Non-cross-bridged tetraazamacrocyclic chelator for stable 64Cu-based radiopharmaceuticals

Article abstract of DOI:10.1021/ml400142s

N-mono/dimethylated TE2A tetraazamacrocycles (MM-TE2A and DM-TE2A) were synthesized in high yields. Both Cu-MM/DM-TE2A complexes showed increased kinetic stability compared to that of Cu-TE2A, whereas Cu-DM-TE2A showed even higher in vitro stability than that of Cu-ECB-TE2A. MM-TE2A and DM-TE2A were quantitatively radiolabeled with ⁶⁴Cu ions and showed rapid clearance from the body to emerge as a potential efficient bifunctional chelator.

Full text of DOI:10.1021/ml400142s

Letter
pubs.acs.org/acsmedchemlett
64
Non-Cross-Bridged Tetraazamacrocyclic Chelator for Stable Cu-
Based Radiopharmaceuticals
Ajit V. Dale,†,# Darpan N. Pandya,†,# Jung Young Kim,‡ Hochun Lee,§ Yeong Su Ha,† Nikunj Bhatt,†
Jonghee Kim,† Jeong Ju Seo,∥ Woonghee Lee,† Sung Hong Kim,⊥ Young-Ran Yoon,∥ Gwang Il An,*,‡
and Jeongsoo Yoo*,†
†Department of Molecular Medicine, Kyungpook National University School of Medicine, Daegu 700-422, South Korea
‡Molecular Imaging Research Centre, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea
§Department of Energy Systems Engineering, Daegu Gyeongbuk Institute of Science & Technology, Daegu 711-873, South Korea
∥Department of Biomedical Science and Clinical Trial Center, Kyungpook National University Graduates School and Hospital,
Daegu, South Korea
⊥Analysis Research Division, Daegu Center, Korea Basic Science Institute, Daegu 702-701, South Korea
S
* Supporting Information
ABSTRACT: N-mono/dimethylated TE2A tetraazamacro-
cycles (MM-TE2A and DM-TE2A) were synthesized in high
yields. Both Cu-MM/DM-TE2A complexes showed increased
kinetic stability compared to that of Cu-TE2A, whereas Cu-
DM-TE2A showed even higher in vitro stability than that of
Cu-ECB-TE2A. MM-TE2A and DM-TE2A were quantitatively
radiolabeled with 64Cu ions and showed rapid clearance from
the body to emerge as a potential efficient bifunctional chelator.
KEYWORDS: Bifunctional chelator, copper complex, imaging agent, radiopharmaceutical
dvances in metal-based radiopharmaceuticals are driving
research and development for medical diagnosis and
A
therapy.1−3 Several copper radioisotopes (60Cu, 61Cu, 62Cu,
64Cu, and 67Cu) have attractive physical properties for medical
applications, and various radioactive copper labeled bioconju-
gates are in the clinical trial pipeline.4−6 The successful
development of Cu(II)-based radiopharmaceuticals is not
only dependent on targeting biomolecules but also highly
dependent on the proper choice of a bifunctional chelator
(BFC) coordinating radioactive Cu(II) ions.7−9
Enormous efforts to construct an ideal BFC have been seen
in recent decades. These BFCs should be radiolabeled with
radioactive copper ions at a mild temperature with fast reaction
kinetics, form stable complex with Cu(II), and possess rapid
body clearance.
Figure 1. Commonly used bifunctional chelators for radioactive Cu
radiolabeling.
