Synthesis of carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as new potential PET AMPA receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2006.01.042

New carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3, 4-tetrahydroisoquinoline derivatives were designed and synthesized as potential positron emission tomography AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid) recep

Full text of DOI:10.1016/j.bmcl.2006.01.042

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2229–2233
Synthesis of carbon-11 and fluorine-18 labeled
N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
derivatives as new potential PET AMPA receptor ligands
Mingzhang Gao,a Deyuan Kong,b Abraham Clearfieldb and Qi-Huang Zhenga,*
aDepartment of Radiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
bDepartment of Chemistry, Texas A&M University, College Station, TX 77843, USA
Received 1 December 2005; revised 9 January 2006; accepted 9 January 2006
Available online 7 February 2006
Abstract—New carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were
designed and synthesized as potential positron emission tomography AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propion-
ic acid) receptor ligands to image brain diseases. The single crystal structure of the most potent compound N-acetyl-1-(40-chlorophe-
nyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5a) is first reported.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-
yl)propionic acid) receptor antagonists may be useful
as potential neuroprotective agents in the treatment of
neurological diseases such as epilepsy, ischemia, Parkin-
son’s disease, and multiple sclerosis, since AMPA recep-
tors are involved in learning, memory, neuronal
degeneration, and even cell death. N-Acetyl-1-aryl-6,7-
N-acetyl-1-aryl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydro-
isoquinolines (7a–b) was performed using a modification
of the literature procedure.1 The synthetic approach is
outlined in Scheme 1. Commercially available starting
materials, suitable aromatic aldehydes (2a–g), were react-
ed with 2-(30,40-dimethoxyphenyl)ethylamine (1) to
afford the desired imine benziliden[2-(30,40-dimeth-
oxyphenyl)ethyl]amines (3a–g). The crude products were
used for the next step reaction without further purifica-
tion. The intramolecular cyclization reaction of the inter-
mediate imines (3a–g) catalyzed by trifluoroacetic acid
(TFA) formed the corresponding 1-aryl-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinolines (4a–g). The acetylation
of the isoquinoline derivatives (4a–g) with acetyl
chloride provided N-acetyl compounds (5a–g). The
demethylation of the N-acetyl compounds (5a–c) with
aluminium trichloride and ethanethiol3 yielded mono-
desmethylated products 6-desmethylated isoquinoline
derivatives (6a–c) and 7-desmethylated isoquinoline
derivatives (7a–b).
dimethoxy-1,2,3,4-tetrahydroisoquinoline
derivatives
are novel and highly potent noncompetitive AMPA
receptor antagonists recently developed by Gitto et al.1
In vivo biomedical imaging technique positron emission
tomography (PET) coupled with appropriate receptor
radioligands has become a clinically valuable and
accepted diagnostic tool to image brain diseases.2 To
further develop potential therapeutic drugs as diagnostic
agents, we designed and synthesized carbon-11 and fluo-
rine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline derivatives.
The synthesis of reference standard and desmethylated
precursors N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinolines (5a–g), N-acetyl-1-aryl-6-hydroxy-7-
methoxy-1,2,3,4-tetrahydroisoquinolines (6a–c), and
The synthesis of target radioligands N-acetyl-1-aryl-6-
[11C]methoxy-7-methoxy-1,2,3,4-tetrahydroisoquinolines
(6-[11C]5a–c), N-acetyl-1-aryl-6-methoxy-7-[11C]meth-
oxy-1,2,3,4-tetrahydroisoquinolines (7-[11C]5a–b), N-ac-
etyl-1-(40-[11C]methoxyphenyl)-6,7-dimethoxy-1,2,3,
4-tetrahydroisoquinoline ([11C]5e), and N-acetyl-1-(40-
[18F]fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline ([18F]5g) is shown in Scheme 2. 6-Desmethy-
lated isoquinoline derivatives (6a–c), 7-desmethylated
Keywords: N-Acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line derivatives; Carbon-11; Fluorine-18; Positron emission tomogra-
phy; 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid
receptor; Brain diseases.
*
Corresponding author. Tel.: +1 317 278 4671; fax: +1 317 278
9711; e-mail: qzheng@iupui.edu
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.01.042

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M. Gao et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2229–2233
CH3O
CH3O
CHO
CH3O
CH3O
N
R
toluene, reflux
NH2
R
1
2a-g
3a-g
TFA
reflux
CH3O
CH3O
CH3O
CH3O
AlCl3
CH3CH2SH
N
R
O
CH3COCl
CH2Cl2
NH
5a-g
R
4a-g
HO
CH3O
N
O
N
O
a, R=4-Cl
b, R=3-Cl
CH3O
HO
c, R=3,4-di-Cl
d, R=4-OH
e, R=4-OCH3
f, R=4-NO2
g, R=4-F
R
7a-b
6a-c
R
Scheme 1. Synthesis of isoquinoline derivatives.
