Rigid and Compact Binuclear Bis-hydrated Gd-complexes as High Relaxivity MRI Agents

Article abstract of DOI:10.1002/chem.202101701

The first binuclear Gd-complex of the 12-membered pyridine-based polyaminocarboxylate macrocyclic ligand PCTA was synthesized by C?C connection of the pyridine units through two different synthetic procedures. A dimeric AAZTA-ligand was also synthesized w

Full text of DOI:10.1002/chem.202101701

Accepted Article
Accepted Article
Title: Rigid and Compact Binuclear Bis-hydrated Gd-complexes as
High Relaxivity MRI Agents
Authors: Loredana Leone, Luca Guarnieri, Jonathan Martinelli,
Massimo Sisti, Andrea Penoni, Mauro Botta, and Lorenzo Tei
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To be cited as: Chem. Eur. J. 10.1002/chem.202101701
Link to VoR: https://doi.org/10.1002/chem.202101701
01/2020

10.1002/chem.202101701
Chemistry - A European Journal
COMMUNICATION
Rigid and Compact Binuclear Bis-hydrated Gd-complexes
as High Relaxivity MRI Agents
Loredana Leone,[a] Luca Guarnieri,[a] Jonathan Martinelli,[a] Massimo Sisti,[b] Andrea Penoni,[b] Mauro
Botta*[a] and Lorenzo Tei*[a]
[a]
Dr L. Leone, Mr L. Guarnieri, Dr J. Martinelli, Prof. M. Botta, Prof. L. Tei
Dipartimento di Scienze e Innovazione Tecnologica
Università del Piemonte Orientale
viale T. Michel 11, 50121, Alessandria (Italy)
E-mail: mauro.botta@uniupo.it; lorenzo.tei@uniupo.it
Prof. M. Sisti, Prof. A. Penoni
[b]
Dipartimento di Scienza e Alta Tecnologia
Università dell'Insubria
Via Valleggio 11, Como, I-22100, Italy
Supporting information for this article is given via a link at the end of the document.
Abstract: The first binuclear Gd-complex of the 12-membered
pyridine-based polyaminocarboxylate macrocyclic ligand PCTA was
synthesized by C-C connection of the pyridine units through two
different synthetic procedures. A dimeric AAZTA-ligand was also
synthesized with the aim to compare the relaxometric results or the
two ditopic Gd-complexes. Thus, the 1H relaxometric study on
[Gd2PCTA2(H2O)4] and for [Gd2AAZTA2(H2O)4]2- highlighted the
remarkable rigidity and compactness of the two binuclear complexes,
which results in molar relaxivities (per Gd), at 1.5 T and 298 K of ca.
12-12.6 mM-1 s-1 with an increase of ca. 80% at 1.5 T and 298 K (+70%
at 310 K) with respect to the corresponding mononuclear complexes.
methylperhydro-1,4-diazepinetetraacetic acid, Scheme 1)[5] were
found to be characterized by excellent inertness in physiological
conditions, even better than that of some non-macrocyclic q = 1
complexes. In particular, it has been recently shown that among
the q = 2 Gd-complexes, those that show the highest kinetic
inertness are GdPCTA and the bicyclic AAZTA derivative
GdCyAAZTA, with half-lives (t1/2) at pH 7.4 of 4.4 × 106 and 8 ×
105 h, respectively.[6]
Although no q = 2 GdIII-complexes have been approved so far for
clinical use, the interest in these bis-hydrated complexes is shown
by the recent development by the pharmaceutical industry
Guerbet of
a novel functionalized tris-serinolamido PCTA
derivative (Gadopiclenol, Scheme 1)[7] that exploits the excellent
stability and kinetic inertness of GdPCTA-like complexes.
Gadopiclenol shows remarkable relaxivity values due to its large
molecular weight, the position of the Gd ion located almost at the
barycentre of the molecule and the presence of hydrophilic
polyalcohol pendants that favour the additional contribution of
second sphere water molecules (SS) to r1. Although the molecule
does not possess the high symmetry typical of the GdDOTA-
derivatives reported in early 2000,[8] the combination of the SS
water molecules contribution and of a longer rotational correlation
time provides high relaxivities over a broad range of magnetic field
strengths.