Various tetraazamacrocyclic BFCs containing N-acetic acid
pendant arms have been utilized for Cu(II) complexation
(Figure 1). The kinetic stability of BFC-Cu(II) complexes
could indicate their in vivo stability more closely than
thermodynamic stability.10 The order of stability for the
BFC-Cu(II) complexes is Cu-ECB-TE2A ≫ Cu-TETA ≈
Cu-DOTA > Cu-EDTA.10,11 It is now well accepted that 64Cu-
TETA and 64Cu-DOTA are prone to transchelation of 64Cu
ions to proteins under physiological conditions resulting in
slow body clearance of radioactivity.12,13 Ethylene cross-bridged
(ECB)-TE2A shows excellent kinetic stability for Cu(II) ions in
acid decomplexation experiments and equally good in vivo
inertness. However, despite this high stability, ECB-TE2A
suffers from shortcomings such as cumbersome synthesis (total
synthesis time: 35 days and 45% overall yield from cyclam), and
harsh radiolabeling conditions for 64Cu ions (1−2 h at 75−95
°C).14,15
We have reported that TE2A (1,8-N,N′-bis-(carboxymethyl)-
1,4,8,11-tetraazacyclotetradecane) is a better chelator for
Cu(II) ions than TETA (1,4,8,11-tetraazacyclotetradecane-
1,4,8,11-tetraacetic acid) and DOTA (1,4,7,10-tetraazacyclodo-
Received: April 16, 2013
Accepted: July 25, 2013
Published: July 25, 2013
© 2013 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
decane-1,4,7,10-tetraacetic acid) in terms of high kinetic
stability and easy radiolabeling.16 TE2A forms a stable Cu(II)
complex by attaining a strong N4 in-plane ligand field in the
trans configuration, whereas the Cu-TETA complex prefers
N2O2 coordination in an equatorial plane, even in the same
trans configuration.17−19
Here, we report the synthesis and physical characterization of
N-dimethyl TE2A (DM-TE2A), which is a structural analogue
of ECB-TE2A with a broken ethylene cross-bridge. In addition,
we also synthesized N-monomethyl TE2A (MM-TE2A) to
determine if there is any systematic change in stability
depending on the N-alkylation number (Figure 2).
TFA treatment to yield MM-TE2A as TFA salt. Dimethylation
on the secondary amines of trans-disubstituted cyclam 6 was
tried using excess MeI but resulted in only a monomethylated
compound as a major product instead of the desired
dimethylated analogue. All intermediates and final chelators
1
were fully characterized by H-/13C NMR and high-resolution
mass spectroscopy (see Supporting Information).
By employing efficient synthetic routes, DM-TE2A and MM-
TE2A were synthesized with overall yields of 85% and 75%
from cyclam, respectively, in a short synthesis time. Substantial
improvement in the synthesis of DM-TE2A was achieved in
terms of high synthesis yield (<13% vs 85%) as well as simple
purification. MM-TE2A is first reported here.
MM-/DM-TE2A were refluxed with Cu(ClO4)2·6H2O in
methanol solution to give Cu-MM-/DM-TE2A complexes at
89% and 85% yields. Acidic decomplexation and cyclic
voltammetry experiments were carried out to verify kinetic
stability of the newly synthesized copper complexes. Drastic
acidic conditions (12 M HCl, 90 °C) were used to assess the
stability of the Cu(II) complexes, and their degradation pattern
was monitored by high performance liquid chromatography
(HPLC) (Figure 3a,b). The current stability data were
Figure 2. Structures of MM-TE2A and DM-TE2A.
DM-TE2A was first synthesized by Chapman et al. and
Comparone et al. in the 1990s, but their synthetic method-
ologies possess some drawbacks such as lower overall synthesis
yield (12.1% and 11.7%, respectively), tedious column
chromatographic purification, and sluggish reaction condi-
tions.18,20 Although the Cu(II) complex was also reported, no
further detailed physical characterization, particularly stability
experiments, have been carried out.
DM-TE2A and MM-TE2A were synthesized in four and five
steps from cyclam, respectively, as shown in Scheme 1.
Intermediates 3 and 6 were synthesized for DM-TE2A and
MM-TE2A, respectively, modifying a method published
previously.21 Intermediate 3 was treated with NaBH4 at room
temperature to yield dimethylated trans-disubstituted cyclam 4
for DM-TE2A synthesis.22 Then, the dimethylated trans-
disubstituted cyclam 4 was converted to DM-TE2A as a
trifluoroacetic acid (TFA) salt after being treated with TFA. For
MM-TE2A synthesis, compound 6 was stirred with CH3I at
room temperature for 1 day to obtain monomethylated trans-
disubstituted cyclam 7, which was hydrolyzed using the same
Figure 3. Time-dependent UV-HPLC chromatograms of Cu-MM-
TE2A (a) and Cu-DM-TE2A (b) during acidic decomplexation in 12
M HCl at 90 °C. Cyclic voltammograms (scan rate 100 mV/s, 0.2 M
phosphate buffer, pH 7) of Cu-MM-TE2A (c) and Cu-DM-TE2A (d).
