The role of the capping bond effect on pyclen natY3+/90Y3+ chelates: Full control of the regiospecific: N -functionalization makes the difference

Article abstract of DOI:10.1039/c7cc05088g

Thanks to a smart regiospecific N-functionalization, a pyclen based ligand bearing one picolinate and two acetate arms organized in a dissymmetric manner was synthesized for Y³⁺ complexation, and compared to its symmetric analogue. The nature of the capping bonds around the metal coordination environment has a dramatic effect on the properties of the chelate, the ^natY³⁺ and ⁹⁰Y³⁺ dissymmetric derivatives presenting enhanced thermodynamic stability and kinetic inertness.

Full text of DOI:10.1039/c7cc05088g

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Beyler, E. Molnar, O. Fougere, D. Esteban-Gómez, G. Tircsó, C. Platas-Iglesias, N. Lepareur, O. Rousseaux
and R. Tripier, Chem. Commun., 2017, DOI: 10.1039/C7CC05088G.
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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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Role of the capping bond effect on pyclen natY3+/90Y3+ chelates: full
control of the regiospecific N-functionalisation makes the
difference
Received 00th January 20xx,
Accepted 00th January 20xx
Mariane Le Fur,a Maryline Beyler,a Enikő Molnár,b Olivier Fougère,c David Esteban-Gómez,d Gyula
Tircsó,b Carlos Platas-Iglesias,d Nicolas Lepareur,e Olivier Rousseaux,*,b and Raphaël Tripier*,a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Thanks to a smart regiospecific N-functionalisation, a pyclen based high proton relaxivity due to the presence of two coordinated water
ligand bearing one picolinate and two acetate arms organized in a molecules endowed with fast water exchange rates, which makes
dissymmetric manner was synthesized for Y3+ complexation, and this complex and related systems interesting alternatives to
compared to its symmetric analogue. The nature of the capping [Gd(dota)]-‡ as non-specific MRI contrast agents.5 In addition, pcta
bonds around the metal coordination environment has a dramatic has been found to present fast chelation kinetics under mild
effect on the properties of the chelate, the natY3+ and 90Y3+ conditions,6 making pcta and its derivatives attractive candidates
dissymmetric derivatives presenting enhanced thermodynamic for application in nuclear medicine. A fast complexation of the
stability and kinetic inertness.
radioisotope compared to its half-life is of crucial importance to
obtain high radiolabelling yields, in particular because of the low
A large variety of metal radioisotopes is currently used in nuclear concentrations employed and the “soft” conditions that can be
medicine due to their important diagnostic or therapeutic tolerated by the biomolecules used for targeting purposes.7
applications. Among the radioisotopes available for therapy 90Y (t1/2
= 64.2 h, Eβ- = 2.28 meV) is one of the most interesting β-
radioisotopes,1 especially for treatment of large solid tumors.2 As
the lanthanide(III) ions, Y3+ typically forms eight- or
nine-coordinated chelates with a preference for hard donor atoms
such
as
negatively
charged
oxygen
atoms
of
carboxylate/phosphonate groups and amine nitrogen atoms.3
Polyazamacrocycles, such as tacn or cyclen,‡ are recognized as
convenient platforms for the coordination of lanthanide cations
after a specific functionalisation of their amine functions.4 Among
the current azamacrocycles, derivatives of the 12-membered
tetraaza-macrocyclic ligand that includes a pyridine unit within the
ring, often denoted as pyclen (or 12-py-N4),‡ have been less
explored. However, the presence of the aromatic moiety confers to
the macrocyclic backbone an important rigidity that constrains the
overall structure and consequently may lead to unexpected
properties compared to its cyclen analogue. For example, the
aminocarboxylic acid derivative of pyclen, pcta,‡ forms stable and
neutral lanthanide complexes. Its Gd3+ chelate presents a relatively
Fig 1. Structures of the pyclen-based mono-picolinate ligands.