A further approach to increase the relaxivity of a Gd-complex at
clinically relevant magnetic fields (1.5-3 T) is the use of multimeric
GdIII-agents of medium molecular weight (1-4 kDa), roughly
corresponding to bi-, tri- or tetranuclear complexes. These
systems allow to attain high ionic relaxivities (per Gd) which reach
maximum values precisely in the range of approx. 1-5 T.[9]
Therefore, oligomeric systems (e.g. 2-4 chelates rigidly linked
together) with R values between ca. 150-500 ps show relaxivity
peaks at high proton Larmor frequencies (> 40 MHz).[9] Several
oligomeric contrast agents have been reported in the literature
based on both q=1 (DOTA-like) and q=2 (AAZTA-like) Gd-
complexes. Remarkable results have been obtained when the
advantages of the slower rotational dynamics are combined with
fast water exchange rates and second hydration sphere
contributions.[10,11] Notably, no examples of multimeric systems
based on PCTA ligand have been reported in the literature. The
synthesis of binuclear Gd-complexes has also been recently
pursued by another contrast media company, that patented a
series of ditopic GdHPDO3A-like systems linked by
A large fraction (~ 40 %) of clinical magnetic resonance imaging
(MRI) examinations requires the use of exogenous contrast
agents (CAs) that allow remarkable improvements in clinical
diagnosis in terms of higher specificity, better tissue
characterization, reduction of image artefacts and functional
information. Paramagnetic GdIII complexes were early recognized
as the candidates of choice for the design of MRI CAs because of
their favourable magnetic properties associated with the presence
of seven unpaired electrons and relatively long electronic
relaxation times.[1,2] The CAs approved for clinical use are
monohydrated (q =1), low molecular weight Gd(III)-complexes
capable of shortening the proton longitudinal relaxation times (T1
= 1/R1) of neighbouring H2O molecules, thus increasing their
signal intensity in T1-weighted (T1w) MR images. This ability to
induce relaxation is called relaxivity (r1,2) and measures the
relaxation rate enhancement of water proton nuclei normalized to
a 1 mM concentration of the paramagnetic ion. At the magnetic
fields used in clinical (1.5 and 3 T) and preclinical scanners (up to
9.4 T) the relaxivity is mainly controlled by three parameters: the
exchange rate (kex = 1/τM) and the number (q) of water molecules
coordinated to the metal centre and the rotational correlation time
(τR).[3] The increase of the hydration state q of the metal ion can
be obtained by reducing the number of donor atoms of the
chelating ligand, which, however, may result in a decreased
stability of the complex. This latter is assessed by measuring the
thermodynamic stability and kinetic inertness toward dissociation/
transmetallation reactions of a Gd-complex that aims for in vivo
applications. However, certain macrocyclic and mesocyclic bis-
hydrated complexes such as GdPCTA (PCTA = 3,6,9,15-
tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-
triacetic acid, Scheme 1)[4] or GdAAZTA (AAZTA = 6-amino-6-
1
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polyaminoalcohol groups to increase the SS contribution.[12] In this
regard, it should be noted that the linker between the
paramagnetic units in an oligomeric agent plays a key role for the
attainment of high relaxivities. The linker needs to be as rigid as
possible to favour an optimal motional coupling between the
discrete interconnected chelates and, possibly, hydrophilic to
enable the formation of strong hydrogen bonds with SS water
molecules.
In this contribution, we combined the two approaches by
synthesising a PCTA dimer in which the two units are directly
connected through the pyridine moieties (PCTA2, Scheme 1) to
minimize local rotational motions. The synthesis of such a dimeric
molecule is quite challenging and we followed two different
strategies. The first involves the Ni(0)-catalysed homo-coupling of
the bromopyridine-functionalized macrocycle, whereas the
second is based on the synthesis of the tetramethylbromide-
bipyridine derivative to be used for bis-macrocyclization. For a
comparison, a dimeric GdAAZTA-complex was also synthesized
by linking together two AAZTA-OH moieties.[13] The Gd-
complexes of these ditopic ligands were then investigated in detail
through 1H NMR relaxometry to assess their structural and
dynamic properties in solution and their relaxation efficiency.
a structure of this type, the local motions of the single units should
be minimized relative to the global molecular tumbling and
therefore the increase in the molecular mass of the binuclear
complex should translate into a corresponding increase in R and
therefore in relaxivity (per Gd).
