeled porphyrins, the potential tracing and detecting agents for tumor have been synthesized and characterized by two convenient routes: one is a mixed aldehyde condensation, which involves acid-catalyzed condensation of pyrrole, m-anisaldehyde and

Full text of DOI:10.1002/jlcr.992

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 749–758.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.992
Research Article
Efficient methods for the synthesis of 5-(4-[18F]fluoro-
phenyl)-10,15,20-tris(3-methoxyphenyl)porphyrin
as a potential imaging agent for tumory
Rajesh R. Kavali1, Byung Chul Lee1, Byung Seok Moon2, Seung Dae Yang2,
Kwon Soo Chun2, Chang Woon Choi2, Chang-Hee Lee3 and Dae Yoon Chi1,*
1 Department of Chemistry, Inha University, 253 Yonghyundong Namgu,
Inchon 402-751, Korea
2 Laboratory of Cyclotron Application, Department of Nuclear Medicine, Korea
Institute of Radiological and Medical Science, Seoul 139-706, Korea
3 Department of Chemistry, Kangwon National University, Chunchon,
Kangwon 200-701, Korea
Summary
F-18-labeled porphyrins, the potential tracing and detecting agents for tumor have
been synthesized and characterized by two convenient routes: one is a mixed aldehyde
condensation, which involves acid-catalyzed condensation of pyrrole, m-anisaldehyde
and 4-[18F]fluorobenzaldehyde. The other is the acid-catalyzed condensation of
tetrapyrrane with 4-[18F]fluorobenzaldehyde. The synthetic methodologies including
solvents, reaction concentrations and catalysts are optimized for radiolabeled
porphyrins. The methods also provide the desired product in reasonable radio-
chemical yield (20–26%) compared with those of cold chemical synthesis (1–3%) and
with high radiochemical purity (>95%). The methods described here would be
effective and convenient ways to produce radiolabeled porphyrin. Copyright # 2005
John Wiley & Sons, Ltd.
Key Words: porphyrin; fluorine-18; 18F-porphyrin; tetrapyrrane; tumor imaging; PET
Introduction
The tetrapyrrolic macrocycles play highly diverse roles in biological systems.1
The more recent and promising applications of porphyrin derivatives in
*Correspondence to: D. Y. Chi, Department of Chemistry, Inha University, 253 Yonghyundong Namgu,
Inchon 402-751, Korea. E-mail: dychi@inha.ac.kr
yPart of this work was presented at the 15th ISRC, Conference, Australia.
Contract/grant sponsor: National Research Laboratory Program
Contract/grant sponsor: Korea Institute of Radiological and Medical Sciences
Copyright # 2005 John Wiley & Sons, Ltd.
Received 18 May 2004
Revised 24 January 2005
Accepted 30 January 2005

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R. R. KAVALI ET AL.
medicine are in the diagnostic detection and treatment of tumors.2,3 The
porphyrins have been recognized as one of the most important prosthetic
groups in biological systems and the diverse chemistry performed by natural
porphyrins has inspired works in various field of chemistry.4,5 Porphyrin
derivatives have been synthesized in various way and their affinities for tumor
tissues in relation with the nature of the side chain and the mechanism of their
physico-chemical action have been studied.6 Among those reported porphyr-
ins, 5,10,15,20-tetra(3-hydroxyphenyl)chlorin has shown promising activity
and tissue selectivity in photonecrosis. The studies indicated that the meta-
isomer of four meso-hydroxyphenyl groups shows 25–30 times more potency
than haematoporphyrin derivatives in sensitizing tumors in vivo.7
Positron emission tomography (PET) is widely used for the medical imaging
and fluorine-18 (t1=2 ¼ 110 min) is a very attractive radionuclide for the
labeling of organic molecules as PET radiotracers, because of its many
favorable characteristics including small steric size, stable bonding to carbon,
convenient half life, low positron energy and ease of production.8,9 Although
many drugs based on porphyrin increase the radiosensitivity of hypoxic cells
in vitro and some of them show marked therapeutic effects in tumor models,
clinical applications have been failed because of insufficient uptake of drugs in
solid tumors and neurotoxicity of the drugs.10–13 Thus the development of
radiosensitizers with high tumor affinity and less neurotoxicity is essential for
their clinical application. As the target compound has a structural resemblance
to 5,10,15,20-tetra(3-hydroxyphenyl)chlorin, the target compound will have a
chance to be useful radiopharmaceuticals. Herein, we report the practical and
convenient synthesis of potential radiotracer, the fluorine-18-labeled title
compound via two different approaches. Is it not only almost impossible to
prepare 3-[18F]fluorobenzaldehyde, but also 4-[18F]fluorobenzaldehyde could
easily be prepared, we used 4-[18F]fluorobenzaldehyde in two different
approaches.