a
Scheme 1. Synthesis of DM-TE2A and MM-TE2A
a
(i) HCHO, H2O, RT, 2 h; (ii) BrCH2CO2t-Bu, MeCN, RT, 1 d; (iii) NaBH4, EtOH, 1 d; (iv) 3 M NaOH, RT, 3 h; (v) MeI, CHCl3, RT, 1 d; (vi)
TFA/CH2Cl2 (1:1), RT, 1 d.
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ACS Medicinal Chemistry Letters
Letter
compared with those of Cu-TE2A and Cu-ECB-TE2A.16,21
Approximately 2.7% and 1.6% of the intact Cu-MM-/DM-
TE2A complexes were found at 4 and 14 h after incubation,
respectively, whereas most of the Cu-TE2A complex degraded
in <1 h in the same acid decomplexation experiment. The Cu-
DM-TE2A showed even higher robustness than Cu-ECB-TE2A
under this harsh acidic condition (Table 1). Only 2.9% of the
Scheme 2. 64Cu Radiolabeling of MM-TE2A (R′ = Me; R″ =
H) and DM-TE2A (R′ and R″ = Me)
Table 1. Acidic Decomplexation Study of Cu(II) Complexes
% of the intact Cu(II) complex
time (h) Cu-MM-TE2A Cu-DM-TE2A Cu-TE2A Cu-ECB-TE2A
1 h by the Cs2CO3 treatment as a base at 50 °C (Figure 4).
Even though DM-TE2A could also be quantitatively radio-
0
100
56.3
35.8
13.1
6.1
100
100
9.7
0.6
100
0.5
1
54.9
35.6
23.8
15.2
6.5
2
61.9
3
4
2.7
32.2
18.2
9.1
6
8
2.9
10
12
14
5.1
2.5
1.6
intact Cu-ECB-TE2A complex was found at 8 h postheating,
compared to 9.1% of Cu-DM-TE2A at the same time point
(Table 1).21 These acidic decomplexation studies clearly
showed that the further alkylation on the TE2A N-atoms
dramatically increased in vitro kinetic stability.
Both Cu-MM-/DM-TE2A complexes yielded irreversible
reduction voltammograms with similar reduction potential
values (Figure 3c,d). In comparison with Cu-TE2A and Cu-
ECB-TE2A, very similar irreversible cyclic voltammograms
were measured in the same scanning conditions (Table 2).21
Table 2. Reduction Potentials and Partition Coefficients of
the Cu(II) Complexes
Figure 4. UV-HPLC (280 nm, black) and radio-HPLC chromatogram
(red) of 64Cu-MM-TE2A (top) and 64Cu-DM-TE2A (bottom).
a
copper(II) complexes
Ered (V) vs Ag/AgCl
log P
labeled in 0.1 M NaHCO3 buffer (pH 9.5) in 1 h, a 95 °C
temperature incubation was required. We did not observe any
radiolabeled peak at a lower temperature (<40 °C) under
buffered conditions. MM-TE2A showed lower labeling yield
(∼70%) than DM-TE2A at the same buffer conditions (0.1 M
NaHCO3, pH 9.5, 1 h, 95 °C). These harsh radiolabeling
conditions were striking when considering the structural
similarity of MM-/DM-TE2A and TE2A. The quantitative
radiolabeling of TE2A with 64CuCl2 was achieved in simple
buffer within 20 min at 30 °C. The 64Cu-radiolabeling
conditions of MM- and DM-TE2A chelators more closely
resembled those of ECB-TE2A. This experiment showed that
the 64Cu-radiolabeling conditions can be highly influenced by
just one or two N-alkylations in the cyclam backbone.
