Octadentate oxine-armed bispidine ligand for radiopharmaceutical chemistry

Article abstract of DOI:10.1021/acs.inorgchem.9b01016

In this study, we present the synthesis and characterization of the octadentate bispidine ligand, H₂bispox² and its complexes with medicinally useful radiometal nuclides (¹¹¹In³⁺ and ¹⁷⁷Lu³⁺), including their X-ray diffraction single crystal structures with the stable isotopes. ¹¹¹InCl₃ radiolabels the ligand quantitatively at ambient conditions ([L] = 10^?5 M, room temperature, pH 7 and 15 min) and the in vitro human serum stability assays demonstrated high stability of the [¹¹¹In(bispox²)]⁺ complex over 5 days. Moreover, the β^? emitter ¹⁷⁷Lu radiolabels the ligand at 37 °C in 30 min (pH 8). These initial investigations reveal the potential of the octadentate bispidine ligand H₂bispox² as a useful chelator for ¹¹¹In and ¹⁷⁷Lu-based radiopharmaceuticals.

Full text of DOI:10.1021/acs.inorgchem.9b01016

Article
pubs.acs.org/IC
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Octadentate Oxine-Armed Bispidine Ligand for
Radiopharmaceutical Chemistry
Neha Choudhary,†,‡ Alexander Dimmling,†,§ Xiaozhu Wang,† Lily Southcott,†,‡ Valery Radchenko,‡,∥
Brian O. Patrick,∥ Peter Comba,*,§ and Chris Orvig*,†
†Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver,
British Columbia V6T 1Z1, Canada
‡Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada
§
̈
Anorganisch-Chemisches Institut and Interdisciplinary Center for Scientific Computing, Universitat Heidelberg, INF 270, D-69120
Heidelberg, Germany
∥Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada
S
* Supporting Information
ABSTRACT: In this study, we present the synthesis and characterization of the
octadentate bispidine ligand, H2bispox2 and its complexes with medicinally useful
radiometal nuclides (111In3+ and 177Lu3+), including their X-ray diffraction single
crystal structures with the stable isotopes. 111InCl3 radiolabels the ligand
quantitatively at ambient conditions ([L] = 10−5 M, room temperature, pH 7
and 15 min) and the in vitro human serum stability assays demonstrated high
stability of the [111In(bispox2)]+ complex over 5 days. Moreover, the β‑ emitter
177Lu radiolabels the ligand at 37 °C in 30 min (pH 8). These initial investigations
reveal the potential of the octadentate bispidine ligand H2bispox2 as a useful
chelator for 111In and 177Lu-based radiopharmaceuticals.
γ)177Lu) with a half-life of 6.6 days that emits β‑ particles, as
INTRODUCTION
■
well as SPECT imageable γ-rays (113 and 208 keV).8 Recently,
Since the first clinical study in 1925 using bismuth-214 as a
177Lu-PSMA therapy has gained popularity as a viable
radiotracer to measure blood flow from arm to opposite arm,1,2
the increasingly diverse use of radionuclides has been expanding
the field of nuclear medicine, both in terms of diagnostic imaging
therapeutic option in men with metastatic prostate cancer.9
Lutetium is a medium-energy β− emitter (490 keV) with a
maximal tissue penetration of <2 mm, which provides better
(e.g., single photon emission computed tomography, SPECT,
irradiation of small tumors.10 The medicinal application of
and positron emission tomography, PET) and targeted therapy
(e.g., alpha (α), beta (β−), and Auger electron-therapy).3 A wide
range of metallic radionuclides with varying physical (e.g., half-
life, specific activity, emission type) and chemical (e.g., hardness,
acidity) properties can be produced by cyclotrons, nuclear
radiometal nuclides usually requires a bifunctional chelator to
bind the radiometal ion in order to form a thermodynamically
stable and kinetically inert metal complex, which can then be
delivered to the desired site in vivo via an attached targeting
vector for imaging or therapy.11 Besides the clinical relevance of
reactors and/or generators to afford a “nuclear chocolate box”
these radionuclides, it is of utmost importance to understand the
fundamental coordination chemistry of these metal complexes
that can be consulted and carefully selected from, depending on
the desired application or need.4
and the influence of the structural differences on their biological
Indium-111 is an attractive SPECT radionuclide that decays
with a half-life of 2.8 days via electron capture (100% EC) and
behavior.12 In terms of the coordination chemistry of In3+, owing
to its relatively large ionic size of 62−92 pm, it usually attains a
emits two high intensity γ-rays (245 and 172 keV) with near-
coordination number of 7−8 in its complexes.13 Although
ideal energy for diagnostic purposes. This radionuclide is widely
hydrated In3+ has a high pKa of 4.0,14 it is usually considered as a