Results and discussion
An essential purpose in designing 18F-associated porphyrins is that these
compounds could be used as a radiotracer and can play an important role in
detecting tumor. Practically, there were no synthetic reports of the directly
fluorine-18 radiolabeled porphyrins. The unlabeled porphyrin 1 could be
synthesized as shown in Scheme 1 (Methods A and B). The synthesis has been
achieved by two methods: one is a mixed aldehyde condensation (Method A)
and another is a stepwise approach (Method B). Initially the cold authentic
compound was prepared by Method A as shown in Scheme 1. Condensation
of pyrrole (4 equiv), 3-methoxybenzaldehyde (3 equiv), and 4-fluorobenzalde-
hyde (1 equiv) in the presence of catalytic amount of trifluoroacetic acid (TFA)
followed by 2,3-dichloro-5,6-dicyanoquinone (DDQ) oxidation afforded
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Method A
Method B
Scheme 1. Method A: Reagents. (a) TFA, CH2Cl2, rt, 40 min (R=19F); ice-bath
5 min, rt, 20 min (R=18F); (b) DDQ, rt, 1 h (R=19F); 20 min (R=18F). Method
B. Reagents. (a) TFA, rt, 10 min; (b) TFA, CH2Cl2, rt, 10 min; (c) TFA, rt,
40 min (R=19F); ice-bath 5 min, rt, 20 min (R=18F); (d) DDQ, rt, 1 h (R=19F);
20 min (R=18F)
5-(4-fluorophenyl)-10,15,20-tris(3-methoxyphenyl)porphyrin (1) in 1% yield.
As an alternative approach, the step-by-step synthesis (Method B) was
performed. The condensation of 3-methoxybenzaldehyde with pyrrole, a large
excess of pyrrole present (40 equiv), catalyzed by TFA, afforded meso-(3-
methoxyphenyl)dipyrromethane (2).14,15 Then the reaction of dipyrromethane
2 (2 equiv) with 3-methoxybenzaldehyde (1 equiv) catalyzed by TFA at rt gave
tetrapyrrane 316,17 in moderate yield (18–20%). This result indicates the
cleavage of 5-(3-methoxyphenyl)dipyrromethane (2) by acid to generate
free pyrrole. The product was easily separated by flash column chromato-
graphy on neutralized silica, using EtOAc/hexane (1:9) as an eluant. The use
of neutralized silica (mildly basic) prevents the tetrapyrrane from the
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R. R. KAVALI ET AL.
decomposition usually observed on slightly acidic conditions. The dipyrro-
methane 2 and tetrapyrrane 3 are stable in the purified form upon storage at
08C under nitrogen atmosphere and absence of light. High-purity dipyrro-
methane and tetrapyrrane seems to be essential for their application in the
synthesis of non-symmetrically meso-substituted porphyrins. The tetrapyrrane
3 is then condensed with the 4-fluorobenzaldehyde, catalyzed by TFA followed
by DDQ oxidation, to afford the cold authentic 1 in 3%. All the spectroscopic
data were in conformity with the cold authentic prepared by Method A. The
radiolabeled porphyrins were synthesized by the same methodologies as shown
in Scheme 1 (Methods A and B) and the yields were moderately low.
The preparation of 4-[18F]fluorobenzaldehyde has been achieved by the
nucleophilic aromatic substitution of (4-formylphenyl)trimethylammonium
triflate by [18F]fluoride ion in DMSO at 908C within 5 min in overall 85% yield
according to the known procedure.18,19 The formation of 4-[18F]fluoroben-
zaldehyde was characterized by radio-thin layer chromatography (TLC) and
change of solvent from DMSO to CH2Cl2 was performed by C-18 Sep-
Pak.18,19 We have carried out number of experiments to optimize the condition
and solvents for the synthesis of radiolabeled porphyrin. The experimental
results were illustrated in Tables 1 and 2. Table 1 summarizes the experiments
carried out to optimize the reaction of synthesis of 4 conditions such as
solvent concentrations, reaction time and temperature and compare with
Methods A and B. We found that radiolabeled porphyrinogen 4 was prepared
in an ice-bath for 5 min and rt for 20 min in 222.5 ml of CH2Cl2 and 2.5 ml of
TFA. It was also found that the Method B gave a maximum radiochemical
yield (22.8%, Table 1, entry 6). The radiochemical yield of the mixed
aldehydes condensation (Method A) was lower than Method B (12.7%,
Table 1, entry 2).
