Ligation driven 19F relaxation enhancement in self-assembled Ln(III) complexes

Article abstract of DOI:10.1039/c4cc09952d

Strong bidentate ligation between a fluorinated isophthalate and binuclear lanthanide-DO3A species yields a new class of ¹⁹F NMR agent with very high nuclear relaxation rates at physiologically-relevant pH.

Full text of DOI:10.1039/c4cc09952d

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1
9
Ligation driven F relaxation enhancement in
self-assembled Ln(III) complexes†
Cite this: Chem. Commun., 2015,
1, 2918
5
Gemma-Louise Davies,‡ Asha Brown, Octavia Blackburn, Manuel Tropiano,
Received 13th December 2014,
Accepted 21st December 2014
Stephen Faulkner, Paul D. Beer and Jason J. Davis*
DOI: 10.1039/c4cc09952d
www.rsc.org/chemcomm
Strong bidentate ligation between a fluorinated isophthalate and Covalent integration of a fluorinated functional group onto a
19
binuclear lanthanide-DO3A species yields a new class of F NMR agent paramagnetic centre, with an optimal distance of 6 Å, has also
1
9
À1
À1
with very high nuclear relaxation rates at physiologically-relevant pH. achieved F relaxation rate boosts of 139–694 s and 220–675 s
16,18–22
(
R
1
and R
2
respectively at 9.4 T).
Ion pairing or reversible
Magnetic resonance imaging (MRI) is a powerful non-invasive coordination between coordinating anions or fluorides and a
imaging modality capable of providing anatomical information paramagnetic moiety can lead to increased contact time between
1
19
with high spatial resolution. The application of its innate the ions, shortening H and, to a lesser extent, F relaxation
1
4,19,22–27
capability for accurate early disease detection and diagnosis is, times.
Reports of fluorinated carboxyl-based ligands
however, weakened by its inherent low signal:noise. In recent coordinating with heptadentate paramagnetic chelates have shown
years there has been growing interest in the possibility of some promise in this area, with R values B100 s at 7 T observed
negligible background) fluorine ( F) MRI. The possibility of for fluorinated L-lactate systems; these are, however, limited by
1
À1
1
1
9
2–5
(
1
19
À1 24
bimodal H and F MRI probes has, in particular, stimulated their impracticably low binding affinities (K
a
o 12 M ).
The ligation chemistry of lanthanides is rich and has been
as opposed to the ubiquitous proton equivalent, is generated associated with the development of sensors and complexes of
6–10 19
research into suitable fluorinated materials.
F image contrast,
19
28–32
directly from introduced F nuclei, and not from the impact of sensitised emission.
Recent reports of the self-assembly of
paramagnetic or superparamagnetic species on local water mole- binuclear lanthanide complexes with a series of dicarboxylates
cules. Unfortunately, the development of practically useful contrast have demonstrated that isophthalate-derived anions bind parti-
has been severely limited by low fluorine content, low agent cularly strongly with metallated binuclear DO3A species (with
1
9
6
À1
aqueous solubility and/or low local/segmental F mobility (factors binding constants 420 Â 10 M in 3 : 1 methanol : water or
1
9
2,11–15
33,34
compounded as attempts are made to increase F content).
buffer systems).
F MR image contrast improvements can, alternatively, be strong bidentate binding motif to prepare fluorinated isophthalate
achieved in a similar manner to protic MR enhancement, by species which ligate to mononuclear and binuclear gadolinium
Herein, we have sought to exploit this
1
9
1
9
employing the so-called paramagnetic relaxation enhancement chelates, generating new agents that demonstrate strong
PRE) effect, where the introduction of a paramagnetic centre relaxation enhancement. Isophthalate species with ethoxy spacing
F
(
1
9
5,9,14,16
accelerates the relaxation of F nuclei.
groups between the ligating carboxyl and fluorinated substituents
1
9
Successful F PRE (both R and concomitant changes in R ) have been designed to overcome the strong electron withdrawing
1
2
can be achieved using various approaches; incorporation of non- effect of fluorine in retaining efficient ligation. This work
coordinating paramagnetic Gd chelates (non-covalently) within represents the first reported example of bidentate ion coordina-
19
the lipid bilayer of highly fluorinated particles yields 2–10 fold tion to facilitate PRE in a F agent and exemplifies a new strategy
1
9
À1
À1
17
improvements in F R
1
and R
2
values (to 2 s and 42 s
of potential utility in MRI.
respectively at 4.7 T), effects due to environmental proximity alone.