11CH3O
isoquinoline derivatives (7a–b), and N-acetyl-1-(40-
hydroxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (5e) were reacted with [11C]methyl triflate
(11CH3OTf)4 under basic conditions through O-
[11C]methylation and isolated by solid-phase extraction
(SPE) purification procedure using a C18 Sep-Pak car-
tridge5 to give carbon-11 labeled isoquinoline derivative
radiotracers 6-[11C]5a–c, 7-[11C]5a–b, and [11C]5e in
30–45% radiochemical yields based on [11C]CO2,
15–20 min overall synthesis time from end of bombard-
ment (EOB), >95% radiochemical purity, and >1.0 Ci/
lmol specific activity at the end of synthesis (EOS) mea-
sured by analytical HPLC method.6 N-Acetyl-1-(40-
nitrophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line (5f) was labeled by a conventional nucleophilic
substitution with K18F/Kryptofix 2.2.2 in acetonitrile
at 120 ꢁC for 15–20 min and purified by HPLC method7
to afford fluorine-18 labeled isoquinoline derivative
radiotracer [18F]5g in 15-25% radiochemical yield at
EOB. The specific activity was 1.0–1.2 Ci/lmol at EOS.
11CH3OTf, CH3CN
6 N NaOH
N
R
O
CH3O
6a-c
a, R=4-Cl
b, R=3-Cl
c, R=3,4-di-Cl
6-[11C]5a-c
CH3O
N
O
11CH3OTf, CH3CN
6 N NaOH
11CH3O
7a-b
a, R=4-Cl
b, R=3-Cl
R
7-[11C]5a-b
CH3O
CH3O
11CH3OTf, CH3CN
6 N NaOH
N
O
5d
Compounds 5b–e are new noncompetitive AMPA
receptor antagonists first synthesized in this laborato-
ry. Compound 5a has been reported to be more po-
[
11C]5e
O
11CH3
tent than talampanel,
a
noncompetitive AMPA
CH3O
receptor antagonist currently being investigated in
phase III trials as an antiepileptic agent, and a highly
effective noncompetitive-type modulator of the AMPA
receptor indicated by electrophysiological studies.1 To
better understand the structure of the new PET radio-
ligands, the structure of the ligand 5a was determined
by X-ray crystallography. Compound 5a was obtained
in the form of air-stable, colorless crystals by slow
evaporation from a solution of 5a in ethyl acetate.
K[18F]F/K2.2.2
CH3CN
N
O
CH3O
5f
[
18F]5g 18
F
Scheme 2. Synthesis of carbon-11 and fluorine-18 labeled isoquinoline
derivatives.

M. Gao et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2229–2233
2231
5. Gao, M.; Miller, K. D.; Sledge, G. W.; Zheng, Q.-H.
Bioorg. Med. Chem. Lett. 2005, 15, 3865.
6. Zheng, Q.-H.; Mock, B. H. Biomed. Chromatogr. 2005, 19, 671.
7. Wang, J.-Q.; Miller, K. D.; Sledge, G. W.; Zheng, Q.-H.
Bioorg. Med. Chem. Lett. 2005, 15, 4380.
8. (a) Experimental details and characterization data. Gener-
al: All commercial reagents and solvents were used without
further purification unless otherwise specified. The
11CH3OTf was made according to a literature procedure.4
1H NMR spectra were recorded on a Bruker QE 300 NMR
spectrometer using tetramethylsilane (TMS) as an internal
standard. Chemical shift data for the proton resonances
were reported in parts per million (d) relative to internal
standard TMS (d 0.0). Low resolution mass spectra were
obtained using a Bruker Biflex III MALDI-Tof mass
spectrometer, and high resolution mass measurements were
obtained using a Kratos MS80 mass spectrometer, in the
Department of Chemistry at Indiana University. Chroma-
tographic solvent proportions are expressed on a volume:
volume basis. Thin layer chromatography was run using
Analtech silica gel GF uniplates (5 · 10 cm2). Plates were
visualized by UV light. Normal phase flash chromatogra-
phy was carried out on EM Science silica gel 60 (230–400
mesh) with a forced flow of the indicated solvent system in
the proportions described below. All moisture-sensitive
reactions were performed under a positive pressure of
nitrogen maintained by a direct line from a nitrogen source.
