Synthesis and β-amyloid binding properties of rhenium 2-phenylbenzothiazoles

Article abstract of DOI:10.1016/j.bmcl.2009.02.096

As a first step toward the development of ^99mTc PiB analogs, we have synthesized six neutral Re 2-phenylbenzothiazoles via pendant or integrated approach. These Re compounds bind to Aβ_1-40 fibrils with fairly good affinities (K_i

Full text of DOI:10.1016/j.bmcl.2009.02.096

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2258–2262
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and b-amyloid binding properties of rhenium 2-phenylbenzothiazoles
b
a
b
Kuo-Shyan Lin a, , Manik L. Debnath , Chester A. Mathis , William E. Klunk
*
a Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA
b Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA
a r t i c l e i n f o
a b s t r a c t
As a first step toward the development of 99mTc PiB analogs, we have synthesized six neutral Re 2-phen-
ylbenzothiazoles via pendant or integrated approach. These Re compounds bind to Ab1–40 fibrils with
fairly good affinities (Ki = 10.0–88.6 nM) and have moderate lipophilicities (logPC18 = 1.21–3.26). The
Re compounds prepared via the integrated approach are smaller in size, and therefore their correspond-
ing 99mTc analogs would have a greater chance of crossing the blood-brain barrier well. For potential clin-
ical applications, further optimization on the structure–activity relationship to obtain Re 2-
phenylbenzothiazoles with higher binding affinities (<10 nM) might be needed. The integrated approach
reported here to obtain neutral, compact and lipophilic Re 2-phenylbenzothiazoles could to be applied to
other high affinity pharmacophores as well as to generate 99mTc analogs that could hold promise for
extending the use of Ab imaging in living human brain to many more clinical settings because they could
be used with SPECT.
Article history:
Received 9 January 2009
Revised 23 February 2009
Accepted 24 February 2009
Available online 27 February 2009
Keywords:
Technetium-99m
Rhenium
SPECT
PiB
b-Amyloid plaques
Alzheimer’s disease
Ó 2009 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is a progressive and fatal neurodegen-
erative disorder characterized by irreversible memory impairment,
continuous cognitive decline and behavioral disturbances. The pro-
duction and accumulation of b-amyloid peptides (Ab) is believed to
be pivotal to the pathogenesis and progression of AD1, and the for-
mation of Ab plaques precedes the appearance of clinical symp-
toms.2 Research on the treatment of AD has focused on the anti-
amyloid strategy and currently there are more than 10 anti-amy-
loid drugs in phase 1 to phase 3 clinical trials.3 The development
of Ab plaque targeting radiotracers has enabled non-invasive imag-
ing and quantification of Ab deposition in living human brain. This
technology could provide a useful tool for identifying preclinical
cases of AD as candidates for early intervention and to follow the
effectiveness of anti-amyloid therapy in individual patients.
Among Ab imaging agents4–9 currently under clinical evaluation,
hospitals have a PET scanner. However, many more hospitals have
the capacity to perform single photon emission computed tomog-
raphy (SPECT). Ab imaging agents labeled with SPECT isotopes
especially the inexpensive and readily available 99mTc will have
more widespread clinical applicability especially in developing
countries that can not afford expensive cyclotron and PET scanners.
The preparation of 99mTc-labeled Ab imaging agents including
antibody 10H310 and derivatives of Congo red and chrysamine
G
11–13 have been reported. These radiotracers have limited clinical
application due to poor brain uptake resulting from the bulky
molecular size and/or charge of the Ab-binding moiety. Recently
several 99mTc-labeled tracers14–16 based on small high affinity
pharmacophores have been prepared. Among them, 99mTc-labeled
biphenyl14 and 2-phenylbenzothiazole16 analogs showed good
brain uptake in mice and their ability to bind to Ab plaques were
demonstrated via autoradiography14 or fluorescent staining16
using brain tissue from AD patients and/or transgenic mice. How-
ever, their binding affinities to aggregated Ab in terms of the equi-
librium dissociation constant Kd or inhibition constant Ki were not
reported. With the success in the development of the PET radio-
tracer PiB, we were also interested in the development of its SPECT
version labeled with 99mTc for more widespread use. Since there is
no stable isotope of Tc available, we used Re, a congener of Tc, for
our initial studies. Re and Tc both belong to the group VIIB of the
periodic table of elements. Because of the lanthanide contraction,
the chemical and physical properties of Re are similar to those of
Tc. The methodologies developed to generate Re complexes are
generally applicable to generate their corresponding Tc analogs.