We attempted to check the formation of labeled porphyrins by tracing
radioactivity in the intermediate before final DDQ oxidation. Indeed, we
were able to detect the formation of porphyrinogen 4 by radio-TLC
(4-[18F]fluorobenzaldehyde, Rf ¼ 0:8; porphyrinogen, Rf ¼ 0:5, EtOAc/hex-
ane (2:8)). Hence, the optimized the solvent volume, reaction time, and
temperature (Table 1, entry 6) were applied to the whole experiment with
DDQ oxidation, which provided the title compound [18F]1 (Rf ¼ 0:6, EtOAc/
hexane (2:8), Table 2, entry 2). Deviation from the 2.5 ml of TFA did not
improve the yield (Table 2, entries 1 and 3). Since we thought that the change
of solvents might lead to increase in the yield of porphyrins, we also used
various solvents such as CH3CN, THF and toluene (Table 2, entries 6–8), but
none of these solvents gave satisfactory results. The obtained results were
represented in Table 2. The formation of the radiolabeled porphyrin was
confirmed on the basis of radio-TLC (Rf ¼ 0:6, EtOAc/hexane=2/8)
(Figure 1) which is well matched with that of the cold authentic. Some
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Table 1. Optimization of reaction condition for the radiolabeled porphyrinogen 4
Reaction time (min)
Products (%)
Entry
Precursora CH2Cl2 Ice-bath rt 508C Unknown 4b
Starting
material
recovered
( ml)
time
time time peakb
1
2
3
4
Pyrrole
(n=2)
Pyrrole
(n=3)
Pyrrole
(n=2)
Pyrrole
(n=2)
200
200
200
200
5
5
10
20
–
–
–
–
–
72.8 ꢀ 3.3
5.4 ꢀ 1.9 21.2 ꢀ 2.0
86.7 ꢀ 0.6 12.7 ꢀ 0.9
–
5
46.8 ꢀ 1.0
34.9 ꢀ 0.1
–
51.2 ꢀ 0.6
25
–
4.9 ꢀ 0.1 59.5 ꢀ 0.2
5
6
7
8
9
10
3 (n=2)
3 (n=3)
3 (n=2)
3 (n=2)
3 (n=2)
3 (n=2)
200
200
400
400
1000
200
5
5
5
5
5
5
10
20
20
20
30
–
–
–
–
5
–
30
66.2 ꢀ 3.8 12.7 ꢀ 0.9 20.0 ꢀ 2.1
74.6 ꢀ 2.2 22.8 ꢀ 2.8
–
17.9 ꢀ 0.7
24.1 ꢀ 0.5
28.5 ꢀ 1.5
45.2 ꢀ 1.1
–
–
81.6 ꢀ 0.8
74.2 ꢀ 1.1
2.5 ꢀ 0.1 65.3 ꢀ 3.5
5.3 ꢀ 0.6 49.3 ꢀ 0.8
a Method A was applied for pyrrole and Method B for 5,10,15-tris(3-methoxyphenyl)tetrapyrrane 3.
Method A: m-anisaldehyde (2.3 ml, 1.8 mmol), pyrrole (2 ml, 2.9 mmol), and 4-[18F]fluorobenzaldehyde (233–
370 MBq) and 2.5 ml of TFA (25 ml solution was taken from the mixture of 50 ml TFA and 450 ml of CH2Cl2)
in dry CH2Cl2 (200 ml) was added. Method B: 5,10,15-tris(3-methoxyphenyl)tetrapyrrane 3 (2 mg, 0.3 mmol),
4-[18F]fluorobenzaldehyde and 2.5 ml of TFA (25 ml solution was taken from the mixture of 50 ml TFA and
450 ml of CH2Cl2) in dry CH2Cl2 (200 ml) was added.
b Yield was based on radio-TLC.