Pyridinecarboxylate (picolinate) groups are
bidentate
coordinating units that are known to provide extraordinary
coordination properties toward different metal ions,8 including
lanthanides,9 particularly when appended on macrocyclic
scaffolds.10 Thus, we firstly thought judicious to conjugate the
favourable binding properties of the pyclen skeleton and the
pyridinecarboxylate group to obtain neutral yttrium(III) chelates
that could be an interesting alternative to the negatively charged
Y(dota)-. Furthermore, we sought to investigate the effect that a
different spatial arrangement of the coordinating functions may
have on the properties of the complexes. Thus, two new regio-
isomeric pyclen-based ligands bearing one picolinate and two
acetate pendant arms, organized either in a symmetric (L1) or non-
symmetric (L2) manner were synthesized, and their coordination
properties towards yttrium(III) were compared (Fig. 1).
L1 was obtained by two successive alkylations controlled by
protection/deprotection sequences starting from N3-Boc-pyclen,
which was previously described by Siaugue et al.11 (see ESI†). The
synthesis of the dissymmetric regio-isomer L2 was more challenging
and required the development of a new route inspired by the
acylation of cyclam with diethyl oxalate, which allows a selective
cis-N2-N3-dialkylation.12 After the neutralisation of pyclen·3HCl,
a.Université de Bretagne Occidentale, UMR-CNRS 6521, UFR des Sciences et
Techniques, 6 avenue Victor le Gorgeu, C.S. 93837, 29238 BREST Cedex 3, France.
E-mail: raphael.tripier@univ-brest.fr
b.Department of Inorganic and Analytical Chemistry, Faculty of Science and
Technology, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary.
c. Guerbet group, Centre de Recherche d’Aulnay-sous-Bois, BP 57400, 95943 Roissy
CdG Cedex, France. E-mail: Olivier.Rousseaux@guerbet-group.com
d.Departamento de Química, Facultade de Ciencias & Centro de Investigaciones
Científicas Avanzadas (CICA), Universidade da Coruña, 15071 A Coruña, Spain
e. Département de Médecine Nucléaire, Centre Eugène Marquis, INSERM U1241,
Avenue de la Bataille Flandres, Dunkerque CS 44229, 35042 Rennes Cedex,
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [experimental section,
analytical data for synthesis, coordination chemistry and radiolabelling]. See
DOI: 10.1039/x0xx00000x
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pyclen oxalate (1) was synthesized in good yield (90 %) by acylation constant of YL2 is higher than that of Y(pcta) (log KYL = 20.28
with diethyl oxalate in MeOH (Fig. 2). The free amine function was determined at 25oC by using 1.0 M KCl), although lower than that of
then reacted with methyl 6-(chloromethyl)picolinate to lead quasi- [Y(dota)]- (log KYL
= 24.9). However, a comparison of the
quantitatively to 2. After hydrolysis of the oxalate bridge and complexation ability of ligands with different basicity might be
esterification of the carboxylic acid, the two other amine functions misleading if the competition of protons is not taken into account. A
were alkylated with the acetate arm. A final hydrolysis step better comparison is provided by the pM values, which were
provided L2. The relatively low yields of the last step obtained for calculated for the Y3+ complexes of L1, L2 and related ligands at pH
the two ligands are related to the difficulties found during HPLC 7.4 (Table 1). The pY value obtained for YL1 (pY = 18.14) is one log
purification.
unit higher than that of Y(pcta) (pY = 17.0) and approaching that of
The yttrium(III) complexes were synthesised in water at pH 5 and [Y(dota)]- (pY = 18.9). More remarkable, the pY value obtained for
isolated in very good yields (~90%). Both regio-isomers and their YL2 (pY = 20.33) is much higher than those of the reference chelates
complexes were characterized by 1H and 13C NMR in D2O (ESI†). The Y(pcta) and [Y(dota)]-. These results highlight the dramatic effect
assignments of the proton signals (Tables S1-S4, ESI†) were based that the arrangement of the ligand donor atoms of the chelators
on HMQC and HMBC 2D heteronuclear experiments as well as has on the stability of the complexes, conferring on L2 higher Y3+
standard 2D homonuclear COSY experiments. At 25°C, YL2 presents complexation properties than the current reference chelators.