Therefore, Re has been widely used as a surrogate for Tc in
2-(4-[11C]methylaminophenyl)-6-hydroxybenzothiazole
(Pitts-
burgh Compound-B, PiB)5 has achieved highest signal-to-noise ra-
tio, and has been adopted to perform AD-related research studies
at more than 40 research centers worldwide. Unfortunately, due
to its short half-life (20 min) the 11C label on PiB limits its use to
major academic PET (positron emission tomography) facilities with
on-site cyclotrons and sophisticated radiochemistry laboratories.
Derivatives of PiB8 labeled with the longer half-life (110 min)
radioisotope 18F have recently been developed and could increase
the availability of Ab imaging to all PET facilities, but this still rep-
resents a minority of modern hospitals, as only a small fraction of
* Corresponding author. Tel.: +1 412 647 4572; fax: +1 412 647 0700.
E-mail address: link@upmc.edu (K.-S. Lin).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.096

K.-S. Lin et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2258–2262
2259
radiotracer development for characterization of complex structure
and determination of binding affinity.12,14,17 Here we report the
synthesis and Ab binding properties of six neutral Re 2-arylbenzo-
thiazoles as our first step toward the development of 99mTc PiB
analogs for use with SPECT. Based on our previous work with
one amide N–H group and two thiol S–H groups. The Re-MAMA
chelate was connected to the 6-position of 2-phenylbenzothiazole
pharmacophore via a 3-C pendant to minimize its interference on
the binding of 2-(4-dimethylaminophenyl)benzothiazole to aggre-
gated Ab. Compound 1 was lipophilic (logPC18 = 3.26; PC18: estima-
tion of Poct by a reverse phase HPLC method19) and showed high
binding affinity (Ki = 10.0 nM) to Ab1–40 fibrils as determined by
previously published procedures19–21 using [3H]BTA-1 as the radio-
active control compound. However, there are concerns that the
corresponding 99mTc analog of 1 may not cross the blood-brain bar-
rier satisfactorily due to its high molecular weight (617 Da). Fur-
thermore, 99mTc complexes derived from amino chelators such as
diaminedithiol (DADT) typically show higher brain uptake than
those derived from tetradentate chelators containing amide groups
such as MAMA.14,22 Therefore, in addition to the pendant approach
used for the preparation of 1, we also designed and synthesized 2–
6 (Table 1) with a tetradentate chelator integrated into the 2-phen-
ylbenzothiazole pharmacophore to lower the overall molecular
PiB, we targeted compounds with a Ki 6 10 nM and a logPoct (Poct
:
octanol–water partition coefficient) between 1 and 3.18
Compound 1 (Table 1) was synthesized in three steps from 2-
(4-dimethylaminophenyl)-6-hydroxybenzothiazole19 as illustrated
in Scheme 1. The dimethylamino substitution at the 40-position
was used to increase the binding affinity to aggregated Ab as we
have demonstrated previously that substitutions at the 6- and 40-
position of 2-phenylbenzothiazole with electron-donating groups
such as amino, methylamino, dimethylamino, hydroxyl or alkoxyl
groups led to analogs with high binding affinity to aggregated
Ab.19 The oxorhenium core [Re(V)O]3+ was chelated by a monoa-
mide-monoamine-dithiol (MAMA) tetradentate chelator, and the
overall charge was balanced by the loss of three protons from
Table 1
Properties of Re 2-phenylbenzothiazoles including molecular weight (MW), binding affinity (Ki) to Ab1–40, and lipophilicity (logPC18
)
Compound number
Structure
MW
Ki (nM)
LogPC18
1
7
2' 3'
HO
S
2
6
5
NH
—
256
4.3
1.23
4'
5'
N
3
6'
4
PiB
O
O
Re
N
S
N
S
O
1
2
704 (617*)
10.0
30.0
3.26
2.59
S
N
N
O
Re
N
N
S
N
629 (542*)
S
N
N
O
S
N
N
S
N
O
Re
3
616 (528*)
86.9
88.6
2.52
1.21
N
HO
S
N
N
S
N
N
O
Re
4
5
602 (514*)
S
O
Re
S
591 (503*)
575 (487*)
43.0
29.7
2.30
1.65
N
N
O
O
S
N
H
H
N
S
O
Re
O
6
S
N
N
*
Molecular weight of their corresponding Tc analogs.