Analytical HPLC was performed using a Prodigy (Phe-
nomenex) 5 lm C18 column, 4.6 ꢀ· 250 mm; 3:1:3
CH3CN:MeOH:20 mM, pH 6.7, KHPO4 (buffer solution)
mobile phase, flow rate 1.5 mL/min, and UV (254 nm) and
c-ray (NaI) flow detectors. Semi-preparative HPLC was
performed using a Prodigy (Phenomenex) 5 lm C-18
column, 10 ꢀ· 250 mm; 3:1:3 CH3CN/MeOH/20 mM, pH
6.7 KHPO4 mobile phase, 5.0 mL/min flow rate, UV
(254 nm) and c-ray (NaI) flow detectors. Semi-prep C18
silica guard cartridge column 1 · 1 cm was obtained from
E. S. Industries, Berlin, NJ, and part number 300121-C18-
BD 10l. Semi-prep SiO2 Sep-Pak type cartridge was
obtained from Waters Corporate Headquarters, Milford,
MA. Sterile vented Millex-GS 0.22 lm filter unit was
obtained from Millipore Corporation, Bedford, MA; (b)
Compounds (4a–g) were synthesized using a modification
of the literature procedure1 in about 90% yield. 1-(40-
Chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line (4a). Mp: 112–114 ꢁC. Rf = 0.68 (1:9 MeOH/CH2Cl2).
1H NMR (300 MHz, CDCl3): d 1.74 (s, 1H, NH), 2.73 (dt,
J = 4.82, 15.45 Hz, 1H, CHH), 2.87–2.97 (m, 1H, CHH),
3.00–3.08 (m, 1H, CHH), 3.15–3.23 (m, 1H, CHH), 3.64 (s,
3H, OCH3), 3.87 (s, 3H, OCH3), 5.02 (s, 1H, H-1), 6.19 (s,
1H, H-5), 6.63 (s, 1H, H-8), 7.18–7.30 (m, 4H, ArH). 1-(30-
Chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line (4b). Mp: 115–117 ꢁC. Rf = 0.27 (EtOAc). 1H NMR
(300 MHz, CDCl3): d 1.78 (s, 1H, NH), 2.72 (dt, J = 5.14,
16.17 Hz, 1H, CHH), 2.87–2.96 (m, 1H, CHH), 2.99–3.07
(m, 1H, CHH), 3.15–3.22 (m, 1H, CHH), 3.66 (s, 3H,
OCH3), 3.87 (s, 3H, OCH3), 5.02 (s, 1H, H-1), 6.22 (s, 1H,
H-5), 6.63 (s, 1H, H-8), 7.12–7.16 (m, 1H, ArH), 7.24–7.25
(m, 3H, ArH). 1-(30,40-Dichlorophenyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (4c). Mp: 130–132 ꢁC.
Rf = 0.48 (1:9 MeOH/CH2Cl2). 1H NMR (300 MHz,
CDCl3): d 1.76 (s, 1H, NH), 2.72 (dt, J = 5.14, 16.22 Hz,
1H, CHH), 2.86–2.99 (m, 1H, CHH), 3.01–3.07 (m, 1H,
CHH), 3.12–3.20 (m, 1H, CHH), 3.65 (s, 3H, OCH3), 3.87
(s, 3H, OCH3), 5.00 (s, 1H, H-1), 6.19 (s, 1H, H-5), 6.63 (s,
1H, H-8), 7.08 (dd, J = 2.20, 8.09 Hz, 1H, ArH), 7.36–7.40
(m, 2H, ArH). 6,7-Dimethoxy-1-(40-hydoxyphenyl)-1,2,3,4-
tetrahydroisoquinoline (4d). Mp: 195–197 ꢁC. Rf = 0.20 (1:9
MeOH/CH2Cl2). 1H NMR (300 MHz, DMSO-d6): d 1.62
Figure 1. Molecular structure of compound 5a.
The single crystal structure of compound 5a is first
reported, and the perspective view of 5a is shown in
Figure 1.
The characterization data for compounds 4a–g and
5a–g, experimental details, and characterization data
for new compounds 6a–c and 7a–b, and new tracers 6-
[11C]5a–c, 7-[11C]5a–b, [11C]5e, and [18F]5g, and crystal
data for compound 5a are given.8
In summary, an efficient and convenient chemical and
radiochemical synthesis of the precursors, reference
standards, and target tracers has been well developed.