Table 2. Optimized condition and result of radiolabeled porphyrin
Entry
Precursora
TFA ( ml)
Solvent
(200 ml)
Unknown
peak (%)b
Product
(%)b
Starting
material
(%)b
1
2
3
4
3 (n=2)
3 (n=3)
3 (n=2)
Pyrrole
(n=3)
Pyrrole
(n=2)
3
0.5
2.5
5.0
2.5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
83.4 ꢀ 1.1
–
80.1 ꢀ 0.5
6.4 ꢀ 0.2
20.5 ꢀ 4.8c
7.6 ꢀ 0.8
9.1 ꢀ 0.1
–
–
–
9.4 ꢀ 5.9c
5
5.0
CH2Cl2
84.4
4.5
–
6
7
8
2.5
2.5
2.5
CH3CN
THF
Toluene
36.9
3.1
58.2
Trace
–
Trace
49.3
89.1
9.2
3
3
a See footnote a in Table 1 with proper amounts of TFA. All reactions were carried out initially in an ice-
bath (5 min) followed by 20 min at rt and oxidation with DDQ (3 mg, 13.2 mmol) for 20 min at rt.
b Yield was based on radio-TLC.
c Isolated yield by HPLC.
unknown radioactive peaks appeared on radio-TLC, but no attempts were
made to analyze these unknown compounds. For further purification, the
reaction mixture was then passed through a bed of Celite (1.5 cm/5 mm) using
EtOAc (1 ml) to remove the unreacted DDQ and the unknown products
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R. R. KAVALI ET AL.
Figure 1. The radio-TLC of the reaction mixture of entry 2 in Table 2.
A=unknown peak, B=[18F]1
Figure 2. The HPLC analysis of the purified [18F]1. UV (400 nm) and c-
detection (511 keV) profiles were recorded simultaneously. HPLC (Alltech
Econosil silica gel, 10 lm, 10 ꢁ 250 mm; Eluant: EtOAc: hexane=3:7, at a flow
rate of 2.5 ml/min) data of the reaction mixture of entry 2 in Table 2. A
radioactive peak at 20.63 min marked with B is [18F]1
before injecting into high-performance liquid chromatography (HPLC). The
HPLC were performed on a semi-preparative column (Alltech Econosil silica
gel, 10 mm, 10 ꢁ 250 mm) simultaneously monitored by a UV detector (400 nm)
and a g-detector with the eluant of EtOAc/hexane (3:7) and a flow rate of
2.5 ml/min. The RA was recorded at tR ¼ 20:63 min (Figure 2). Identity of the
product was confirmed by coelution with cold authentic compound.
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Conclusion
We have described two effective and convenient methods of radiolabeling
porphyrin. The approaches are condensation of aldehydes with pyrrole
(Method A) and aldehyde with tetrapyrrane (Method B). Both provided
radiolabeled 5-(4-[18F]fluorophenyl)-10,15,20-tris(3-methoxyphenyl)porphyrin
([18F]1) in better radiochemical yields (9.4%, Method A and 20.5%, Method
B) than the chemical yields of cold synthesis (1 and 3%, respectively). In the
course of developing these practical syntheses a number of interesting
observations were made and further applications to the synthesis of
radiolabeled porphyrins are feasible.
Materials and methods
Chemicals were purchased from Sigma-Aldrich Chemical Company (Milwau-
kee, WI, USA) and HPLC solvents from Fisher Scientific (Pittsburgh, PA,
USA) and other solvents were distilled and dried prior to use. HPLC was
carried out on a Young-Lin System with a semi preparative column (Alltech
Econosil silica gel, 10 mm, 10 ꢁ 250 mm). The eluant was simultaneously
monitored by a Young-Lin UV instrument (400 nm) and g-detection a Raytest
GABI instrument. TLC was performed on Merck F254 silica plates and
visualized by UV illumination. Flash column chromatography was performed
on silica gel 230-400 mesh. For radiolabeled compounds TLC was analyzed on
1
a Bioscan AC-3000 scanner (Washington, DC, USA). H and 13C NMR
spectra were recorded on a Varian Gemini–200 and Varian Gemini–400 and
chemical shifts were reported in d units (ppm) from internal standard
tetramethylsilane. Electron impact (EI) mass spectra were obtained on a GC/
MS QP5050A spectrometer (Shimadzu, Kyoto, Japan) and MALDI-TOF
mass spectra was performed on Voyager-DE STR MALDI-TOF mass
spectrometer (San Francisco, USA).