In a first synthetic approach of PCTA2, the key step was the Ni(0)-
catalysed homocoupling reaction[16] between two units of the N-
tosyl-protected p-bromo-pyclen derivative (Scheme 2). First of all,
the diethyl ester of dipicolinic acid incorporating a bromo group in
the para position, was obtained from chelidamic acid by
bromination with PBr5 and esterification, following the literature
procedure.[17] Then, the cyclization reaction was carried out using
the procedure optimized for PCTA,[18] i.e. reaction of 4-bromo-2,6-
bis-bromomethylpyridine and 1,4,7-tritosyl-1,4,7-triazaeptane in
anhydrous acetonitrile in the presence of potassium carbonate.
The homocoupling reaction was carried out in DMF in the
presence of NiCl2, triphenilphosphine and Zn dust obtaining the
ditopic ligand in good yield after column chromatography.
Hydrolysis of the tosylate groups was accomplished with HBr 33%
in acetic acid followed by alkylation of the six secondary amines
with tert-butylbromoacetate. Deprotection of the tert-butyl esters
with a 1:1 mixture of CH2Cl2 and trifluoroacetic acid resulted in the
final ligand PCTA2 in good yield.
In the literature there are no examples of the formation of ditopic
or multimeric macrocyclic ligands linked together through homo-
or cross-coupling reactions, although coupling reactions are used
for the synthesis of large macrocycles or of porphyrin systems.[19]
On the other hand, pyridine-based ditopic chelators are reported
in the literature, but their synthesis starts from the formation of
functionalized 4,4'-bipyridine. In one case, 4,4'-bipyridine was
acetylated in the 2,2',6,6' positions using pyruvic acid, AgNO3 e
ammonium persulfate;[20] the tetraacethylated bipyridine was then
used to form a bis-pentaaza macrocycle by Mn(II) template imine
formation. In other examples,[21] the 2,2’,6,6’-tetramethyl-
4,4’bipyridine was synthesized using Hunig’s method by reductive
coupling of 2,6-lutidine with Na in THF followed by oxidation with
SO2.[22]
Scheme 1. Ligands discussed in the text.
In the second synthetic path, we followed the same procedure to
obtain the bis-PCTA macrocycle. Thus, the tetramethyl derivative,
obtained by Hunig’s approach,[22] was oxidized with CrO3 and
esterified passing through the tetraacyl chloride derivative. Then,
reduction of the esters followed by treatment of the tetraol 5 with
thionyl bromide produced the tetrabromomethyl bipyridine 6 in
good yield.[21]
In this case, the cyclization was carried out by using the
diethylentriamine-N,N’,N’’-triacetic acid in the presence of
Na2CO3 in acetonitrile at reflux following the method reported by
Picard and colleagues.[23] With this approach, the
macrocyclization reaction is carried out in diluted conditions
(concentration 2 x 10-3 M) and controlled by a sodium template
effect. No sign of oligomerization or other by-product formation
were detected by HPLC-MS analysis. Finally, the tert-butyl ester
groups in the bis-macrocycle 4 were deprotected to obtain the
final dimeric ligand PCTA2 in reasonable yield.