The chemistry result provides the foundation for further
evaluation of carbon-11 and fluorine-18 labeled N-ace-
tyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
derivatives as new potential PET radioligands for imag-
ing AMPA receptors in brain diseases.
Acknowledgments
This work was partially supported by the Indiana
Genomics Initiative (INGEN) of Indiana University,
which is supported in part by Lilly Endowment Inc.
A. Clearfield acknowledges the financial support from
the Department of Energy, Basic Sciences Division
through Grant number DE-FG03-00ER 15806. The
authors thank Dr. Bruce H. Mock, Barbara E. Glick-
Wilson, and Michael L. Sullivan for their assistance in
production of 11CH3OTf and K18F/Kryptofix 2.2.2.
The referees’ criticisms and editor’s comments for the
revision of the manuscript are greatly appreciated.
References and notes
1. Gitto, R.; Barreca, M. L.; De Luca, L.; De Sarro, G.;
Ferreri, G.; Quartarone, S.; Russo, E.; Constanti, A.;
Chimirri, A. J. Med. Chem. 2003, 46, 197.
2. Vera, D. R.; Eckelman, W. C. Nucl. Med. Biol. 2001, 28,
475.
3. Node, M.; Nishide, K.; Fuji, K.; Fujita, E. J. Org. Chem.
1980, 45, 4275.
4. Mock, B. H.; Mulholland, G. K.; Vavrek, M. T. Nucl. Med.
Biol. 1999, 26, 467.

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M. Gao et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2229–2233
methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline(5e).
(s, 1H, NH), 2.56–2.64 (m, 1H, CHH), 2.71–2.84 (m, 2H,
Mp:
CH2), 2.95–3.02 (m, 1H, CHH), 3.47 (s, 3H, OCH3), 3.70 (s,
3H, OCH3), 4.77 (s, 1H, H-1), 6.16 (s, 1H, H-5), 6.68–6.98
(m, 3H, 2H, ArH and 1H, H-8), 6.98 (d, 2H, J = 8.82 Hz,
2H, ArH), 8.31 (s, 1H, ArOH). LRMS (EI): 285 (M+, 89%),
284 [(MꢀH)+, 100%]. HRMS (EI): calcd for C17H19NO3
285.1359, found 285.1346. 6,7-Dimethoxy-1-(40-methoxy-
phenyl)-1,2,3,4-tetrahydroisoquinoline (4e). Mp: 89–91 ꢁC.
Rf = 0.65 (1:9 MeOH/CH2Cl2). 1H NMR (300 MHz,
CDCl3): d 2.04 (s, 1H, NH), 2.74 (dt, J = 5.14, 16.18 Hz,
1H, CHH), 2.88–3.07 (m, 2H, CH2), 3.18–3.25 (m, 1H,
CHH), 3.64 (s, 3H,40-OCH3), 3.80 (s, 3H, 6-OCH3), 3.87 (s,
3H, 7-OCH3), 5.00 (s, 1H, H-1), 6.25 (s, 1H, H-5), 6.62 (s,
1H, H-8), 6.83 (d, J = 8.83 Hz, 2H, ArH), 7.16 (d,
J = 8.09 Hz, 2H, ArH). 6,7-Dimethoxy-1-(40-nitrophenyl)-
1,2,3,4-tetrahydroisoquinoline (4f). Mp: 143–144 ꢁC.
Rf = 0.71 (1:9 MeOH/CH2Cl2). 1H NMR (300 MHz,
CDCl3): d 1.76 (s, 1H, NH), 2.73 (dt, J = 5.14, 16.18 Hz,
1H, CHH), 2.88–2.97 (m, 1H, CHH), 3.01–3.09 (m, 1H,
CHH), 3.12–3.20 (m, 1H, CHH), 3.63 (s, 3H, OCH3), 3.87
(s, 3H, OCH3), 5.14 (s, 1H, H-1), 6.14 (s, 1H, H-5), 6.65 (s,
1H, H-8), 7.42 (d, J = 8.83 Hz, 2H, ArH), 8.16 (d,
J = 8.09 Hz, 2H, ArH). 6,7-Dimethoxy-1-(40-fluorophe-
nyl)-1,2,3,4-tetrahydroisoquinoline (4g). Mp: 84–86 ꢁC.