available as it is commonly cyclotron-produced via 111Cd-
(p,n)111In and is clinically FDA approved for use in drugs such as
borderline acidic metal ion (IA = 6.3) with affinity for soft donor
groups, such as thiols,15,16 as well as hard donor groups, such as
phenolates and carboxylates.17,18 While the lanthanide Lu3+ is a
larger metal ion with an ionic radius of 86−103 pm and
Octreoscan (111In-pentetreotide), Prostascint (111In-capro-
mab), CEA-Scan (111In-arcitumonab), MPI indium DTPA
In111 (111In- DTPA), and indium In111 oxyquinoline
(111In-oxyquinoline).5 In addition, 111In emits Auger electrons
that can potentially be used for radiotherapy.6,7 Lutetium-177 is
a reactor-produced therapeutic radiometal ion (176Lu(n,
Received: April 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.9b01016
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coordination number 6−9,13 the metal ion has a strong
preference for hard basic donor atoms (IA = 10.07) such as
carboxylates.19
Over the past several decades, a plethora of both macrocyclic
and nonmacrocyclic chelating ligands have been developed for a
variety of radiometal ions.6,11,14,20,21 Some of these chelators
(Chart 1) include DTPA (diethylenetriamine pentaacetic acid),
DOTA (1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic
acid), H4octapa, H4neunpa, H4octox, and H2bispa2.10,21−25
DTPA is an FDA-approved 111In-based radiopharmaceutical
that can radiolabel 111In3+ within 15 min at ambient conditions;
however, it is known that DTPA complexes suffer from relatively
low kinetic stability, potentially leading to complex degradation
and free radiometal release in vivo. Conversely, metal complexes
of macrocyclic ligands (e.g., DOTA) generally retain higher
thermodynamic stability and kinetic inertness in vivo than the
nonmacrocyclic chelators, but typically exhibit slow complex-
ation kinetics. Therefore, they often require radiolabeling at
higher temperatures and longer reaction times; a major
drawback when working with heat-sensitive antibodies as a
targeting vector for the radiopharmaceutical.
Chart 1. Structures of Ligands Discussed
Among the nonmacrocyclic chelators, the recently reported
H4octox shows fast chelation with medicinally relevant trivalent
metal ions (i.e., Y3+, In3+, La3+, Lu3+, and Gd3+) and forms very
thermodynamically stable complexes in solution.24 Bispidines
are claw-like ligands with a very rigid adamantane-derived
backbone, enforcing axial coordination geometries and, depend-
ing on the type and number of pendent arms, tetra- up to
octadentate ligands with various donor sets have been
reported.25,26 The ensuing reactivities and thermodynamic
properties give rise to interesting applications in Fe-based
oxidation catalysis,27 Cu-based aziridination catalysis28,29 and
64/67Cu30−32 as well as 111In, 177Lu, and 225Ac based radio-
pharmaceutical chemistry.33 The ligand H2bispa2 consists of the
highly preorganized, rigid bispidine backbone, which enforces a
particular coordination geometry to the metal ions34 (a
characteristic usually more typical of macrocyclic ligands) and
the picolinic acid pendent arms help in faster complexation
(characteristic of acyclic chelators).31,33
Herein, we report an octadentate chelator, H2bispox2, the
design of which was inspired by the H2bispa2 bispidine backbone
and H4octox oxinate arms.24,33,35,36 The complexation behavior
Scheme 1. Synthesis of H2bispox2, 7
B
DOI: 10.1021/acs.inorgchem.9b01016
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Figure 1. 1H NMR spectra (CD3OD, room temperature, 300 MHz) of H2bispox2 (top) and [In(bispox2)]+ (bottom).
of the N6O2 donor set ligand, H2bispox2 was investigated with
nonradioactive In3+ and Lu3+ ions and the corresponding binary
metal complexes were characterized by nuclear magnetic
resonance (NMR) spectroscopy, mass spectrometry (MS),
single-crystal X-ray analysis, and infrared spectroscopy (IR). In
addition, radiolabeling studies were performed with 111In3+ and
177Lu3+ ions. In vitro human serum stability tests with
from N-alkylation of the secondary amines of the intermediate 4.
The unreacted side arm 5 was separated from the desired
product 6 by eluting through a silica plug with DCM, followed
by recrystallization of 6 using EtOAc. Deprotection of the
acetate groups of precursor 6 in mildly basic conditions yielded
H2bispox2 7. The ligand H2bispox2 was characterized by 1H and
13C NMR spectroscopy, and low- and high-resolution mass
spectrometry.
[
111In(bispox2)]+ were also performed to evaluate the potential
application of H2bispox2 as a chelator component in 111In-based
radiopharmaceuticals.