To compare the data on the Gd-complex of PCTA2, another fairly
rigid q = 2 dimeric AAZTA-based ligand was synthesized by
reaction of 1,4-phenylene diisocyanate with AAZTA-OH,[13]
followed by deprotection of the tert-butyl esters with a 1:1 mixture
of CH2Cl2 and trifluoroacetic acid (Scheme 3). In this case,
although the linker is much longer than that used for PCTA2, it
contains only two sp3 carbon atoms and the aromatic ring and the
Design and synthesis. The design of a dimeric Gd-complex
requires the rational choice of the monomeric chelate and of the
linker connecting the two units. We have already discussed the
choice of a stable q = 2 Gd-complex, such as GdPCTA or
GdAAZTA, to achieve a higher inner sphere contribution to the
relaxivity. In addition, it is important to avoid the easy rotation
around the linker because this implies a poor correlation between
the motions of the single chelates and the global molecular
reorientation.[14] A poor motional coupling invariably results in
decreased relaxivity. As noted above, a further important
contribution to r1 arises from the presence of H-bonded water
molecules in the proximity of the paramagnetic centres either by
interaction with the linker or with the hydrophilic moieties of the
chelates. Several examples of ditopic Gd-complexes have been
designed to obtain improved relaxivity enhancement with respect
to the monomeric units following these approaches.[15]
Nonetheless, the advantage of PCTA as compared to the other
polyaminocarboxylate ligands such as DOTA or AAZTA is related
to the presence of a pyridine unit within the bis-macrocyclic
structure that can be used to connect two ligands together. Thus,
by directly linking two pyridine moieties in position 4 through a
metal-catalysed homocoupling reaction a rigid and compact
dimeric system with a zero-length cross linker can be obtained. In
2
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Scheme 2. Synthesis of PCTA2. i. K2CO3, CH3CN; ii. NiCl2, PPh3, Zn, DMF; iii. HBr 33% in AcOH; iv. BrAcOtBu, NEt3, N-methylpyrrolidone; v. NaBH4, CaCl2, EtOH;
vi. SOBr2; vii. diethylentriamine-N,N’,N’’-tris-tertbutyl acetate, Na2CO3, CH3CN; viii. TFA/DCM 1:1.
rotational correlation time associated with the increased
molecular size, while the state of hydration remains unchanged (q
= 2). Thus, since only the inner-sphere contribution to relaxivity
depends on R, whereas the outer-sphere contribution remains
essentially unaffected, we can infer that the binuclear complexes
are remarkably rigid and compact, hence their tumbling motion is
largely isotropic as expected, in both cases, by the nature of the
linkers connecting the two coordination cages.
The pH dependence of r1 was measured for both complexes in
the 4 - 11 pH range, at 20 MHz and 298 K as it provides useful
insights into their solution behaviour and stability. The data
reported in Figure 1A shows r1 values constant over the entire pH
Scheme 3. Synthesis of AAZTA2.
range for [Gd2AAZTA2(H2O)4]2- to indicate that the coordinated
2-
water molecules are not displaced by CO3 anions, even when
present at relatively high concentration as in the basic pH region.
In the case of [Gd2PCTA2(H2O)4], r1 remains constant up to ca.
carbamate moieties should substantially hinder the local flexibility
of the monomeric units.
pH 8.5 where it begins to decrease until it reaches the value of
Complexation reactions were carried out at pH = 6.5 by mixing at
8.5 mM-1s-1 at pH 11.2 (-32%), likely as a result of a partial water
room temperature two molar equivalents of GdCl3 with one
equivalent of the dimeric ligand and the formation of the
displacement by carbonate anions present in the aerated solution.
This behaviour is rather common for q > 1 Gd-complexes, such
complexes were supported by ESI MS analysis and HPLC
as GdDO3A or GdEDTA.[24]
method (Supporting Information Figure S1-S5).
1H NMR relaxometric study. The ionic (per Gd) relaxivity (r1)
The magnetic field dependence of the relaxivity, the so-called
NMRD (nuclear magnetic relaxation dispersion) profile, has been
values of the dimeric complexes [Gd2PCTA2(H2O)4] and
measured at 25 and 37 °C (for [Gd2PCTA2(H2O)4] also at 10°C)
[Gd2AAZTA2(H2O)4]2-, measured at pH 7, 20 MHz (0.47 T) and
over the proton Larmor frequency range 0.01 to 500 MHz,
298 K, are 12.1 and 12.6 mM−1 s−1, respectively (8.8 and 8.6 mM−1
corresponding to magnetic field strengths varying between 2.34 ×
s−1 at 310 K). The corresponding mononuclear complexes
10−4 T and 11.7 T (Figure 2). The temperature dependence of r1
was also measured for both complexes at 20 MHz over the range
274−340 K and is shown in Figure 1B. The shape of the NMRD
profiles and their temperature dependence (r1 decreases with
increasing temperature) reproduce the general behaviour of low
molecular weight Gd-complexes, for which r1 is not limited by the
[GdPCTA(H2O)2][24] and [GdAAZTA-OH(H2O)2]-[25] show r1 values
of 6.9 and 7.6 mM-1 s-1, respectively, measured under identical
experimental conditions. Therefore, the binuclear Gd-complexes
exhibit a relaxivity gain of +76% ([Gd2PCTA2(H2O)4]) and +66%
([Gd2AAZTA2(H2O)4]2-), easily attributed to a longer value of the
3
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water exchange rate (fast exchange regime) but rather by the
rotational motion, as for the related monomeric complexes.