Rf = 0.66 (1:9 MeOH/CH2Cl2). 1H NMR (300 MHz,
CDCl3): d 1.87 (s, 1H, NH), 2.73 (dt, J = 4.42, 16.18 Hz,
1H, CHH), 2.88–2.98 (m, 1H, CHH), 3.00–3.09 (m, 1H,
CHH), 3.17–3.24 (m, 1H, CHH), 3.64 (s, 3H, OCH3), 3.87
(s, 3H, OCH3), 5.03 (s, 1H, H-1), 6.20 (s, 1H, H-5), 6.63 (s,
1H, H-8), 6.96–7.03 (m, 2H, ArH), 7.20–7.25 (m, 2H, ArH);
(c) Compounds (5a–g) were synthesized using a modifica-
tion of the literature procedure1 in about 90% yield. N-
Acetyl-1-(40-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline (5a). Mp: 143–145 ꢁC. Rf = 0.60 (EtOAc).
1H NMR (300 MHz, CDCl3): d 2.14 (s, 3H, NCOCH3),
2.73 (dt, J = 3.30, 14.71 Hz, 1H, CHH), 2.89–3.00 (m, 1H,
CHH), 3.29–3.39 (m, 1H, CHH), 3.68–3.75 (m, 1H, CHH),
3.75 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.48 (s, 1H, H-1),
6.66 (s, 1H, H-5), 6.83 (s, 1H, H-8), 7.16 (d, J = 8.09 Hz,
2H, ArH), 7.22 (d, J = 8.09 Hz, 2H, ArH). N-Acetyl-1-(30-
chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line (5b). Mp: 194–195 ꢁC. Rf = 0.66 (EtOAc). 1H NMR
(300 MHz, CDCl3): d 2.17 (s, 3H, NCOCH3), 2.73 (dt,
J = 3.68, 15.44 Hz, 1H, CHH), 2.89–3.00 (m, 1H, CHH),
3.31–3.41 (m, 1H, CHH), 3.69–3.74 (m, 1H, CHH), 3.77 (s,
3H, OCH3), 3.89 (s, 3H, OCH3), 6.49 (s, 1H, H-1), 6.66 (s,
1H, H-5), 6.83 (s, 1H, H-8), 7.14–7.16 (m, 1H, ArH), 7.19–
7.22 (m, 3H, ArH). LRMS (EI): 345 (M+, 100%). HRMS
(EI): calcd for C19H20ClNO3 345.1126, found 345.1126. N-
Acetyl-1-(30,40-dichlorophenyl)-6,7-dimethoxy-1,2,3,4-tet-
rahydroisoquinoline (5c). Mp: 125–127 ꢁC. Rf = 0.59
(EtOAc). 1H NMR (300 MHz, CDCl3): d 2.17 (s, 3H,
NCOCH3), 2.73 (dt, J = 3.50, 14.70 Hz, 1H, CHH), 2.89–
3.00 (m, 1H, CHH), 3.29-3.39 (m, 1H, CHH), 3.69–3.75 (m,
1H, CHH), 3.77 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.46 (s,
1H, H-1), 6.67 (s, 1H, H-5), 6.80 (s, 1H, H-8), 7.10 (dd,
J = 1.84, 8.09 Hz, 1H, ArH), 7.26–7.35 (m, 2H, ArH).
LRMS (EI): 379 (M+, 100%). HRMS (EI): calcd for
C19H19Cl2NO3 379.0737, found 379.0725. N-Acetyl-6,7-
dimethoxy-1-(40-hydroxyphenyl)-1,2,3,4-tetrahydroisoquin-
oline (5d). Mp: 208–210 ꢁC. Rf = 0.70 (1:9 MeOH/CH2Cl2).