Metal Complexes. The coordination chemistry of the
octadentate ligand H2bispox2 with In3+ and Lu3+ ions was
studied for potential application in nuclear medicine. The 1:1
metal complexes were successfully synthesized from equimolar
solutions of the ligand and metal salts in methanol. The
formation of the metal complexes was confirmed by HR-ESI-MS
RESULTS AND DISCUSSION
■
Ligand Synthesis and Characterization. The synthetic
route (Scheme 1) for the bispidine-based ligand H2bispox2
[dimethyl 9-hydroxy-3,7-bis((8-hydroxyquinolin-2-yl)methyl)-
2,4-di(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicar-
boxylate] relies on the bispidol scaffold 4, which was synthesized
via a well-established protocol from commercially available
starting materials.33 The synthesis involves two consecutive
Mannich reactions to yield 2 and reduction of the C9 keto group
to yield bispidol 3 to prevent a retro-Mannich reaction.37−39
Deprotection with trifluoroacetic acid led to the intermediate 4,
which was isolated as the trifluoroacetic salt. The alkylating
agent 2-(bromomethyl)quinoline-8-yl acetate 5 was synthesized
from commercially available 8-hydroxy-2-methylquinoline in
two steps via protection of the phenolic −OH as acetate ester,
followed by free radical bromination.40,41 One drawback of using
NBS as a brominating agent was its tendency to disubstitute the
hydrogens of the methyl group via formation of 2,2′-
dibromomethyl-8-hydroxyquinoline. To optimize the reaction
conditions NBS and AIBN were added in small aliquots over 4 h
reaction time. The alkyl-protected ligand 6 was then synthesized
1
1
and ATR-IR as well as H NMR spectroscopy. The H NMR
spectrum of [In(bispox2)]+ shows significant changes in the 1H
NMR chemical shifts of both the aromatic (downfield shift) as
well as the aliphatic hydrogen atoms of the ligand due to
coordination of the ligand to the 3+ cation (Figure 1). In
contrast to the corresponding metal complexes of H2bispa2 (In3+
and La3+) and the [In(octox)]− complex, there is no splitting of
the diasterotopic methylene hydrogen atoms of the five-
membered chelate rings involving N3 or N7 and the N atoms
of the oxine arm.24,33 This suggests fluxionality at ambient
temperature of the puckered chelate rings of the [bispox2]2− vs
the [bispa2]2− complex. We attribute this to less puckering
resulting in lower barriers for chelate ring inversion and
therefore to more fluxionality, supporting a higher rigidity of
the oxine vs the picolinate arms and hence an increase in stability
and inertness. Note that other dynamic processes such as
changes from 8- to 9-coordination or semidetachment of one of
the pyridine donors (as observed in the solid state structures of
C
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Figure 2. ORTEP diagram of H2bispox2. Ellipsoids are shown at the 50% probability level. All hydrogen atoms on carbon atoms are omitted for clarity.
The following color code was used: C, gray; H, white; N, blue; O, red; F, green.
Figure 3. ORTEP diagrams of the cation in [In(bispox2)](ClO4) (left) and [Lu(bispox2)(HCO3)] (right). Ellipsoids are shown at the 50% probability
level; cocrystallized solvent molecules, counterions, and all hydrogen atoms are omitted for clarity. The following color code was used: C, gray; N, blue;
O, red; In, silver; Lu, green.
[In(bispa)2]+, and in bispidine−copper(I) complexes) may also
occur but the simple 1H NMR spectrum and the relatively sharp
lines suggest fast dynamics and a highly symmetrical
structure.33,42 However, the 1H NMR spectrum combined
with the solid state X-ray analysis confirms the structure and the
formation of the metal complex, and it can be concluded that
only a single species [In(bispox2)]+ is formed at room
temperature in solution as well as in solid state.
Molecular Structures. Colorless crystals suitable for single
crystal X-ray diffraction were obtained from a saturated solution
of the ligand H2bispox2 in methanol that was subjected to diethyl
ether diffusion at room temperature. The X-ray diffraction
analysis showed that the ligand crystallizes with a TFA anion in a
highly preorganized chair−chair conformation, where the
pyridine N-donor atoms occupy the favored equatorial position
with respect to the six membered azacyclohexane, which is
perfectly suitable for metal coordination (Figure 2). Also, one of
the rigid 8-hydroxy quinoline moieties in the ligand points
toward the metal binding site, which implies that the ligand is
partially preorganized (see Supporting Information for detailed
experimental structural data).
X-ray Crystal Structures of Metal Complexes. Brown
colored crystals of [In(bispox2)](ClO4) and orange colored
needle-like crystals of [Lu(bispox2)(HCO3)] suitable for solid-
state X-ray analysis were obtained by slow diffusion of diethyl
ether into a saturated solution of the respective metal complex in
MeOH. In the structures shown in Figure 3, In3+ is in an eight
coordinate environment, with four N-donor atoms from the
bispidine backbone and the N2O2 donor set from the oxine arms,
while Lu3+ is nine coordinate with an additional O-donor atom
from hydrogen carbonate. It is interesting to note that the In−
O1 and In−O2 bond lengths are longer than the Lu−O1 and
Lu−O2 bond distances (M−Ooxine, see Table 1). Each structure
features a perfect fit of the metal center into the cavity of the
ligand.