2260
K.-S. Lin et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2258–2262
O
N
O
HO
O
Re
N
S
O
Cl
O
S
N
NH
N
S
O
a
S
N
S
N
S
N
b
c
N
N
N
N
S
S
1
Tr t Tr t
Scheme 1. Synthesis of 1. Reagents and conditions: (a) 1-bromo-3-chloropropane, K2CO3, acetone, 63 h, reflux, 76%; (b) N-[2-[(triphenylmethyl)thio]ethyl]-2-[[2-
[(triphenylmethyl)thio]ethyl]amino]acetamide, K2CO3, KI, CH3CN, 67 h, reflux, 68%; (c) (1) TFA, Et3SiH, 5 min, rt; (2) ReO(PPh3)2Cl3, NaOAc, MeOH, 20 h, 75 °C, 7%.
weight of their corresponding 99mTc analogs to <550 Da. All the
nitrogen moieties in the integrated tetradentate chelators are ami-
no groups, in hopes that the 99mTc analogs of 2–6 would show ra-
pid and high brain entry.
(X = O in 5 and X = S in 6) chelators used for our studies were mod-
ified from the XH-diamide-thiol chelators reported by Le Gal and
coworkers.24 The complexation of [Re(V)O]3+ with Le Gal’s XH-dia-
mide-thiol chelators led to Re complexes with one negative charge
due to the loss of four protons. In order to produce neutral Re com-
plexes and have higher brain uptake of their 99mTc analogs, we re-
placed the two amide groups with two amino groups. Our results
showed that, after Re complexation, only three protons were lost
(from the phenol O–H, the thiol S–H, and the aromatic amino N–
H group for 5; from the aromatic amino N–H and two thiol S–H
groups for 6). With relatively higher pKa value, the aliphatic amino
N–H group was not deprotonated after Re complexation reaction,
and therefore, the overall charge was balanced.
The last step in the preparation of 1–6 involved a two-stage
reaction.25 The tetradentate chelating systems were first restored
by removing the trityl (Trt), p-methoxybenzyl (PMB) and/or
methoxymethyl (MOM) protecting groups under acidic conditions,
followed by an exchange labeling reaction using a labile Re com-
plex Re(V)O(PPh3)2Cl3. During the reaction, the oxorhenium core
[Re(V)O]3+ chelated by weak ligands triphenylphosphine and chlo-
ride was transferred to the stronger tetradentate chelating sys-
tems. Compounds 1–6 were isolated in 7–41% yields. In spite of
potential existence of cis- and anti-isomers, only one single isomer
was isolated in the preparation of 1–6. The chemical identities of
1–6 were confirmed by NMR26 and HRMS,27 but their absolute con-
figurations have not yet been determined by X-ray crystallography.
Compounds 2–6 were designed to be neutral, lipophilic and
compact by integrating the Re chelate into the 2-phenylbenzo-
Compounds 2–4 were synthesized with an integrated triamine-
thiol chelator as depicted in Schemes 2 and 3. The lateral amino
group of the triamine-thiol chelator was integrated into the 6-po-
sition at the benzothiazole ring in 2 or the 40-position at the phenyl
ring in 3 and 4. This triamine-thiol chelating system was modified
from a previously reported mercaptoacetylglycylglycylaminoben-
zene SN3 system.23 In the mercaptoacetylglycylglycylaminoben-
zene SN3 system, complexation with [Re(V)O]3+ led to a Re
chelate with one negative charge due to the loss of four protons
from three amide N–H groups and one thiol S–H group. It is well
documented that charged Tc complexes do not cross the blood-
brain barrier. Therefore, we modified the original SN3 chelating
system by replacing the three amide groups with three amino
groups for potentially higher brain uptake. We also added a small
methyl group to one of the aliphatic amino groups in order to ob-
tain neutral Tc/Re complexes. Through such modification the over-
all charge was balanced by losing all three protons (from two
amino N–H groups and one thiol S–H group) after [Re(V)O]3+ com-
plexation reaction and the desired neutral compounds 2–4 were
obtained.