1H NMR (300 MHz, DMSO-d6): d 2.06 (s, 3H, NCOCH3),
2.60–2.70 (m, 1H, CHH), 2.79–2.90 (m, 1H, CHH), 3.19–
3.27 (m, 1H, CHH), 3.61–3.65 (m, 1H, CHH), 3.61 (s, 3H,
OCH3), 3.73 (s, 3H, OCH3), 6.55 (s, 1H, H-1), 6.60 (s, 1H,
H-5), 6.63 (d, J = 8.09 Hz, 1H, ArH), 6.77 (s, 1H, H-8), 6.88
(d, J = 8.09 Hz, 2H, ArH), 9.32 (s, 1H, OH). LRMS (EI):
327 (M+, 100%). HRMS (EI): calcd for C19H21NO4
327.1465, found 327.1460. N-Acetyl-6,7-dimethoxy-1-(40-
110–112 ꢁC. Rf = 0.57 (EtOAc). 1H NMR (300 MHz,
CDCl3): d 2.14 (s, 3H, NCOCH3), 2.71–2.76 (m, 1H,
CHH), 2.88–2.99 (m, 1H, CHH), 3.32–3.42 (m, 1H, CHH),
3.65–3.70 (m, 1H, CHH), 3.74 (s, 3H, OCH3), 3.77 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 6.50 (s, 1H, H-1), 6.64 (s, 1H,
H-5), 6.78 (s, 1H, H-8), 6.80 (d, J = 8.09 Hz, 2H, ArH), 7.14
(d, J = 8.09 Hz, 2H, ArH). N-Acetyl-6,7-dimethoxy-1-(40-
nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (5f). Mp: 181–
183 ꢁC. Rf = 0.67 (EtOAc). 1H NMR (300 MHz, CDCl3): d
2.16 (s, 3H, NCOCH3), 2.72 (dt, J = 3.38, 16.18 Hz, 1H,
CHH), 2.91–3.02 (m, 1H, CHH), 3.29–3.39 (m, 1H, CHH),
3.71–3.76 (m, 1H, CHH), 3.76 (s, 3H, OCH3), 3.89 (s, 3H,
OCH3), 6.47 (s, 1H, H-1), 6.69 (s, 1H, H-5), 6.90 (s, 1H, H-
8), 7.41 (d, J = 8.09 Hz, 2H, ArH), 8.11 (d, J = 8.82 Hz, 2H,
ArH). N-Acetyl-6,7-dimethoxy-1-(40-fluorophenyl)-1,2,3,4-
tetrahydroisoquinoline (5g). Mp: 162–164 ꢁC. Rf = 0.66
(EtOAc). 1H NMR (300 MHz, CDCl3): d 2.16 (s, 3H,
NCOCH3), 2.72 (dt, J = 3.30, 14.71 Hz, 1H, CHH), 2.89–
3.00 (m, 1H, CHH), 3.30–3.40 (m, 1H, CHH), 3.68–3.74
(m, 1H, CHH), 3.75 (s, 3H, OCH3), 3.89 (s, 3H, OCH3),
6.48 (s, 1H, H-1), 6.66 (s, 1H, H-5), 6.85 (s, 1H, H-8), 6.95
(t, J = 8.45 Hz, 2H, ArH), 7.21 (dd, J = 5.51, 8.09 Hz, 2H,
ArH); (d) General procedure for preparation of compounds
6a–c and compounds 7a–b from mono-demethylation of
compounds 5a–c. To a stirred solution of 5 (1.5 mmol) in
ethanethiol (1 mL) and dichloromethane (10 mL) cooled in
an ice-water bath was added AlCl3 (6.0 mmol, 0.8 g, 4 equiv
of 5a–c). The reaction mixture was kept to stir for 2 h.
Subsequently the mixture was poured into water, extracted
with dichloromethane, washed with brine, dried by
Na2SO4, filtered, and then evaporated to give a crude
product, which was purified by column chromatography
(20% EtOAc/hexane) on silica gel to afford 6a–c in about
40% yield and 7a–b in about 25% yield. N-Acetyl-1-(40-
chlorophenyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroiso-
quinoline (6a). Mp: 168–169 ꢁC. Rf = 0.67 (EtOAc). 1H
NMR (300 MHz, CDCl3): d 2.13 (s, 3H, NCOCH3), 2.73
(dt, J = 3.68, 16.18 Hz, 1H, CHH), 2.84–2.95 (m, 1H,
CHH), 3.29-3.39 (m, 1H, CHH), 3.64–3.71 (ddd, J = 2.94,
5.14, 13.23 Hz, 1H, CHH), 3.77 (s, 3H, OCH3), 5.68 (t,
J = 3.62 Hz, 1H, OH), 6.47 (s, 1H, H-1), 6.74 (s, 1H, H-5),
6.82 (s, 1H, H-8), 7.16 (d, J = 8.82 Hz, 2H, ArH), 7.22 (d,
J = 8.09 Hz, 2H, ArH). LRMS (EI): 331 (M+, 100%).
HRMS (EI): calcd for C18H18ClNO3 331.0970, found
331.0965. N-Acetyl-1-(30-chlorophenyl)-6-hydroxy-7-meth-
oxy-1,2,3,4-tetrahydroisoquinoline (6b). Mp: 173–175 ꢁC.