D
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Table 1. Selected Bond Distances in [In(bispox2)](ClO4) and
[Lu(bispox2)(HCO3)]
Table 2. Radiochemical Yields (RCY in %) of the
Concentration Dependent Experiments for the 111In−
H2bispox2 and 177Lu−H2bispox2 System
distance [Å]
[In(bispox2)](ClO4)
[Lu(bispox2)(HCO3)]
a
b
[ligand] (M)
111In RCY (%)
177Lu RCY (%)
M−O1
M−O2
M−O8
M−N1
M−N2
M−N3
M−N4
M−N6
M−N7
2.511(2)
2.565(2)
NA
2.393(2)
2.400(2)
2.352(2)
2.222(2)
2.443(2)
2.196(2)
2.334(6)
2.293(7)
2.254(7)
2.607(8)
2.627(9)
2.711(8)
2.459(9)
2.704(8)
2.456(8)
10−4
10−5
10−6
99
95
71
99
98
42
a
b
Room temperature, 10 mM NaOAc, pH = 7, 15 min. 37 °C, 10
mM NaOAc, pH = 8, 30 min.
temperature, further experiments with 225Ac were not
attempted.
Human Serum Stability with [111In(bispox2)]+. Human
serum contains several endogenous ligands, such as apo-
transferrin, albumin, and metallothionein that can compete for
and displace chelator bound metal ions in vivo. Therefore, it is
necessary that any metal−chelate complex must be able to
withstand transchelation to such endogenous ligands in order to
deliver the radiotracer to the desired molecular target. As a
result, the in vivo kinetic inertness of the [111In(bispox2)]+
system was estimated by incubating a preformed [111In-
(bispox2)]+ complex in an excess of human serum (37 °C, pH
7.4). Aliquots of each reaction mixture were then removed at 24
h and 5 day time points. The percentage of intact 111In3+
complex was determined by iTLC and was found to be
exceptionally high (stable) over 5 days, remaining 89% intact.
This stability is comparable to that of [111In(bispa2)]+ and
exceeds the 5 day stability of [111In(octox)]− (see Table 3).
It is interesting to compare these two structures with the
corresponding In3+, Ho3+, and Tb3+ structures of H2bispa2
(oxine vs picolinate).33,43 Both ligands lead to structures that
are asymmetric with respect to the M−N3/M−N7 (bispidine−
N
amine) distances, as usually observed with the bispidine
platform.44 Interestingly, the two In3+ structures are 8- while
all others are 9-coordinate. This might be due to the
crystallization procedure, specifically in the case of [In-
(bispa2)]+, where a very unsymmetrical structure is obtained
and spectroscopic data suggest that in solution, a solvent
molecule is coordinated.33,43 For the four known structures of
the two octadentate bispidine ligands coordinated to Ln3+ ions
(Tb3+, Ho3+, and Lu3+), the average of the eight bonds to the
Ln3+ ion is practically identical (2.51−2.53 Å), for In3+ these
average distances are significantly shorter (2.38, 2.41 Å),
although the ionic radius of In3+ (0.92 Å, CN 8) is close to
that of Lu3+ (0.97 Å, CN 8). This may be due to the relatively
soft donor sets, which are better suited for In3+ than for the
lanthanides, and this is supported by the observation that for
H2bispox2 the In−Ooxine bonds are significantly longer and the
In−N bonds shorter than the corresponding bonds for the Lu3+
complex (see Table 1). While the average metal-donor bonds
are, due to the rigidity of the bispidine cavity, very similar for the
complexes with H2bispa2 and H2bispox2 (see above), the
distances to the ox arms in general are shorter than the distances
to the pa arms, and this may reflect the pKa values of the
corresponding donors (8-hydroxyquinoline; picolinate: 4.94,
9.82; 1.01, 5.39),45 i.e., the oxine arms are much more basic and
may lead to stronger bonds, specifically for softer metal ions
(e.g., In3+).
Table 3. Human Serum Stability Challenge Data Performed
at 37 °C (n = 2), with Stability Shown as Percentage of Intact
111In Complex
complex
24 h stability
5 day stability
[
[
[
[
[
[
[
[
111In(bispox2)]+
94.6 0.4
91.4 0.6
19.7 1.5
92.3 0.04
89.4 2.2
88.3 2.2
97.8 0.1
87.4 0.6
89.4 0.6
83.6 1.4
NA
NA
NA
<60
97.8 0.7
87.4 1.5
a
111In(octox)]−
111In(dedpa)]+
a
a
111In(octapa)]−
111In(DOTA)]−
111In(DTPA)]2−
a
a
b
111In(p-NO2−Bn-neunpa)]−
c
111In(bispa2)]+
a
Mouse serum stability data performed at ambient temperature; data
b
c
included from ref 24 for comparison. From ref 46. From ref 33.
Radiolabeling Experiments. Initial radiolabeling experi-
ments were done to test the ability of H2bispox2 to radiolabel the
SPECT radionuclide 111In (t1/2= 2.8 days) and the theranostic
isotope 177Lu (t1/2 = 6.6 days). Quantitative radiolabeling was
achieved with 111InCl3 (57 MBq μmol−1, [L] = 10−5 M) at
ambient temperature within 15 min, whereas radiolabeling with
177LuCl3 (60 MBq μmol−1, [L] = 10−5 M) required gentle
heating at 37 °C for 30 min to achieve quantitative labeling
(RCY > 97%). The concentration-dependent radiolabeling was
performed at pH 7 and 8 (10 mM NaOAc buffer), respectively
and the results are summarized in Table 2. The efficiency of
radiolabeling with 111In3+ and 177Lu3+ is very similar to that with
the corresponding picolinate ligand H2bispa2 and significantly
better than with the “gold standard” DOTA.33
These human serum stability results coupled with the mild and
efficient radiolabeling protocol suggest that H2bispox2 is a
promising chelator for 111In and 177Lu pharmaceuticals.