To further reduce the molecular weight we also prepared 5 and
6 in which two electron-donating groups of a tetradentate chelat-
ing system were incorporated into the phenyl ring at the 30- and 40-
position as shown in Scheme 4. The semi-rigid XH-diamine-thiol
H
H2N
Cl
N
S
N
S
N
a
N
N
O
N
S PMB
N
S PMB
c
d
H
N
H
N
NH
NH
S
N
N
NH2
S
N
O
b
N
N
NH HN
O
CF3
S
PMB
N O S
Re
e
N
N
S
N
N
2
Scheme 2. Synthesis of 2. Reagents and conditions: (a) 2-chloroacetyl chloride, K2CO3, THF, 14 h, rt, 92%; (b) (1) 2-(4-methoxybenzylthio)ethyl bromide, CH2Cl2, 18 h, reflux;
(2) NaOH, H2O, MeOH, 4 h, rt, 67%; (c) KI, K2CO3, CH3CN, 14 h, reflux, 68%; (d) LAH, THF, 17 h, rt, 44%; (e) (1) TFA, anisole, CH3SO3H, 1 h, rt; (2) ReO(PPh3)2Cl3, NaOAc, MeOH,
24 h, 75 °C, 17%.
O
O
RO
RO
S
N
RO
RO
S
N
S
N
S
N
a
b
c
NH2
NH Cl
NH HN
NH HN
PMB
S
N
PMB
S
N
R= CH3 or MOM
R1O
S
d
O
Re
N
S
N
3: R1= CH3
4: R1= H
N
N
Scheme 3. Synthesis of 3 and 4. Reagents and conditions: (a) 2-chloroacetyl chloride, K2CO3, THF, 15 h, rt, 83–92%; (b) N-methyl-N-[2-[(4-methoxybenzyl)thio]ethyl]-1,2-
ethanediamine, KI, K2CO3, CH3CN, 14 h, reflux, 87–88%; (c) LAH, THF, 20 h, rt, 43–58%; (d) (1) TFA, anisole, CH3SO3H, 1 h, rt; (2) ReO(PPh3)2Cl3, NaOAc, MeOH, 24 h, 75 °C, 27–
41%.

K.-S. Lin et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2258–2262
2261
OMOM
NO2
OH
NO2
O
F
O
S
N
S
N
c
a
e
R
R
O
Cl
SH
O
O
S
N
S
N
H
f
N
NH2
NH2
O
d
S
b
O
NO2
R= OMOM or S-PMB
N
PMB
PMB
S
S
S
O
X
R
R
i
Re
g
h
O
N
5: X= S
6: X= O
O
HN
O
HN
H
S
N
S
N
S
N
H
H
N
N
N
O
Scheme 4. Synthesis of 5 and 6. Reagents and conditions: (a) 3-hydroxy-4-nitrobenzaldehyde, DMSO, 31 h, 125 °C, 65%; (b) 3-fluoro-4-nitrobenzoyl chloride, NMP, 23 h,
125 °C, 73%; (c) MOMCl, DIEA, THF, 16 h, reflux, 51%; (d) (1) 4-methoxy- -toluenethiol, K2CO3, DMF, 17 h, 95 °C; (2) SnCl2, THF, EtOH, 3 h, reflux, 56%; (e) Cu(OAc)2, NaBH4,
a
EtOH, 17 h, rt, 100%; (f) 2-chloroacetyl chloride, K2CO3, THF, 18 h, rt, 81–82%; (g) 2-(4-methoxybenzylthio)ethylamine, KI, K2CO3, CH3CN, 18 h, reflux, 75–98%; (h) LAH, THF,
20 h, rt, 45–81%; (i) (1) TFA, anisole, CH3SO3H, 1 h, rt; (2) ReO(PPh3)2Cl3, NaOAc, MeOH, 24 h, 75 °C, 17–23%.