sharp signals with methylene resonances showing a diastereotopic
Table 1. Stability constants of Y3+ complexes formed with pyclen based
pattern (see Fig. S2 in ESI†). In fact, all the non-aromatic protons
located on a same carbon atom give two signals, which indicates
mono-picolinates (25oC, 0.15 M NaCl) and related ligands.
the presence of a single diastereoisomer in solution with no
L1
L2
pcta
20.28b
17.0
dota
24.09c
18.9
log KYL
pYd
19.89(1)a
22.44(2)a
fluxional behaviour within the NMR timescale. YL1 shows however
broad signals in the region 2-5 ppm at room temperature that
become sharp at 55°C. At the latter temperature, the number of 1H
and 13C NMR signals is consistent with an effective Cs symmetry,
likely resulting from a fast interconversion between enantiomeric
forms of the complex by rotation of the pendant arms and inversion
of the macrocyclic ring (see Fig. S3 and S4 in ESI†).
18.14
20.33
aStability constants of the Y3+ complexes were determined by Gd3+ competition; bRef. 6
(25°C, 1.0 M KCl); cRef. 17 (25°C, 0.1 M Me4NNO3); dCalculated at pH = 7.4 for 100%
excess of ligand with [Y3+ tot = 10-5 M based on stability constants given in this Table.
]
Another essential feature that must fulfil chelate-based
radiopharmaceuticals is a good kinetic inertness in order to avoid
release of the metal ion in vivo. A preliminary assessment of the
kinetic inertness of a chelate can be carried out by studying the
dissociation of the complex in acidic media, which provides
interesting information on the behaviour of a complex in very
competitive media. The acid-assisted dissociation of YL1 and YL2
was studied in 0.5, 1 and 2 M HCl solutions at 25°C by following the
changes in the π-π* absorption band of the complexes in the UV
range (Fig. S6 and S7 in the ESI†). The different N-functionalization
pattern has a very significant impact on the chelate properties, as
an impressive gain of kinetic inertness is observed for the
yttrium(III) complex of the dissymmetrical pyclen-based mono-
picolinate L2 compared to its symmetric analogue L1 (Table 2). One
can especially note that the inertness of YL2 is significant with
respect to the reference Y(pcta)6 complex.
Fig 2. Synthesis of the dissymmetric pyclen-based mono-picolinate L2.
The thermodynamic protonation constants of L1 and L2 and the
stability constants of their complexes with Y3+ were determined at
25°C in 0.15 M NaCl using potentiometric titrations. Both L1 and L2
present a protonation behaviour similar to H3pcta. The first
protonation constant (logK1 = 9.69 and 10.43 for L1 and L2
respectively) corresponds to the protonation of the N atom trans to
Table 2. Determined half-times (in minutes) of dissociation of YL1 and YL2 in
HCl media.