CONCLUSIONS
■
In3+ and Lu3+ complexes of the octadentate oxine-armed
bispidine ligand H2bispox2 have, as expected, very similar
structural properties as the corresponding complexes of the
picolinate-armed bispidine H2bispox2, except that, due to the
differences in basicity, the bonds to the oxine arms are stronger
than those to the picolinate arms. It is counterintuitive that these
ligands have significantly faster complexation kinetics and higher
stabilities than other ligands such as the macrocycle-based
DOTA and NOTA familieswith microscopic reversibility,
faster complexation kinetics should lead to faster transchelation.
This suggests that the decomplexation mechanism is (slightly)
different from the complexation pathway.25 The efficient
Initial radiolabeling studies with the α-emitter 225Ac (∼4 MBq
μmol−1, [L] = 10−4) were attempted with ligand concentrations
of 10−4 M but unlike milder labeling kinetics with 111In and
177Lu, radiolabeling with 225Ac required heating at 85 °C for 1 h.
Due to the inability to quantitatively radiolabel 225Ac at room
E
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Hz, 1H), 2.74 (s, 3H), 2.53 (s, 3H). 13C NMR (75 MHz, CDCl3, 25
°C): δ = 33.4 (s), 41.6 (s), 122.1 (s), 124.0 (s), 126.7 (s), 126.8 (s),
128.7 (s), 128.8 (s), 134.0 (s), 137.4 (s), 157.3 (s).
radiolabeling at ambient conditions has been suggested to be
due to the open cavity of the tetradentate bispidine platform and
the planar tridentate N3 or N7-appended picolinate or oxine
arms. The stronger bonds to the oxine arms together with the
increase in rigidity obviously leads to an improvement with
respect to decomplexation. Decomplexation may be induced by
protonation of the pendant arms or rather by hydrolysis, i.e.,
coordination of OH−. Also, it must be noted that compared to
H2bispa2, H2bispox2 is more lipophilic and this will have a direct
impact on the pharmacokinetics as well as the binding
properties. Recently, it has been noted that the increased
lipophicility of the chelators leads to the higher tumor uptake
and reduced nonspecific binding compared with the hydrophilic
chelators.47,48 Further improvement of these ligands may
therefore involve replacement of one of the oxine arms by a
tridentate substituent to the bispidine backbone, leading to
nonadentate ligands, i.e., preventing a monodentate coligand or
solvent molecule from coordinating to the lanthanide center as
in the structures observed with H2bispox2. This, together with
mechanistic work and in vivo experiments, are now of
importance to further develop this area.
2-(Bromomethyl)quinolin-8-yl Acetate (5). To a solution of 2-
methylquinolin-8-yl acetate (4 g, 19.9 mmol, 1.0 equiv) in benzene (40
mL) N-bromosuccinimide (1.59 g, 8.94 mmol, 0.45 equiv) was added,
followed by addition of AIBN (652 mg, 3.97 mmol, 0.2 equiv). The
yellow mixture was refluxed, and after 2 h, second aliquots of NBS (1.59
g, 8.94 mmol, 0.45 equiv) and AIBN (652 mg, 3.97 mmol) were added.
After heating for additional 2 h, the reaction mixture was cooled to
room temperature, and the solvent was removed under reduced
pressure. The residue was dissolved in EtOAc (80 mL) and was washed
with saturated aqueous Na2S2O3 (200 mL). The aqueous layer was
extracted with EtOAc (2 × 80 mL), and the combined organic layers
were dried over anhydrous Na2SO4. The crude product was purified
using flash column chromatography (EtOAc/hexane: 25/75) to afford
1
a yellow colored product (3.06 g, 8.01 mmol, 48%). H NMR (300
MHz, CDCl3, 25 °C): δ = 8.16 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 8.5 Hz,
1H), 7.59 (d, J = 7.8, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 8.5 Hz,
1H), 4.68 (s, 2H), 2.50 (s, 3H). 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 169.7 (s), 156.9 (s), 147.4 (s), 140.2 (s), 137.1 (s), 128.5 (s), 126.6
(s), 125.5 (s), 121.8 (s), 121.8 (s), 34.4 (s), 20.9 (s).