1
Rf = 0.67 (EtOAc). H NMR (300 MHz, CDCl3): d 2.16 (s,
3H, NCOCH3), 2.69 (dt, J = 3.66, 16.15 Hz, 1H, CHH),
2.84–2.89 (m, 1H, CHH), 3.31–3.41 (m, 1H, CHH), 3.65–
3.72 (ddd, J = 2.94, 5.14, 13.24 Hz, 1H, CHH), 3.78 (s, 3H,
OCH3), 5.69 (t, J = 4.68 Hz, 1H, OH), 6.49 (s, 1H, H-1),
6.74 (s, 1H, H-5), 6.82 (s, 1H, H-8), 7.11–7.15 (m, 1H,
ArH), 7.17–7.25 (m, 3H, ArH). LRMS (EI): 331 (M+,
100%). HRMS (EI): calcd for C18H18ClNO3 331.0970,
found 331.0963. N-Acetyl-1-(30,40-dichlorophenyl)-6-hy-
droxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (6c). Mp:
197–199 ꢁC. Rf = 0.63 (EtOAc). 1H NMR (300 MHz,
CDCl3): d 2.14 (s, 3H, NCOCH3), 2.70 (dt, J = 3.68,
16.18 Hz, 1H, CHH), 2.84-2.95 (m, 1H, CHH), 3.29-3.39
(m, 1H, CHH), 3.66–3.73 (ddd, J = 2.94, 5.15, 13.23 Hz,
1H, CHH), 3.78 (s, 3H, OCH3), 5.69 (s, 1H, OH), 6.45 (s,
1H, H-1), 6.75 (s, 1H, H-5), 6.78 (s, 1H, H-8), 7.09 (dd,
J = 1.84, 8.82 Hz, 1H, ArH), 7.26–7.35 (m, 2H, ArH).
LRMS (EI): 365 (M+, 100%). HRMS (EI): calcd for
C18H17Cl2NO3 365.0580, found 365.0577.N-Acetyl-1-(40-
chlorophenyl)-7-hydroxy-6-methoxy-1,2,3,4-tetrahydroiso-
quinoline (7a). Rf = 0.58 (EtOAc). 1H NMR (300 MHz,
CDCl3): d 2.14 (s, 3H, NCOCH3), 2.73 (dt, J = 2.94,

M. Gao et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2229–2233
2233
12.51 Hz, 1H, CHH), 2.84–2.97 (m, 1H, CHH), 3.31–3.41
(m, 1H, CHH), 3.66-3.75 (m, 1H, CHH), 3.86 (s, 3H,
OCH3), 5.80 (s, 1H, OH), 6.58 (s, 1H, H-1), 6.64 (s, 1H, H-
5), 6.74 (s, 1H, H-8), 7.13–7.20 (m, 4H, ArH). LRMS (EI):
331 (M+, 100%). HRMS (EI): calcd for C18H18ClNO3
331.0970, found 331.0966. N-Acetyl-1-(30-chlorophenyl)-7-
Pyrex vessel which contains K2CO3 (4 mg, in 0.2 mL H2O)
and Kryptofix 2.2.2 (10 mg, in 0.5 mL CH3CN). Azeotropic
distillation at 115 ꢁC with HPLC grade CH3CN (3· 1 mL)
under a nitrogen steam efficiently removed water to
form anhydrous K18F-Kryptofix 2.2.2 complex. The
nitro-precursor 5f (2–3 mg, dissolved in 0.5 mL CH3CN)
was introduced to the K18F-Kryptofix 2.2.2 complex.
The radiolabeling reaction was monitored by analytical
radio-HPLC method. Retention times (RTs) in the
analytical HPLC system were: RT5f = 2.93 min,
RT[18F]5g = 3.68 min, and RTK18F = 1.88 min. The reac-
tion mixture was sealed and heated at 120 ꢁC for 15–20 min
and was subsequently allowed to cool down, at which time
the crude product was passed through a Silica Sep-Pak
cartridge to remove Kryptofix 2.2.2 and unreacted K18F.