thiazole pharmacophore. In addition, they also have electron-
donating groups substituted at both 6- and 40-position to promote
high binding affinity to aggregated Ab. The integration of a tetra-
dentate chelator into the benzothiazole ring provides an elec-
tron-donating group at the 6-position (compound 2) whereas the
integration of a tetradentate chelator into the phenyl ring provides
an electron-donating group at the 40-position (compounds 3–4) or
at both the 30- and 40-position (compounds 5–6). In vitro binding
assays showed that 2–6 also bind aggregated Ab with good affini-
ties (29.7–88.6 nM). In addition, 2–6 are all lipophilic with the
logPC18 values in the range of 1.21 to 2.59. Comparing 3 with 4,
the binding affinity did not change (86.9 vs 88.6 nM) when the
methoxy group at the 6-position was replaced with a hydroxyl
group, but its logPC18 value was reduced from 2.52 to 1.21. The
ꢀ1.3 unit reduction in logPC18 value when replacing the 6-position
methoxy group of 2-phenylbenothiazole with a hydroxyl group
was consistent with our previous observation during the develop-
ment of PiB.19 Comparing 5 with 6, the replacement of a thiol
group at the 30-position with a more hydrophilic and electron-
donating hydroxyl group reduced its logPC18 value (2.30 vs 1.65)
and slightly enhanced its binding affinity to aggregated Ab (43.0
vs 29.7 nM). MAMA13 (in 1) and semi-rigid SH-diamine-thiol28
(in 6) chelating systems have previously been used for the prepa-
ration of neutral Tc/Re complexes. However, to the best of our
knowledge, neutral Tc/Re complexes derived from the triamine-
thiol (in 2–4) and semi-rigid OH-diamine-thiol (in 5) chelating sys-
tems used for our studies have never been reported before. While
triamine-thiol and semi-rigid XH-diamine-thiol (X = S or O) chela-
tors all form neutral Re complexes, the use of different tetradentate
chelators or the same chelator integrated at different positions
combined with substitutions of electron-donating groups at other
positions might generate compact Tc/Re 2-phenylbenzothiazoles
with different binding affinity, lipophilicity and in vivo pharmaco-
kinetics. A more systematic exploration on the structure-activity
relationship is likely to provide the desired 2-phenylbenzothiazole
to be labeled with 99mTc for imaging Ab deposition with SPECT.
In summary, we have synthesized six neutral Re 2-phen-
ylbenzothiazoles and measured their binding affinity to aggregated
Ab. Synthesized via the pendant approach, compound 1 displayed
high binding affinity to aggregated Ab (Ki = 10 nM). However, the
introduction of a 3-C aliphatic linker also resulted in higher molec-
ular weight (>550 Da) and lipophilicity (logPC18 = 3.26) that ex-
ceeded our target range of 1–3. Both high molecular weight and
lipophilicity might limit the passage of 99mTc analog of compound
1 across the blood-brain barrier. Synthesized via the integrated ap-
proach, 2–6 were smaller in size and displayed moderate lipophi-
licities (logPC18 = 1.21–2.59) that fell into our target range and
binding affinities to aggregated Ab (Ki = 29.7–88.6 nM) that were
near our target of Ki 6 10 nM. By simply replacing only the Re atom
on 2–6 with a 99mTc isotope, the resulting 99mTc 2-phenylbenzo-
thiazoles are expected to retain the high binding affinity to aggre-
gated Ab. Since these 99mTc 2-phenylbenzothiazoles would be
small (<550 Da), neutral and lipophilic as well, they are likely to
cross the blood-brain barrier and enter the brain. However, for
clinical application, further modification to obtain Tc/Re 2-phen-
ylbenzothiazoles with ever higher binding affinity might be needed
since most of the Ab imaging agents currently in clinical evaluation
have binding affinities less than 10 nM. Nevertheless, the binding
affinities of 1–6 presented here are the first Ab binding data of
Re complexes derived from PiB ever to be reported. In addition,
our preliminary results also have demonstrated that it is feasible
to obtain small, neutral, and lipophilic Re 2-phenylbenzothiazoles
with fairly good binding affinity to aggregated Ab through the inte-
grated design introduced here. Further optimization on the struc-
ture-activity relationship of 2-phenylbenzothiazole and the
application of this approach to other high affinity pharmacophores
such as stilbene6 and diphenylacetylene29 have great potential to
generate promising 99mTc analogs for imaging Ab deposition in liv-
ing human brain with SPECT.