Dimethyl 3,7-Bis((8-acetoxyquinolin-2-yl)methyl)-9-hydroxy-2,4-
di(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxylate
(6). To a solution of 4 (450 mg, 1.09 mmol) in dry ACN (20 mL) was
added Na2CO3 (693 mg, 6.54 mmol) and 2-(bromomethyl)quinolin-8-
yl acetate (5) (610 mg, 2.18 mmol). The reaction mixture was refluxed
overnight, filtered to remove Na2CO3, and concentrated in vacuo. The
residue was dissolved in a minimum amount of DCM and poured onto
a silica pad and washed several times with EtOAc/hexane (20:80) to
remove excess 2-(bromomethyl)quinolin-8-yl acetate followed by a
final wash with DCM/MeOH (90:10) to elute the compound. The
solvent was evaporated under reduced pressure and the crude product
was recrystallized from hot MeOH to afford the product 6 (383 mg, 472
μmol, 43%). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 8.46 (d, J = 7.9
Hz, 1H), 7.96 (d, J = 7.6 Hz, 2H), 7.74 (t, J = 7.9 Hz, 2H), 7.67 (s br,
1H), 7.63−7.48 (m, 7H), 7.01−6.94 (t, 2H), 6.80 (d, J = 7.2 Hz, 2H),
6.31 (d, J = 8.6 Hz, 1H), 5.68 (s, 2H), 5.09 (s, 1H), 4.87 (s, 2H), 4.58
(d, J = 12.4 Hz, 2H), 4.35 (d, J = 10.2 Hz, 2H), 3.67 (s, 2H), 3.63 (s,
6H), 2.94 (s, 3H), 2.37 (s, 3H). 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 14.2 (s), 20.9 (s), 21.3 (s), 29.7 (s), 52.7 (s), 60.4 (s), 64.1 (s), 64.7
(s), 67.41 (s), 110.8 (s), 117.9 (s), 119.1 (s), 119.3 (s), 119.8 (s), 121.7
(s), 122.0 (s), 125.6 (s), 125.7 (s), 126.1 (s), 126.3 (s), 127.3 (s), 136.9
(s), 147.5 (s), 151.8 (s), 157.9 (s), 159.3 (s). HR-ESI-MS: m/z calcd
for C45H43N6O9+ ([M + H]+), 811.3092; found, 811.3096.
EXPERIMENTAL SECTION
■
Materials and Methods. All solvents and reagents were purchased
from commercial suppliers (Sigma-Aldrich, TCI America, Fischer
Scientific, Alfa Aesar) and were used as received. Reactions were
monitored by TLC (MERCK Kieselgel 60 F254, aluminum sheet).
Flash chromatography was performed using Silicaflash F60 silica gel
(40−63 μM particle size), Redisep Rf HP silica columns, and a
Combiflash Rf column machine. Water used was ultrapure (18.2 MΩ
cm−1 at 25 °C, Milli-Q, Millipore, Billerica, MA).
1H and 13C NMR spectroscopy was performed on either a Bruker
Advance 300 or Bruker AV III HD 400 MHz spectrometer. Chemical
shifts (δ) are quoted in ppm relative to residual solvent peaks as
1
appropriate. Coupling constants (J) are provided in Hertz (Hz). H
NMR signals were designated as follows: s (singlet), d (doublet), t
(triplet), q (quartet), quin (quintet), sxt (sextet), spt (septet), m
(multiplet), or a combination of these, with br representing a broad
signal. Low resolution ESI-MS was performed on a Waters 2965 HPLC-
MS with the sample prepared in methanol or ACN. Results are labeled
with m/z (abundance percentage) values - [M+X]∓. High resolution
ESI-MS was performed on a Waters/Micromass LCT TOF-MS with
the sample prepared in methanol. Results are labeled with m/z
(abundance percentage) values −[M + X]∓. Semipreparative reverse
phase high-performance liquid chromatography (HPLC) for H2bispox2
and [In(bispox2)](ClO4) was performed on a Phenomenex 16 synergi
hydro-RP 80 A°, 250 × 21.2 mm column connected to a Waters 600
controller, a Waters 2487 dual wavelength absorbance detector, and a
Waters delta 600 pump. The HPLC solvents were (A) H2O containing
0.1% trifluoroacetic acid (TFA) and (B) CH3CN containing 0.1% TFA.
Silica gel impregnated TLC plates (MERCK Kieselgel 60 F254,
aluminum sheet) were used to analyze 111In and 177Lu radiolabeling
reaction progress and the complex stability, human serum stability tests
were counted on a BioScan System 200 imaging scanner equipped with
a BioScan Autochanger 1000.
Dimethyl 9-Hydroxy-3,7-bis((8-hydroxyquinolin-2-yl)methyl)-
2,4-di(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxy-
late, H2bispox2 (7). To a solution of (OAc)2-bispox2 (6) (200 mg, 247
μmol) in MeOH (10 mL) was added saturated aqueous NaHCO3 (5
mL). The reaction mixture was stirred overnight at room temperature.
Water was added until a white precipitate formed that was filtered off
and carefully washed multiple times with water and diethyl ether. The
remaining solid was dried under vacuum and purified by reverse phase
(RP)-HLPC using eluents: (A) 0.1% H(TFA) in H2O and (B) 0.1%
TFA in ACN with a linear gradient 40 to 100% B over a period of 35 min
and flow rate set to 1 mL/min. The retention time of the ligand was tR =
9.5 min. The desired fractions were combined and concentrated in
vacuo to afford the ligand as yellow solid (61 mg, 83.8 μmol, 34%).