Lipophilicity of the radiolabeled MM/DM-TE2A complexes
was measured using the octanol/water method (Table 2).21 As
expected, 64Cu-TE2A showed the most negative value (−3.36),
and lipophilicity increased in 64Cu-MM-TE2A and 64Cu-DM-
TE2A (−3.19 and −3.05, respectively) as the secondary amines
were converted to tertiary amines by N-methylation. The log P
value of 64Cu-ECB-TE2A fell in-between those of 64Cu-MM-
TE2A and 64Cu-DM-TE2A (−3.15).
Cu-DM-TE2A
Cu-MM-TE2A
Cu-TE2A
−0.97 (irrev)
−1.05 (irrev)
−1.05 (irrev)16
−1.07 (irrev)21
−3.05 0.06
−3.19 0.05
−3.36 0.02
−3.15 0.01
Cu-ECB-TE2A
a
Log P values were measured using 64Cu-labeled complexes.
Even though the reduction potential values of the Cu-MM-/
DM-TE2A complexes were slightly shifted to positive values
compared to those of TE2A and ECB-TE2A, the differences
were <100 mV.
Thus, N-methylation seemed to have a limited effect on the
electrochemical behavior of the TE2A Cu(II) complex
derivatives. Furthermore, both Cu-MM/DM-TE2A complexes
were expected to show similar inertness as Cu-TE2A and Cu-
ECB-TE2A to reduce Cu(II) to Cu(I) and subsequent
demetalation of the Cu(I) ions from chelators under
physiological conditions.
After analyzing the robustness of the synthesized Cu(II)
complexes, 64Cu radiolabeling of the BFCs was attempted
under a variety of conditions, i.e., different base and buffers, pH
(5−9.5), and temperature (25−99 °C) (Scheme 2). The
radiolabeling yield was measured by radio-thin-layer chroma-
tography and reconfirmed by radio-HPLC. Both MM- and
DM-TE2A were quantitatively radiolabeled with 64CuCl2 within
64Cu-MM/DM-TE2A did not show any signs of decom-
plexation for up to 24 h in the serum stability test (fetal bovine
serum, 37 °C).
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ACS Medicinal Chemistry Letters
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Finally, the in vivo stability and clearance pattern of 64Cu-
MM-/DM-TE2A were monitored by biodistribution experi-
ments in Balb/c mice (Figure 5).23 Both radiocomplexes
These biodistribution data suggest that the 64Cu-DM-TE2A
and 64Cu-MM-TE2A complexes cleared rapidly with minimum
transchelation of 64Cu ions from the chelators to the
biomolecules.12,26
Notably, even though DM-TE2A and ECB-TE2A share
structural similarity, their core coordination spheres of Cu(II)
complexes of the two chelators are very different.27 DM-TE2A
forms a Cu(II) complex in the trans-III configuration, in which
the Cu(II) ion exhibits coordination with four short bonds to
nitrogen in a ring plane and two longer bonds to oxygen in axial
positions.18 In contrast, the Cu-ECB-TE2A complex has a cis-V
configuration with Jahn−Teller elongation along a N−Cu−O
axis.14
A different conjugation strategy will be employed when MM-
and DM-TE2A are conjugated with biomolecules. The
additional functional group is to be introduced on the
remaining secondary amine for facile conjugation of MM-
TE2A with biomolecules, while one of two acetate groups of
DM-TE2A will be used for amide bond formation with amine
group of biomolecules.28 Cross-bridged monoamides, model
compounds of peptide-conjugated ECB-TE2A, showed high in
vivo stability and fast body clearance.29 On the basis of high
structural similarity between ECB-TE2A and DM-TE2A, high
in vivo stability of 64Cu-radiolabeled DM-TE2A-bioconjugate is
also expected. However, all further conjugation using MM/
DM-TE2A and following in vivo stability of conjugates should
be evaluated by appropriate experiments.
In summary, two non-cross-bridged TE2A derivatives
showing high kinetic stability were synthesized in an efficient
manner. MM- and DM-TE2A showed high similarity with
ECB-TE2A rather than TE2A in terms of high kinetic stability
and harsh radiolabeling conditions. Easy synthesis, high stability
of the Cu complex, and quantitative radiolabeling yield with
64Cu ions make MM/DM-TE2A a good candidate as a
potential BFC. Our results clearly demonstrate that there is
still room for developing a better chelator for 64Cu-radio-
labeling by simple structural fine-tuning of non-cross-bridged
tetraazamacrocyclic compounds.