HCl 0.5M
55
HCl 1M
27
HCl 2M
11
the pyridine ring.13 The second protonation induces
a
YL1
YL2
1014
31.9
357
19.6
137
12.7
rearrangement of the protonated sites, so that the two N atoms in
cis to the pyridine unit are protonated (logK2 = 7.63 and 6.47 for L1
and L2 respectively).6 As for previous systems, a decreasing basicity
occurring when carboxylate groups are replaced by picolinate
moieties is observed.14 The third protonation process is likely
associated to the protonation of the picolinate unit, while the
Y(pcta)6
In the absence of crystallographic data, a DFT study was
undertaken to rationalise the very different stability and
dissociation kinetics of the YL1 and YL2 complexes. Our
fourth protonation constant is attributed to a carboxylate group calculations provide optimised structures showing nine-
coordinate Y3+ ions, where coordination number nine is
(Table S5, ESI). The protonation constants show that L1 and L2 have
a similar overall basicity, which is lower than that of H4dota.15 The
completed by the presence of a water molecule (Fig 3). During
thermodynamic stability of the yttrium(III) complexes YL1 and YL2
the calculations two second-sphere water molecules were
were determined by competition with Gd3+ using the relaxometric
included in order to obtain more accurate bond distances
technique (Table 1 and in the ESI†, Table S5 and Fig. S5).16 The
involving the coordinated water molecules.18 The two isomeric
stability constant obtained for YL2 is very high and significantly
complexes present tricapped trigonal prismatic coordination
higher than that of YL1 (log KYL = 22.44 and 19.89 respectively), in
environments, which are however defined by different donor
spite of the similar basicity of the ligands. In addition, the stability
2 | Chem. Comm., 2017, 00, 1-4
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2.652, Y-N5 2.530, Y-O1 2.379, Y-O2 2.401, Y-O3 2.313 and Y-O4 2.320.
YL2(H2O)·2H2O: Y-N1 2.602, Y-N2 2.665, Y-N3 2.594, Y-N4 2.593, Y-N5 2.465,
Y-O1 2.490, Y-O2 2.295, Y-O3 2.280 and Y-O4 2.327.
atoms of the ligand in each case. In YL1, the three capping
positions of the polyhedron are taken by the nitrogen atom of
the picolinate unit (N5), an amine N donor atom (N4) and the
oxygen atom of a carboxylate group (O2). The capping
positions in YL2 are delineated by the amine nitrogen atoms
N2 and N4 and the oxygen atom of the coordinated water
90Y radiolabelling experiments were performed with L1 and L2 to
evaluate their labelling rates and efficiencies under different
molecule (O1). The bound water molecule presents a much conditions (in 0.1 M HCl (pH = 3) or in acetate buffer (pH = 4.65-9)).
The optimal radiolabelling conditions were then determined by
varying the reaction time, the temperature, the concentration and
the pH (Fig. S8, ESI†). Influence of the temperature was evaluated
with CL = 10-3 M at pH 5.2. A radiochemical purity (RCP) of 96% was
obtained with L2 when heating at 60°C, while the RCP dropped to
79% at rt. High RCP (85%) with L1 could be obtained only after
heating up to 100°C (Fig S8 B, ESI†). The optimal conditions for the
formation of the 90YL complexes were found to be a reaction time
of 15 min, CL = 0.1-1 mM and pH = 3.0-7.0 for L2 and 4.7-5.2 for L1.
These results clearly underline the faster and more efficient
radiolabelling of L2 compared to L1 with 90Y. The 90Y radiolabelling
shorter distance in YL1 (2.379 Å) than in YL2 (2.490 Å), which is
in line with the capping position occupied by the water
molecule in the latter. The distances involving the metal ion
and oxygen atoms of carboxylate groups are rather similar in
YL2 (2.28-2.33 Å). However, two of these distances are
considerably shorter (2.31-2.32 Å) than the third one (Y-O2 =
2.40 Å) in YL1, which appears to be related to the capping
position occupied by this donor atom. Indeed, we have
recently shown that water molecules occupying capping
positions in the coordination sphere are particularly labile
because they are hindered by the environment.19 The results of L2 is as efficient as the one performed in similar conditions with
dota (90Y-acetate, pH = 7.5, 15 min at 60°C, CL = 1 mg/mL).20 The
reported here suggest that the labile capping bond
stabilities of the 90YL complexes were studied both in human serum
phenomenon can be extended to donor atoms of the ligand,
and in an aqueous solution containing 0.1 M EDTA (Fig. 4). 90YL2
other than water molecules. The weak coordination of a
was found to be very stable both in serum and in the presence of an
carboxylate group at a capping position explains the lower
excess of EDTA, with no decrease of its RCP after 72h. Again, 90YL1
stability of the YL1 complex with respect to YL2, as also
is less stable with a progressive dissociation in human serum
confirmed by the relative free energy obtained from DFT,
which favours YL2 by 20.2 kJ mol-1. The fluxional behaviour of
solution (Fig. 4a) and an immediate decrease of RCP in the EDTA
solution. These results are in perfect agreement with the
thermodynamic stability and kinetic inertness studies performed
with the cold analogues, which already underlined the superior
stability of YL2.