Suitable crystals for X-ray analysis were obtained by slow diffusion of
diethyl ether into a solution in MeOH. 1H NMR (300 MHz, MeOD, 25
°C): δ = 8.27 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.83 (m, J =
8.1 Hz, 4H), 7.66 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.50 (t, J
= 8.1 Hz, 1H), 7.39 (d, J = 7.0 Hz, 5H), 7.11 (d, J = 7.4 Hz, 1H), 7.03
(m, J = 7.2 Hz, 2H), 6.73 (d, J = 8.4 Hz, 1H), 5.13 (s, 1H), 5.04 (s, 2H),
4.81 (s, 2H), 4.17 (d, J = 13.1 Hz, 2H), 3.96 (s, 2H), 3.77 (d, J = 13.7
Hz, 2H), 3.73 (s, 6H). 13C NMR (75 MHz, MeOD, 25 °C): δ = 168.8
(s), 154.6 (s), 152.9 (s), 149.4 (s), 138.4 (s), 137.8 (s), 128.9 (s), 128.1
(s), 125.5 (s), 124.2 (s), 122.7 (s), 121.7 (s), 118.2 (s), 117.8 (s), 114.6
(s), 111.7 (s), 70.7 (s), 70.2 (s), 62.1 (s), 52.9 (s), 52.0 (s), 49.5 (s).
Synthesis and Characterization. Bispidol (4). Compound 4 was
prepared according to the literature preparation with appropriate
characteristic spectra.49
2-Methylquinolin-8-yl Acetate (8). A solution of 8-hydroxy-2-
methylquinoline (5 g, 31.4 mmol) in acetic anhydride (50 mL) was
refluxed overnight. The reaction mixture was quenched by the addition
of saturated aqueous NaHCO3 (30 mL) and the aqueous layer was
extracted with EtOAc (3 × 20 mL). The combined organic layers were
dried over anhydrous Na2SO4 and filtered, and the filtrate was
concentrated in vacuo to afford the product as yellow oil (6.32 g, 31.1
mmol, 99%). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 8.04 (d, J = 8.5
Hz, 1H), 7.54 (d, J = 7.6, 1H), 7.46 (m, J = 7.6 Hz, 2H), 7.29 (d, J = 8.5
+
HR-ESI-MS: m/z calcd for C41H38KN6O7 ([M+K]+), 765.2439;
F
DOI: 10.1021/acs.inorgchem.9b01016
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
found, 765.2438. IR (KBr pellet): ν
1678 s, 1593 m, 1572 m, 1512 m, 1463 m, 1438 m, 1255 m, 1199 vs,
1174 vs, 1129 vs, 1093 s, 949 m, 833 m, 801 s, 752 s, 720 vs.
̃
[cm−1] = 3060 w, 2958 w, 1734 m,
using the intrinsic phasing solution method. The model was refined
with version 2017/1 of XL51 using least squares minimization.
Single orange rectangular-shaped crystals of [Lu(bispox2)(HCO3)]
were obtained by recrystallization from methanol solution. A suitable
crystal (0.16 × 0.12 × 0.06 mm3) was selected and mounted on a
suitable support on an Bruker APEX-II CCD diffractometer. The
crystal was kept at a steady T = 98(2) K during data collection. The
structure was solved with the SIR200452 structure solution program by
using the direct methods solution method and by using Olex250 as the
graphical interface. The model was refined with version 2018/1 of
ShelXL53 using least squares minimization.
[In(bispox2)](ClO4). To a solution of H2bispox2 (15 mg, 20.6 μmol,
1.0 equiv) in MeOH (5 mL) was added a solution of In(ClO4)3·8H2O
(11.5 mg, 20.6 μmol, 1.0 equiv) in MeOH (5 mL), the pH of the
solution was adjusted to pH ∼ 8 using 0.1 M NaOH, and the resultant
yellow colored solution was stirred at room temperature for 5 h. The
solvent was concentrated in vacuo, the crude solid was purified by
reverse phase (RP)-HPLC using eluents: (A) 0.1% TFA in H2O and
(B) ACN with a linear gradient 5 to 100% B over a period of 35 min and
flow rate set to 1 mL/min. The retention time of the metal complex was
tR = 15.25 min. The desired fractions were combined and concentrated
in vacuo to yield orange colored product (7.64 mg, 8.13 μmol, 39%).
Suitable crystals for X-ray analysis were obtained by slow evaporation of
a solution in MeOH. 1H NMR (300 MHz, MeOD, 25 °C): δ = 8.84 (d,
J = 8.5 Hz, 1H), 8.31 (d, J = 4.8 Hz, 2H), 8.17 (d, J = 8.5 Hz, 1H), 7.