Method A: condensation of aldehydes with pyrrole
5-(4-Fluorophenyl)-10,15,20-tris(3-methoxyphenyl)porphyrin ð1Þ: m-Anisalde-
hyde (660 mg, 4.8 mmol) and 4-fluorobenzaldehyde (200 mg, 1.6 mmol) and
pyrrole (430 mg, 6.4 mmol) were dissolved in dry CH2Cl2 (20 ml) and the
reaction flask was protected from light. Nitrogen gas was bubbled through this
solution for 10 min. TFA (50 ml, 0.64 mmol) was added at 08C and the reaction
was stirred under nitrogen for about 40 min at rt DDQ (6.4 mmol) was added
and the reaction was stirred for 60 min exposed to air. The reaction mixture
was evaporated to dryness to produce black tarry solid. This crude product
was adsorbed onto silica gel and purified by flash column chromatography
using EtOAc/hexane (2:8) as an eluant. The major product was meso-
tetramethoxyphenylporphyrin (10%). The desired product was collected as
1
a purple solid (12 mg, 1%); H NMR (200 MHz, CDCl3) d 3.99 (s, 9H), 7.21
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(t, J ¼ 8:8 Hz, 1H), 7.32–7.36 (m, 3H), 7.46 (t, J ¼ 8:6 Hz, 2H), 7.65
(t, J ¼ 7:2 Hz, 3H), 7.78–7.84 (m, 6H), 7.95–8.01 (m, 1H), 8.14–8.21
(m, 2H), 8.81 (d, J ¼ 5:2 Hz, 2H), 8.91 (d, J ¼ 5:2 Hz, 6H); 13C NMR
(100 MHz, CDCl3): d 55.5, 113.5, 113.6, 113.8, 115.7, 115.9, 118.1, 118.7,
119.9, 120.4, 124.8, 127.5, 127.6, 131.6, 131.7, 135.7, 135.7, 138.0, 143.4, 157.9.
MALDI-TOF MS: 722.63 (MH+); (calculated for C47H35FN4O3, 722.27).
Method B: condensation of aldehyde with tetrapyrrane
5-(3-Methoxyphenyl)dipyrromethane ð2Þ.14,15 A mixture of m-anisaldehyde
(270 mg, 2.0 mmol) and pyrrole (5.40 g, 80 mmol) was degassed by bubbling
with nitrogen for 10 min then TFA (15 ml, 0.2 mmol) was added and the
solution was stirred for 10 min at rt. The mixture was diluted with CH2Cl2
(30 ml) then washed with 0.1 N NaOH (10 ml), washed with water, the organic
layer separated and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure and the unreacted pyrrole was removed by vacuum
distillation at rt. The resulting thick oily liquid was further distilled using
Kugelrohr apparatus to get 5-(3-methoxyphenyl)dipyrromethane 2 as brown
viscous liquid (64%): 1H NMR (400 MHz, CDCl3) d 3.76 (s, 3H), 5.45 (s, 1H,
meso-H), 5.91–5.93 (m, 2H), 6.13–6.15 (q, J ¼ 2:8 Hz, 2H ), 6.65–6.66 (m, 2H),
6.76–6.81 (m, 3H), 7.20–7.24 (m, 1H), 7.90 (brs, 2H, NH); 13C NMR
(100 MHz, CDCl3) d 43.9, 55.1, 107.2, 108.4, 112.2, 114.3, 17.2, 120.8, 129.6,
132.3, 143.6, 159.8; MS (EI) m/z: 252 (M+).
5,10,15,-Tris(3-methoxyphenyl)tetrapyrrane ð3Þ.16 In dry CH2Cl2 (20 ml) was
added a solution of m-anisaldehyde (75 mg, 0.55 mmol) and 5-(3-methox-
yphenyl)dipyrromethane (2, 280 mg, 1.11 mmol) under nitrogen atmosphere.
To this stirred solution, TFA (4 ml, 0.05 mmol) was added and stirred for
10 min at rt. Solvent was evaporated and the resulting crude thick liquid was
purified by flash column chromatography over silica gel neutralized with 1%
Et3N in EtOAc/hexane (1:9) to get the product as pale brown semi-solid
1
(20%): H NMR (200 MHz, CDCl3) d 3.72 (s, 9H), 5.23 (s, 1H), 5.31 (s, 2H),
5.71–5.75 (m, 2H), 5.85–5.87 (m, 4H), 6.09–6.12 (m, 2H), 6.63–6.78 (m, 11H),
7.15–7.25 (m, 3H), 7.69 (brs, 2H, NH), 7.90 (brs, 2H, NH); 13C (100 MHz,
CDCl3) d 44.0, 44.1, 55.1, 55.1, 107.1, 107.3, 108.3, 112.2, 112.4, 113.8, 114.1,
117.1, 120.7, 120.7, 129.4, 129.5, 132.0, 132.0, 132.3, 143.6, 143.6, 159.7, 159.8.