YL1 evidenced by NMR measurements can be also attributed
to the presence of a weakly bound carboxylate, which likely
facilitates dynamic processes involving the rearrangement of
the ligand donor atoms around the metal ion. The location of a
negatively charged carboxylate at a capping position in YL1
also justifies the faster proton-assisted dissociation kinetics,
which are likely the result of an easier decoordination of the
carboxylate group upon protonation. This proton is then
transferred to a nearby amine nitrogen atom, which in turn
triggers the complex dissociation.
(a)
YL1(H2O)·2H2O
(b)
Fig. 4. Stability of 90YL complexes in (a) human serum, (b) EDTA 0.1 M.
In conclusion, we synthetized the two first mono-picolinate di-
acetate pyclen derivatives and proved their very interesting
YL2(H2O)·2H2O
yttrium(III) complexation properties. We developed
a new
regiospecific N-functionalization of the pyclen framework, which
allows tuning the arrangement of the pendant arms. This led to the
preparation of the dissymmetric L2 chelator, which forms a very
stable and inert Y3+ complex, representing a very attractive
Figure 3. Optimized structures of the YL1(H2O)·2H2O (top) and
YL2(H2O)·2H2O (bottom) systems obtained with DFT calculations. Bond
distances (Å), YL1(H2O)·2H2O: Y-N1 2.572, Y-N2 2.614, Y-N3 2.709, Y-N4
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alternative to dota for 90Y3+ radiotherapy applications. The different
arrangement of the donor atoms of L1 and L2 leads to very
different complexation properties. For instance, the YL1 complex
was found to be considerably more labile with respect to
dissociation, which showcases the labile capping bond
phenomenon. However, the YL1 complex also shows a considerably
lower thermodynamic stability with respect to YL2, which can be
attributed to a weaker coordination of a carboxylate group
occupying a capping position in YL1. Therefore, the labile capping
bond phenomenon introduced recently19 has profound
consequences not only in the water exchange and proton-assisted
dissociation rates of the complexes, but also in their
thermodynamic stabilities. Since the weak coordination of ligands
or donor atoms at capping positions affect both kinetic and
thermodynamic properties, we propose to rename this
phenomenon as the capping bond effect.
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R. T. acknowledges the Ministère de l’Enseignement Supérieur et
de la Recherche, the Centre National de la Recherche Scientifique
and the “Service Commun” of NMR facilities of the University of
Brest. R. T. and O. R. also thanks the Guerbet group and the
Association Nationale de la Recherche et de la Technologie for the
CIFRE fellowship. C. P.-I. thanks Centro de Supercomputación de
Galicia (CESGA) for providing the computer facilities. Gy. T. is
grateful for support arriving form the Hungarian Scientific Research
Fund (NKFIH K-120224 project) and for the János Bolyai Research
Scholarship of the Hungarian Academy of Sciences. The research
was also supported in a part by the EU and co-financed by the
European Regional Development Fund under the project GINOP-
2.3.2-15-2016-00008. N.L. acknowledges Labex IRON (Grant no.
ANR-11-LABX-0018).
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Notes and references
‡ Full names: tacn (1,4,7-triazacyclononane), cyclen (1,4,7,10-
(3,6,9,15
pcta
tetraazacyclododecane),
tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene),
pyclen
(3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-
3,6,9-triacetic acid), dota (1,4,7,10-tetraazacyclododecane-
1,4,7,10-tetraacetic acid)
1
2
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