residence lifetime of the coordinated water molecules, M, does
not affect the relaxivity of the systems under the regime of fast
exchange and their values were fixed to those reported for the
mononuclear GdPCTA and GdAAZTA complexes (70 and 90 ns,
respectively).[24,25] The fit was performed using as adjustable
parameters R and the electronic relaxation parameters 2 (trace
of the squared zero-field splitting, ZFS, tensor) and V (correlation
time for the modulation of the transient ZFS). The NMRD profiles
are well reproduced with the set of parameters reported in Table
1, which clearly show that the improved r1 values of the dimeric
complexes and their frequency dependence can be well
accounted for by the longer R values, i.e. slower molecular
tumbling. For the neutral dimer [Gd2PCTA2(H2O)4], the R value is
more than double that reported for GdPCTA, confirming the
almost total absence of local rotational motions superimposed on
the global molecular reorientation. This makes it possible to
effectively translate the increase in molecular mass into a
corresponding increase in R. This is not entirely true for the other
dimeric complex, [Gd2AAZTA2(H2O)4]2-, where the increments of
the molecular mass and R are not entirely proportional. This
suggests the occurrence of some degree of internal mobility
through the CH2 groups connecting the phenyl-bis-carbamate unit.
Noteworthy, the values reported in Table 1 are the ionic
relaxivities (per Gd3+). The molecular relaxivities correspond to
double values that, at 20 MHz and 298 K, are equivalent to ca.
24-25 mM-1 s-1. It is also important to highlight that for these
dimeric systems the r1 values per Gd at the clinical fields of 1.5
and 3 T are significantly higher than those of the mononuclear
complexes (at 310 K ca. 70% for [Gd2PCTA2(H2O)4] and 68% for
[Gd2AAZTA2(H2O)4]2-] (Figure 3).
Figure 1. Plots of the 1H relaxivity for [Gd2PCTA2(H2O)4] (black squares) and
for [Gd2AAZTA2(H2O)4]2- (red circles) as a function of pH (A, 20 MHz and 298
K) and temperature (B, 20 MHz, pH 7).
It is worth noting that, unlike the binuclear complexes herein
reported, other binuclear GdDO3A-like complexes with xylene
group as spacers were reported to form large supramolecular
aggregates. The aggregates show high relaxivity values at low
field (ca. 12 mM-1 s-1 at 20 MHz and 298 K), which drop down at
higher field (> 1 T) due to R values in the order of 0.5-1 ns.[28]
Table 1. Parameters obtained from the simultaneous analysis of 1H NMRD
profiles for [Gd2PCTA2(H2O)4] and for [Gd2AAZTA2(H2O)4]2- compared to the
related monomeric complexes.
[Gd2PCTA2
(H2O)4]
[GdPCTA
(H2O)2] [a]
[Gd2AAZTA2
(H2O)4]2-
[GdAAZTA
Parameters
(H2O)2]-
[b]
298/310
20r1
12.0 / 8.8
6.9 / 5.2
12.5 / 8.6
7.1 / 5.2
(mM-1 s-1)
2 (1019 s-2)
V298 (ps)
2.6 ± 0.2
5.9
15
3.1 ± 0.1
2.2
31
30.7 ± 0.7
29.5 ± 0.9
298
kex
14.3
14.3
11.1
11.1
Figure 2. 1/T1 1H NMRD relaxivity data for [Gd2PCTA2(H2O)4] (top) and for
[Gd2AAZTA2(H2O)4]2- (bottom) at pH = 7.0: 283 K (■); 298 K (●); 310 K (♦). The
solid lines represent the best results of the fitting to the experimental points (see
Table 1).