Acknowledgments
This work was supported by the National Institutes of Health
(R01 AG018402, P50 AG005133, R01 AG020226, R37 AG025516,
and P01 AG025204), the Alzheimer’s Association (TLL-01-3381),
and the US Department of Energy (DE-FD02-03 ER63590).
References and notes
1. Hardy, J.; Selkoe, D. J. Science 2002, 297, 353.
2. Pike, K. E.; Savage, G.; Villemagne, V. L.; Ng, S.; Moss, S. A.; Maruff, P.; Mathis, C.
A.; Klunk, W. E.; Masters, C. L.; Rowe, C. C. Brain 2007, 130, 2837.
3. Pangalos, M. N.; Jacobsen, S. J.; Reinhart, P. H. Biochem. Soc. Trans. 2005, 33, 553.
4. Shoghi-Jadid, K.; Small, G. W.; Agdeppa, E. D.; Kepe, V.; Ercoli, L. M.; Siddarth,
P.; Read, S.; Satyamurthy, N.; Petric, A.; Huang, S. C.; Barrio, J. R. Am. J. Geriatr.
Psychiatry 2002, 10, 24.
5. Klunk, W. E.; Engler, H.; Nordberg, A.; Wang, Y. M.; Blomqvist, G.; Holt, D. P.;
Bergstrom, M.; Savitcheva, I.; Huang, G. F.; Estrada, S.; Ausen, B.; Debnath, M.
L.; Barletta, J.; Price, J. C.; Sandell, J.; Lopresti, B. J.; Wall, A.; Koivisto, P.; Antoni,
G.; Mathis, C. A.; Langstrom, B. Ann. Neurol. 2004, 55, 306.
6. Verhoeff, N. P. L. G.; Wilson, A. A.; Takeshita, S.; Trop, L.; Hussey, D.; Singh, K.;
Kung, H. F.; Kung, M. P.; Houle, S. Am. J. Geriatr. Psychiatry 2004, 12, 584.
7. Kudo, Y.; Okamura, N.; Furumoto, S.; Tashiro, M.; Furukawa, K.; Maruyama, M.;
Itoh, M.; Iwata, R.; Yanai, K.; Arai, H. J. Nucl. Med. 2007, 48, 553.
8. Mathis, C.A. Abstract of Papers, 54th Society of Nuclear Medicine Annual
Meeting, Washington, DC. Society of Nuclear Medicine: Reston, VA, 2007;
Abstract 187.
9. Rowe, C.C. Abstract of Papers, 54th Society of Nuclear Medicine Annual Meeting,
Washington, DC. Society of Nuclear Medicine: Reston, VA, 2007; Abstract 188.
10. Friedland, R. P.; Majocha, R. E.; Reno, J. M.; Lyle, L. R.; Marotta, C. A. Mol.
Neurobiol. 1994, 9, 107.
11. Han, H.; Cho, C. G.; Lansbury, P. T. J. Am. Chem. Soc. 1996, 118: 4506.
12. Zhen, W.; Han, H.; Anguiano, M.; Lemere, C. A.; Cho, C. G.; Lansbury, P. T. J. Med.
Chem. 1999, 42, 2805.

2262
K.-S. Lin et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2258–2262
13. Dezutter, N. A.; Dom, R. J.; de Groot, T. J.; Bormans, G. M.; Verbruggen, A. M.
Eur. J. Nucl. Med. 1999, 26, 1392.
14. Zhuang, Z. P.; Kung, M. P.; Hou, C.; Ploessl, K.; Kung, H. F. Nucl. Med. Biol. 2005,
32, 171.
was heated at 75 °C for 24 h. After cooling to rt, the solution was diluted with
water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate
phase was dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The crude product was purified by chromatography on silica
gel eluting with 10:90 methanol/ethyl acetate to give the expected product in
17–41% yields.