5-(4-Fluorophenyl)-10,15,20-tris(3-methoxyphenyl)porphyrin ð1Þ: 5,10,15-Tris
(3-methoxyphenyl)tetrapyrrane (3, 400 mg, 0.64 mmol), 4-fluorobenzaldehyde
(80 mg, 0.64 mmol) and TFA (7 ml, 0.064 mmol) in dry CH2Cl2 (20 ml) were
stirred under nitrogen for 40 min at rt. To this stirred solution was added
DDQ (1.28 mmol) exposing the reaction mixture to air for 60 min. The
resulting dark solution was adsorbed over silica gel and further purified over
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silica gel flash chromatography using EtOAc/hexane (2:8) as an eluant to get
the product as purple crystals (14 mg, 3%).
Synthesis of radiolabeled porphyrin
4-[18F]Fluorobenzaldehyde.18,19 [18F]Fluoride was produced in a cyclotron by
the 18O(p,n) 18F reaction. A volume of 100–300 ml of [18F]fluoride (370–
1800 MBq) in water was added to a vacutainer containing n-Bu4NOH (40%
aq., 3.5 ml, 5.44 mmol). The azeotropic distillation was carried out each time
with 200 ml of aliquote of CH3CN at 858C under a stream of nitrogen. A
[18F]fluoride ion nucleophilic aromatic substitution on (4-formylphenyl)tri-
methylammonium triflate (2 mg, 6.4 mmol) with n-Bu4N[18F]F in DMSO
(200 ml) was carried out in a reaction vial at 908C for 5 min. The reaction vessel
was cooled in an ice-bath, and HCl (0.2 M, 2 ml) was added to the mixture.
The crude mixture was loaded on C-18 Sep-Pak and then washed with H2O
(5 ml) and CH2Cl2 (1 ml). The solvent CH2Cl2 was passed through a bed of
Na2SO4 and the solvent collected. The collected solvent contained the
[18F]fluorobenzaldehyde.
5-(4-[18F]Fluorophenyl)-10,15,20-tris(3-methoxyphenyl)porphyrin ð1Þ: Method A:
To m-anisaldehyde (2.3 ml, 1.8 mmol), pyrrole (2 ml, 2.9 mmol), and 4-[18F]fluor-
obenzaldehyde (233–370 MBq) in dry CH2Cl2 (200 ml) was added 2.5 ml of TFA
(25 ml solution was taken from the mixture of 50 ml TFA and 450 ml of CH2Cl2).
The mixture was stirred in an ice-bath for 5 min. This solution was further stirred
at rt for 20 min. The reaction vial was protected from light. DDQ (3 mg,
13.2 mmol) was added and the reaction was stirred further for 20 min at rt. The
resulting black mixture was filtered through a bed of Celite and washed with
EtOAc (1 ml). The formation of product was conformed by radio-TLC (Rf ¼ 0:6,
EtOAc/hexane (2:8)).
Method B: 5,10,15-Tris(3-methoxyphenyl)tetrapyrrane (3, 2 mg, 0.3 mmol),
4-[18F]fluorobenzaldehyde (233–370 MBq) and TFA (2.5 ml) in dry CH2Cl2
(200 ml) was stirred in an ice-bath for 5 min. This solution was further stirred at
rt for 20 min. The reaction vial was protected from light. DDQ (3 mg,
13.2 mmol) was added and the reaction was stirred further for 20 min at rt. The
resulting black mixture was filtered through a bed of Celite and washed with
EtOAc (1 ml). The formation of product was conformed by radio-TLC
(Rf ¼ 0:6, EtOAc/hexane (2:8)).
HPLC condition. The mixture solvent of EtOAc and CH2Cl2 was removed
with a gentle stream of nitrogen. After removing the solvent, the mixture was
dissolved with an eluant of HPLC solvent (EtOAc/hexane=3:7). The crude
compound was injected onto HPLC with a semi-preparative column (Alltech
Econosil silica gel, 10 mm, 10 ꢁ 250 mm). An eluant EtOAc/hexane (3:7) with a
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R. R. KAVALI ET AL.
flow rate of 2.5 ml/min was simultaneously monitored by a UV detector
(400 nm) and a g-detector. The desired compound was collected from HPLC
tR ¼ 20:63 min with a radiochemical yield (20–26%) and radiochemical purity
(>95%). Authenticity of the product was confirmed by coelution with cold
compound.
Acknowledgements
This work was supported by the National Research Laboratory Program in
Korea and Korea Institute of Radiological and Medical Sciences.
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