87−7.78 (m, 3H), 7.70 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H),
7.51−7.45 (m, 3H), 7.15−7.01 (m, 5H), 6.84 (d, J = 7.8 Hz, 1H), 5.44
(s, 2H), 5.17 (s, 1H), 4.76 (s, 2H), 4.65 (s, 2H), 3.68−3.66 (m, 8H),
3.49 (d, J = 13.3 Hz, 2H). 13C NMR (75 MHz, MeOD, 25 °C): δ =
168.9 (s), 152.1 (s), 149.5 (s), 142.9 (s), 141.1 (s), 140.4 (s), 130.7 (s),
130.5 (s), 130.3 (s), 129.1 (s), 125.7 (s), 125.3 (s), 120.9 (s), 119.0 (s),
114.1 (s), 113.9 (s), 71.7 (s), 70.5 (s), 63.7 (s), 54.4 (s), 52.2 (s), 51.5
(s). HR-ESI-MS, (pos, MeOH): [InIII(bispox2)]+ calcd for
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.9b01016.
■
S
Detailed information on 1H NMR and 13C NMR spectra
of compounds, FT-IR spectra, X-ray crystallography data
(including tables of bond lengths and angles), and
detailed i-TLC radiochromatographs (PDF)
Accession Codes
CCDC 1908810−1908812 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
C41H36InN6O7 [M]+, 837.1686; found, 837.1677. IR (KBr pellet): ν
[cm−1] = 2953 m, 2924 m, 2854 m, 1733 m, 1606 m, 1507 w, 1466 m,
1441 m, 1276 m, 1255 m, 1089 vs, 1054 vs, 959 m, 836 m, 755 s.
̃
Radiolabeling. A stock solution of H2bispox2 was made (1.3 mg/
mL, ∼10−3 M) in 1:1 ACN/DI water. Using serial dilution, ligand
solutions with concentrations of 10−4- 10−6 M were prepared by
addition of pH 7 NaOAc (10 mM) buffer in screw-cap mass
spectrometry vials such that the total volume per reaction was 500
μL after the addition of 111InCl3 or 177LuCl3. An aliquot of 111InCl3 or
177LuCl3 (∼100−300 kBq) was added to the vials containing the ligand
and buffer, and allowed to react (radiolabel) at ambient temperature for
15 min for 111In or was heated at 37 °C for 30 min for 177Lu
radiolabeling. The reaction mixture was analyzed by spotting a small
aliquot on aluminum-backed silica TLC plated developed in mobile
phase: 10 mM EDTA solution (pH = 7). With EDTA as mobile phase,
uncomplexed 111In or 177Lu migrates up the plate as EDTA complex (Rf
> 0.5) while [111In(bispox2)]− or [177Lu(bispox2)]− species stay on the
baseline (Rf = 0). Developed plates were counted immediately and the
radiolabeling yields were calculated by integrating the peaks in the
radio-chromatogram, which is consistent with the well-separated
radiopeaks of the free metal and the complex on the HPLC radiotraces
(tR = 4.8 min for “free” 111In and 12.8 min for [111In(bispox)]+ complex.
111In Complex Stability Studies in Human Serum. The compound
AUTHOR INFORMATION
Corresponding Authors
*(C.O.) E-mail: orvig@chem.ubc.ca.
■
*(P.C.) E-mail: Peter.Comba@aci.uni-heidelberg.de.
ORCID
Xiaozhu Wang: 0000-0002-5882-0066
Peter Comba: 0000-0001-7796-3532
Chris Orvig: 0000-0002-2830-5493
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge both the Canadian Institutes for
Health Research (CIHR) and the Natural Sciences and
Engineering Research Council (NSERC) for grant support,
NSERC for an IsoSiM CREATE at TRIUMF studentship
(N.C.) and for CGS M and PGS D scholarships (L.S.) as well as
MITACS for a Globalink Graduate fellowship (N.C.) and UBC
for a FYF (L.S.). P.C. acknowledges support by the Deutsche
Forschungsgemeinschaft (DFG) and Heidelberg University.
TRIUMF receives funding from the National Research Council
of Canada. We also thank Mr. Thomas Kostelnik for thoughtful
editing.
[
111In(bispox2)]− was prepared with radiolabeling procedure as
described above. To the reaction vial containing the radiometal-chelate
complex (500 μL), an equal volume of human serum was added and the
competition mixture was incubated at 37 °C. At time points 1 day and 5
days, aliquots were spotted on aluminum-backed silica TLC plates and
developed with 10 mM EDTA solution (pH = 7) as mobile phase.
Solid State X-ray Analysis. Single colorless rectangular-shaped
crystals of H2bispox2 were recrystallized from a methanol/diethyl ether
mixture by slow evaporation. A suitable crystal (0.47 × 0.31 × 0.36
mm3) was selected and mounted on a Mylar loop with oil on a Bruker
APEX II area detector diffractometer. The crystal was kept at T =
100(2) K during data collection. Using Olex2,50 the structure was
solved with the XT51 structure solution program, using the Intrinsic
Phasing solution method. The model was refined with version 2017/1
of XL51 using least squares minimization.
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DOI: 10.1021/acs.inorgchem.9b01016
Inorg. Chem. XXXX, XXX, XXX−XXX