15. Kung, H.F. Abstract of Papers, 16th International Symposium on
Radiopharmaceutical
Radiopharmaceutical Sciences: Reston, VA, 2005; Abstract 251.
16. Chen, X.; Yu, P.; Zhang, L.; Liu, B. Bioorg. Med. Chem. Lett. 2008, 18, 1442.
Chemistry,
Sydney,
Australia.
Society
of
26. NMR spectra were recorded using
a Bruker AVANCE 300 MHz NMR
spectrometer, and were reported in parts per million downfield from
internal tetramethylsilane. Compound 1 (DMSO-d6): 1.48–1.60 (m, 1H), 2.16–
2.38 (m, 2H), 2.80–3.10 (m, 3H), 2.99 (s, 6H), 3.32–3.72 (m, 3H), 3.92–4.17 (m,
4H), 4.29 (d, J = 16.8 Hz, 1H), 4.34–4.43 (m, 1H), 5.02 (d, J = 16.8 Hz, 1H), 6.80
(d, J = 8.9 Hz, 2H), 7.08 (dd, J = 8.9, 2.2 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.77–
7.83 (m, 3H); Compound 2 (CDCl3): 2.10–2.20 (m, 1H), 2.55–2.70 (m, 2H), 3.06
(s, 6H), 3.20–3.41 (m, 3H), 3.29 (s, 3H), 3.61–3.82 (m, 2H), 3.90–4.03 (m, 2H),
4.21–4.33 (m, 1H), 4.80–4.89 (m, 1H), 6.75 (d, J = 8.9 Hz, 2H), 7.41 (dd, J = 8.9,
2.1 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.88–7.99 (m, 3H); Compound 3 (CDCl3):
2.11–2.21 (m, 1H), 2.60–2.71 (m, 2H), 3.20–3.40 (m, 3H), 3.38 (s, 3H), 3.56–
3.68 (m, 1H), 3.70–3.82 (m, 1H), 3.89 (s, 3H), 3.90–4.03 (m, 2H), 4.13–4.25 (m,
1H), 4.76–4.85 (m, 1H), 7.05 (dd, J = 8.9, 2.1 Hz, 1H), 7.28–7.36 (m, 3H), 7.90 (d,
J = 8.9 Hz, 1H), 7.98 (d, J = 8.3 Hz, 2H); Compound 4 (DMSO-d6): 2.09–2.20 (m,
1H), 2.70–2.81 (m, 1H), 3.19 (s, 3H), 3.20–3.52 (m, 5H), 3.60–3.72 (m, 1H),
3.80–4.03 (m, 3H), 4.58–4.70 (m, 1H), 6.92 (dd, J = 8.9, 2.1 Hz, 1H), 7.20 (d,
J = 8.6 Hz, 2H), 7.35 (d, J = 2.3 Hz, 1H), 7.72–7.89 (m, 3H), 9.75 (s, 1H);
Compound 5 (DMSO-d6): 2.02–2.14 (m, 1H), 2.81–3.00 (m, 2H), 3.30–3.46 (m,
2H), 3.84 (s, 3H), 3.89–3.98 (m, 1H), 4.27–4.43 (m, 2H), 7.08 (dd, J = 8.9, 2.3 Hz,
1H), 7.17 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 7.1 Hz, 1H), 7.86
(d, J = 8.9 Hz, 1H), 8.1 (s, 1H), 9.64 (s, 1H); Compound 6 (DMSO-d6): 2.09–2.21
(m, 1H), 2.81–2.92 (m, 1H), 2.95–3.03 (m, 1H), 3.14–3.24 (m, 1H), 3.60–3.71
(m, 1H), 3.83 (s, 3H), 3.85–4.03 (m, 2H), 4.34–4.44 (m, 1H), 6.97 (d, J = 8.1 Hz,
1H), 7.07 (dd, J = 8.9, 2.3 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H),
7.60 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H), 9.45 (s, 1H).