The binding of an ethoxy-fluorinated benzoic acid molecule,
1
, with a heptadentate Ln-DO3A moiety was initially investigated
1
9
Department of Chemistry, University of Oxford, South Parks Road, Oxford,
OX1 3QR, UK. E-mail: Jason.davis@chem.ox.ac.uk; Fax: +44 (0)1865 272 690;
Tel: +44 (0)1865 275 914
(Fig. 1). Relaxation studies resolved slow F relaxation rates of 1
À1
À1
(
R = 0.72 Æ 0.06 s , R = 4.39 Æ 0.17 s at pH 6–7 and 7 T),§
1
2
due to its low molecular weight and fast rotational correlation
time (t ). Upon monodentate ligation to yield 2 (Fig. 1), up to
†
Electronic supplementary information (ESI) available: Synthetic and characteri-
sation detail, spectra, Table S1 and Fig. S1–18. See DOI: 10.1039/c4cc09952d
Current address: Department of Chemistry, University of Warwick, Gibbet Hill
Road, Coventry, CV4 7AL, UK.
R
1
9
3
1
0-fold enhancement of F relaxation was observed (R =
‡
À1
= 39.56 Æ 12.7 sÀ1 at pH 6–7 and 7 T).
22.26 Æ 2.36 s , R
2
2
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a
pK ’s (B3.70 and 4.60), relaxation enhancements were dramati-
cally lower (as expected). Somewhat counter-intuitively, relaxo-
metric characteristics were less strongly enhanced at high
solution pH (9–12) also. The binding affinity of Ln-bis-m-xylyl
compounds and similar species with dicarboxylates is, how-
ever, well-known to vary dramatically with pH, due to local
ligation-restricting conformational changes in the lanthanide
34,37,38
species.
These conformational changes will, of course, have
Fig. 1 Fluorinated carboxylate species and mono- and binuclear lanthanide
direct consequences on the relaxation through self-assembly.
These sensitively pH dependent effects were confirmed through
analogous Eu luminescence titrations, where association results
in increased luminescence emission intensity (Fig. S7–S10, ESI†)
3+
DO3A coordination compounds prepared, where Ln = Gd (in relaxation
3+
studies) or Eu (in luminescent binding studies).
It should be noted that, for all samples studied herein, a single due to the removal of quenching hydroxyl oscillator groups;
À1
principal resonance representing the fluorinated ligating species association constants (K ) ranging between 574 and 83 283 M
a
19
was observed in F NMR spectra (Fig. S5, ESI†). Paramagnet were calculated, using Dynafit, with the strongest binding associ-
proximity can, of course, result in severe line broadening, limiting ation observed at pH 6–7 (69 859–83 283 M , Table S1, ESI†).§
À1
detection sensitivity; indeed some line broadening was observed
The strong binding and relaxation enhancements observed
upon ligation (from 0.11 to 0.22 ppm), but this was not severe with 4 represent a 20-fold improvement over those previously
1
4,25–27
(
Table S1 and Fig. S5, ESI†),¶ and concomitant changes in R
2
observed for ionic coordination species.
Similar relaxation
19
indicate the potential utility of these materials as F contrast rate observations were made with trifluoromethyl-lactate coordi-
agents. No pseudocontact chemical shift was observed as indeed nated Gd-DO3A chelate species (R B 100 s at 7 T), however,
À1
1
3+
5
À1
expected for Gd ions.
a
extremely poor aqueous binding was observed (K 6–12 M ),
Recent investigations into the chelation of binuclear lanthanide likely due to the strong electron-withdrawing nature of the
2
4
chelates with dicarboxylate species have demonstrated that strongly fluorine atoms weakening its coordinating capability. In our
bound adducts can be formed due to the unique binding pocket case, the introduction of an ethoxy group between the fluorine
available, where both mono- and bi-dentate binding of carboxylate and coordinating carboxylate groups serves to lessen this effect
33–36
groups can occur with 7-coordinate lanthanide centres.
We and promote the strong binding observed. This results in the
postulated that effective ligation of ethoxy-fluorinated isophthalic observation of high relaxation rate enhancements, up to 68-fold
acid analogues to binuclear gadolinium adducts would facilitate improvements over the native ethoxy-fluorinated isophthalic
effective, and distance-optimised, PRE. The fluorinated isophthalic acid, with strong coordination. Importantly, this work represents
acid compound or derivative 3, demonstrated slow relaxation the most effective ligation induced PRE reported to date and the
À1
À1
(
Fig. 1 and 2, R
1
= 1.47 Æ 0.27 s , R
2
= 4.89 Æ 0.19 s at pH 6–7 only one where ligation is effective.