The Sep-Pak column was eluted with 15% MeOH/CH2Cl2
(5.0 mL), and the fractions were passed onto a rotatory
evaporator. The solvent was removed by evaporation under
high vacuum (0.1–1.0 mmHg) to give a crude product
[18F]5g. The mixture containing precursor and product was
purified with semi-preparative HPLC method. The contents
of the mixture residue were diluted with HPLC mobile
phase 3:1:3 CH3CN/MeOH/20 mM, pH 6.7 KHPO4ꢀ, and
injected onto the semi-preparative HPLC column. The
product fraction was collected, the solvent was removed by
rotatory evaporation under vacuum, and the final product
[18F]5g was formulated in saline, sterile-filtered through a
sterile vented Millex-GS 0.22 lm cellulose acetate mem-
brane, and collected into a sterile vial. Total radioactivity
was assayed and total volume was noted. The overall
synthesis, purification, and formulation time was 60–70 min
from EOB. RTs in the semi-preparative HPLC system were:
RT5f = 4.57 min, RT[18F]5g = 6.92 min. The radiochemical
yield of [18F]5g was 15–25%. Chemical purity, radiochem-
ical purity, and specific radioactivity were determined by
analytical HPLC method. The chemical purities of precur-
sor 5f and standard sample 5g were >96%, the radiochem-
ical purity of target radiotracer [18F]5g was >99%, and the
chemical purity of radiotracer [18F]5g was ꢁ92%; (g) X-ray
crystallography. The crystallographic measurements were
carried out on a Siemens P4 diffractometer with graphite-
hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline
(7b).
Rf = 0.62 (EtOAc). 1H NMR (300 MHz, CDCl3): d 2.15
(s, 3H, NCOCH3), 2.73 (dt, J = 3.68, 16.18 Hz, 1H, CHH),
2.88–2.99 (m, 1H, CHH), 3.36-3.46 (m, 1H, CHH), 3.68–
3.75 (m, 1H, CHH), 3.90 (s, 3H, OCH3), 5.82 (s, 1H, OH),
6.61 (s, 1H, H-1), 6.66 (s, 1H, H-5), 6.77 (s, 1H, H-8), 7.17–
7.21 (m, 4H, ArH). LRMS (EI): 331 (M+, 100%). HRMS
(EI): calcd for C18H18ClNO3 331.0970, found 331.0962; (e)
Tracers 6-[11C]5a–c, 7-[11C]5a–b, and [11C]5e, typical exper-
imental procedure for the radiosynthesis: The precursor
(6a–c, 7a–b, or 5d) (0.3-0.5 mg) was dissolved in CH3CN
(300 lL). To this solution was added 6 N NaOH (2-3 lL).
The mixture was transferred to a small volume, three-
necked reaction tube. 11CH3OTf was passed into the
air-cooled reaction tube at ꢀ15 to ꢀ20 ꢁC, which was
generated by a Venturi cooling device powered with 100 psi
compressed air, until radioactivity reached a maximum
(ꢁ3 min), then the reaction tube was heated at 70–80 ꢁC for
3 min. The contents of the reaction tube were diluted with
NaHCO3 (1 mL, 0.1 M). This solution was passed onto a
C18 cartridge by gas pressure. The cartridge was washed
with H2O (2· 3 mL), and the aqueous washing was
discarded. The product was eluted from the column with
EtOH (2· 3 mL) and then passed onto a rotatory evapo-
rator. The solvent was removed by evaporation under high
vacuum. The labeled product 6-[11C]5a–c, 7-[11C]5a–b, or
[11C]5e was formulated with NaH2PO4 (50 mM), whose
volume was dependent upon the use of the labeled product
6-[11C]5a–c, 7-[11C]5a–b, or [11C]5e in tissue biodistribution
studies (ꢁ6 mL, 3· 2 mL) or in micro-PET imaging studies
(1–3 mL), sterile-filtered through a sterile vented Millex-GS
0.22 lm cellulose acetate membrane, and collected into a
sterile vial. Total radioactivity was assayed and total
volume was noted. The overall synthesis time was
15–20 min. The decay corrected radiochemical yield, from
11CO2, was 30–45%, and the radiochemical purity was
>95% by analytical HPLC. Retention times in the analyt-
ical HPLC system were: RT6a–c, 7a–b, 5d = 2.10–2.95 min,
RT6-[11C]5a–c, 7-[11C]5a–b, [11C]5e = 3.35–4.40 min. The
chemical purities of the target tracers 6-[11C]5a–c,
7-[11C]5a–b, and [11C]5e were >93%; (f) Tracer [18F]5g:
No-carrier-added (NCA) aqueous H18F (0.5 mL) prepared
by 18O(p,n)18F nuclear reaction in a RDS-112 cyclotron on
an enriched H218O water (95+%) target was added to a
˚
monochromated Mo-Ka radiation (k = 0.71073 A) and 12-
kW rotating generator. The data were collected at 110 K.
The structure was solved and refined using the programs
SHELXS-97 (Sheldrick, 1997) and SHELXL (Sheldrick
1997). The program X-Seed (Barbour, 1999) was used as an
interface to the SHELX programs. X-ray coordinates have
been deposited with the Cambridge Crystallographic Data
Centre (CCDC) for small molecules and the deposition
number is CCDC 294643.