Figure 5. Biodistribution data of 64Cu-MM-TE2A and 64Cu-DM-
TE2A at 30 min, 4 h, and 24 h postinjection in Balb/c mice (n = 5).
rapidly cleared from the body. The highest uptake of 64Cu-
MM-TE2A was observed in kidneys at 30 min (3.49 0.40% of
injected dose per gram, % ID/g) but decreased dramatically to
0.85 0.36 and 0.16 0.02% ID/g at 4 and 24 h postinjection,
respectively. Less than one-third of kidney uptake was seen in
the liver at 30 min (0.93 0.24% ID/g), indicating that 64Cu-
MM-TE2A is excreted mainly by the renal track. Very minimal
64Cu-MM-TE2A activity was observed in nonclearance organs
such as blood, heart, muscle, bone, and spleen at 24 h (<0.08%
ID/g).
A similar renal excretion pattern was observed for 64Cu-DM-
TE2A, but the hepatobilliary excretion portion via the liver was
higher than that of 64Cu-MM-TE2A at all time points.
Additionally, uptake in the lung, heart, and spleen also
increased for 64Cu-DM-TE2A compared to that of 64Cu-MM-
TE2A. This observation could be the consequence of higher
lipophilicity of 64Cu-DM-TE2A than that of 64Cu-MM-TE2A.
It is well documented that small lipophilic molecules show
persistent uptake in the liver, lung, heart, and spleen along with
elevated uptake in kidneys.24,25 However, liver uptake of 64Cu-
DM-TE2A also decreased dramatically from 1.43 0.54% ID/g
at 4 h to 0.42 0.03% ID/g at 24 h.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and detailed characterization for
synthesis of MM/DM-TE2A, Cu(II) complexation, acidic
decomplexation, cyclic voltametry, 64Cu radiolabeling, in vitro
serum stability experiments, partition coefficient, and com-
parative biodistribution experiments of 64Cu-MM/DM/ECB-
TE2A. This material is available free of charge via the Internet
at http://pubs.acs.org.
The blood, liver, and kidney uptake of 64Cu-MM-/DM-
TE2A at 24 h was compared with that of 64Cu-ECB-TE2A
because the late time biodistribution data could be a good
Table 3. Selected Organ Biodistribution (% ID/g) of 64Cu-
MM-TE2A, 64Cu-DM-TE2A, and 64Cu-ECB-TE2A at 24 h
Postinjection in Balb/c Mice (n = 5)
AUTHOR INFORMATION
Corresponding Author
■
64Cu-BFC complex
blood
kidney
liver
*(J.Y) Fax: (+82) 53-426-4944. E-mail: yooj@knu.ac.kr.
(G.I.A.) Fax: (+82) 2-970-2409. E-mail: gwangil@kirams.re.kr.
64Cu-MM-TE2A
64Cu-DM-TE2A
64Cu-ECB-TE2A
0.019 0.003
0.053 0.004
0.055 0.010
0.162 0.021
0.382 0.031
0.280 0.026
0.168 0.035
0.426 0.033
0.297 0.038
Author Contributions
#These authors contributed equally to this work.
Funding
indicator of in vivo Cu(II) complex stability (Table 3).12,26
64Cu-MM-TE2A showed the lowest values in all three organs
and 64Cu-DM-TE2A showed the highest uptake in the liver and
kidney, which seemed to have some correlation with their
lipophilicity. However, the uptake differences of the three
complexes were rather small and comparable with each other.
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government
(MSIP) (No. 20090081817, 2012-0006386, 20090078235, and
2013R1A2A2A01012250), and Brain Korea 21 Project. This
research was also partially supported by Kyungpook National
University Research Fund, 2012. The Korea Basic Science
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ACS Medicinal Chemistry Letters
Letter
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Institute (Daegu) is acknowledged for the NMR and MS
measurements.
Notes
The authors declare no competing financial interest.
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