17. Le Gal, J.; Latapie, L.; Gressier, M.; Coulais, Y.; Dartiguenave, M.; Benoist, E. Org.
Biomol. Chem. 2004, 2, 876.
18. Mathis, C. A.; Wang, Y.; Klunk, W. E. Curr. Pharm. Des. 2004, 10, 1469.
19. Mathis, C. A.; Wang, Y. M.; Holt, D. P.; Huang, G. F.; Debnath, M. L.; Klunk, W. E.
J. Med. Chem. 2003, 46, 2740.
20. Klunk, W. E.; Wang, Y. M.; Huang, G. F.; Debnath, M. L.; Holt, D. P.; Mathis, C. A.
Life Sci. 2001, 69, 1471.
21. Mathis, C. A.; Bacskai, B. J.; Kajdasz, S. T.; McLellan, M. E.; Frosch, M. P.; Hyman,
B. T.; Holt, D. P.; Wang, Y. M.; Huang, G. F.; Debnath, M. L.; Klunk, W. E. Bioorg.
Med. Chem. Lett. 2002, 12, 295.
22. Oya, S.; Plossl, K.; Kung, M. P.; Stevenson, D. A.; Kung, H. F. Nucl. Med. Biol. 1998,
25, 135.
23. Hansen, L.; Cini, R.; Taylor, A., Jr.; Marzilli, L. G. Inorg. Chem. 1992, 31, 2801.
24. Le Gal, J.; Tisato, F.; Bandoli, G.; Gressier, M.; Jaud, J.; Michaud, S.;
Dartiguenave, M.; Benoist, E. Dalton Trans. 2005, 23, 3800.
25. (a) Synthesis of compound 1: To a solution of the trityl-protected precursor
(198 mg, 0.2 mmol) in trifluoroacetic acid (3 mL), triethylsilane was added
dropwise until the color of the solution became colorless. The mixture was
stirred for 5 min at rt, and then trifluoroacetic acid was removed under
reduced pressure. ReO(Ph3)2Cl3 (208 mg, 0.25 mmol) and NaOAc methanolic
solution (1.0 M, 20 mL) were added to the residue, and the resulting solution
was heated at 75 °C for 20 h. After cooling to rt, the solution was diluted with
water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate
phase was dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The crude product was purified by chromatography on silica
gel eluting with 10:90 methanol/ethyl acetate to give the title compound 1 as a
brown powder (10 mg, 7%). (b) Synthesis of compounds 2–6: To a solution of the
27. HRMS experiments were performed at the Department of Chemistry Mass
Spectrometry Facility, University of Pittsburgh, on a Waters LC/Q-Tof mass
spectrometer using electronspray ionization method. Compound 1: m/z calcd
for C24H30N4O3ReS3 (M+H) 705.1038, found 705.1032; Compound 2: m/z calcd
for C22H29N5OReS2 (M+H) 630.1371, found 630.1350; Compound 3: m/z calcd
for C21H26N4O2ReS2 (M+H) 617.1055, found 617.1055; Compound 4: m/z calcd
for C20H24N4O2ReS2 (M+H) 603.0898, found 603.0895; Compound 5: m/z calcd
for C18H19N3O2ReS3 (M+H) 592.0197, found 592.0198; Compound 6: m/z calcd
for C18H19N3O3ReS2 (M+H) 576.0426, found 576.0432.
respective
p-methoxybenzyl-protected
precursor
(0.27 mmol)
in
trifluoroacetic acid (3 mL) and anisole (0.2 mL), methanesulfonic acid
(1.5 mL) was added dropwise. The mixture was stirred for 1 h at rt, and then
cooled in ice/water bath. The solution was neutralized with NH4OH, and then
extracted with ethyl acetate (10 mL ꢁ 3). The ethyl acetate phases were
combined, dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. ReO(Ph3)2Cl3 (208 mg, 0.25 mmol) and NaOAc methanolic
solution (1.0 M, 20 mL) were added to the residue, and the resulting solution
28. Kagotani, H. Japan Patent 2000219674, 2000.
29. Chandra, R.; Oya, S.; Kung, M.-P.; Hou, C.; Jin, L.-Y.; Kung, H. F. J. Med. Chem.
2007, 50, 2415.