(106 s-1)
R298(ps)
r (Å)
163 ± 2
3.1
70
145 ± 1
3.1
74
3.1
3.1
[a] Ref. 24; [b] Ref. 25; * Values fixed in the fitting: the hydration number q; the
distance between Gd3+ and the protons of the bound water molecule, r; the
distance of closest approach, a, of the outer sphere water molecules to Gd3+
was set to 4.0 Å and for the relative diffusion coefficient D standard value of 1.7,
2.24 and 3.1 × 10−5 cm2 s−1 (at 283, 298 and 310 K, respectively).
The NMRD profiles were fitted in terms of the established theory
of paramagnetic relaxation expressed by the Solomon-
Bloembergen-Morgan (SBM)[26] and Freed’s[27] equations for the
inner- (IS) and outer sphere (OS) proton relaxation mechanisms,
respectively. Some of the parameters (q, rGdH, a, D) were fixed to
known or reasonable values as indicated in Table 1. The
4
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In conclusion, we have reported the synthesis of the first binuclear
complex making it a valid alternative to the Gd-based CAs applied
in clinics.
Gd-complex
of
the
12-membered
pyridine-based
polyaminocarboxylate macrocyclic ligand PCTA by connecting
two pyridine units via a simple C-C bond. This was achieved
through two distinct synthetic procedures: 1) by synthesizing first
the p-bromopyridine moiety already included in a protected pyclen
macrocycle, followed by the Ni(0) catalysed homocoupling; 2) by
synthesizing the 2,2’,6,6’-bromomethyl-substituted bis-pyridine
by a multistep procedure, followed by the cyclization with a
triaminotris-tButylcarboxylate moiety. A dimeric AAZTA-ligand
was also successfully synthesized with the purpose of collecting
relaxometric data in parallel for two binuclear complexes of similar
size but different molecular structure and thus be able to make a
useful comparison.
The 1H relaxometric study on [Gd2PCTA2(H2O)4] and for
[Gd2AAZTA2(H2O)4]2- highlighted the remarkable rigidity and
compactness of the two binuclear complexes, which results in r1
increases of ca. 80% at 1.5 T and 298 K (+70% at 310 K). In
particular, [Gd2PCTA2(H2O)4] showed a rotational correlation time
more than doubled with respect to the monomeric GdPCTA
complex, as a consequence of the zero-length linker between the
two GdPCTA units. In the case of the binuclear AAZTA-like
complex the relaxometric performance are in line with other
dimeric AAZTA systems previously reported in the literature.
It is also interesting to note that these binuclear complexes have
a relaxivity about three times higher than commercial contrast
agents (q = 1), allowing the injection of lower doses of Gd(III) and
thus mitigating potential toxicity problems.
Finally, we would like to emphasize that pyclen-diacetates (PC2A)
has been recently investigated as highly efficient ligands for MnII-
based MRI contrast agents.[29] Thus the dimerization approach
reported for Gd2PCTA2 can have further application also in the
field of MnII agents.
Acknowledgements
L.T. and M.B. gratefully acknowledge the support from the
Università del Piemonte Orientale (Ricerca locale 2019). The
authors would like to thank Prof. S. Tollari (Università
dell’Insubria) for helpful discussions.
Keywords: macrocycles • binuclear complexes • gadolinium •
contrast agents • relaxometry
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Figure 3. Plot of the relaxivity values of [Gd2PCTA2(H2O)4] and
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Entry for the Table of Contents
Two novel binuclear PCTA2 and AAZTA2 ligands were synthesized with a multistep process. Their GdIII-complexes results in molecular
relaxivities at 1.5 T and 298 K of ca. 24-25 mM-1 s-1 thanks to the rigidity and compactness of the ligands. These values are remarkably higher
that those found for the corresponding mononuclear complexes.
7
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