and 7 T), similar to those observed for the monodentate benzoic
The binding model employed to describe these observations
acid analogue (1).§ Upon ligation to a binuclear gadolinium chelate assumes a 1 : 1 ratio of the lanthanide moiety and ethoxy-
to form 4, the R and R relaxation rates increased dramatically fluorinated compound (as traditionally observed for coordina-
Fig. 2, R = 99.95 Æ 7.33 s and R = 265.40 Æ 46.82 s at pH 6–7 tion compounds of this kind)
1
2
À1
À1
33,37
(
yielding a single chelated
1
2
and at 7 T), reducing the T and T relaxation times of compound compound where binding through both of the carboxylic acid
1
2
or derivative 3.
groups of the isophthalic acid derivative is assumed (leading to
37
In analysing relaxivity characteristics as a function of solution the ‘preferred binding conformer’ represented in Fig. 1). In order
pH, the most dramatic increases in relaxation rate occurred at to confirm that this is the case, a series of control experiments
pH 6–7, indicating the strongest binding environment (Fig. 2 and were carried out. Binding of ethoxy-fluorinated isophthalic acid 3
Table S1, ESI†). At pH’s less than or in the region of the ligand with a mononuclear DO3A (to provide 5, Fig. S11, ESI†), resulted in
19
enhancement of F relaxation rates, with the strongest improve-
À1
ments once again occurring at pH 6–7 (R = 41.42 Æ 7.57 s , R =
1
2
À1
6
1.56 Æ 5.43 s at 7 T, Fig. S12, ESI†). The relaxation rate
enhancements were, however, notably lower than those observed
for the binuclear system 4. This can be attributed to a weaker
33
binding pocket of the monodentate lanthanide-DO3A chelator.
Association constants confirm this behaviour, demonstrating
values several times lower than those observed for the binuclear
species and follow the trend observed in binding at different pH
À1
(
Ka 21 000–33 000 M , Table S1 and Fig. S13–S16, ESI†). Similarly,
1
9
Fig. 2
1 2
F relaxation rate (R and R ) behaviour of the fluorinated isophthalic
the binding of fluorinated benzoic acid, 1, with the binuclear
lanthanide, resulting in 6 (Fig. S11, ESI†), enhanced relaxation
acid derivative, 3, after binding with the binuclear lanthanide chelate to yield
the complex 4, measured at different pH ranges in 50: 40 : 10 methanol :
water : D O solutions, at 7 T and 25 1C. Error bars represent cumulative errors
2
À1
À1
rates (R
1
= 83.79 Æ 24.75 s , R
2
= 260.95 Æ 99.23 s at pH 6–7
arising from triplicate repetitions of relaxation rate assessment.
and 7 T). In this case, the relaxation rate enhancement was
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reasonably strong, but notably slower than the optimised
bidentate ligation system, 4. The large errors associated with
this species could be due to some weak electrostatic association
of the ethoxy-fluorinated group of 1 with the second metal
centre in the strong binding pocket of the binuclear lanthanide
complex, or the approach of a second fluorinated benzoic acid
group, creating multiple distinct lanthanide–fluorine distances.
It has previously been reported that the exchange rate of
coordinating carboxylate species is modulated by the structural
and electronic properties of the (native) lanthanide macrocyclic
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relative impact of paramagnetism on R and R is important in
terms of MR signal:noise. Excessive acceleration of R
1
1
2
, in particular, 14 H. Lee, R. R. Price, G. E. Holburn, C. L. Partain, M. D. Adams and
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is detrimental. Species 4 and 5 display R /R ratios of 0.4 and 0.7
1
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10,39
are well within the window of effective practical application.
1
1
Coordination through ion binding of lanthanide derivatives and
carboxylates is well-known, with luminescent sensitisation a prime
example of the potential of such strong (yet reversible binding
19
systems). F MRI has emerged, in recent years, as a useful comple-
1
1
19
mentary diagnostic technique, although F contrast agents are
often plagued by solubility and sensitivity issues. The PRE effect
has been exploited for decades to enhance protic MRI relaxation;
2
0 K. H. Chalmers, E. De Luca, N. H. M. Hogg, A. M. Kenwright,
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a
2
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19
can result in exceptional enhancements in F MRI relaxation
À1
À1
(
R
1
= 99.95 Æ 7.33 s and R
2
= 265.40 Æ 46.82 s , at 7 T), an
2
effect which is most pertinent in the physiologically-relevant pH
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1
9
can provide efficient amplified paramagnetic F relaxation
enhancement. The approach would also lend itself to exploitation
of exchange between bulk and bound isophthalate species in
achieving greatly enhanced contrast at low concentrations of probe.
The authors acknowledge financial support from the Wellcome
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§
All relaxation rate assessments were carried out in 50 : 40 : 10
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methanol : water : D
solution due to the low water solubility of the fluorinated isophthalic acid.
2
O solution and binding studies in pure methanol 35 J. Lehr, J. Bennett, M. Tropiano, T. J. Sørensen, S. Faulkner,
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¶
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920 | Chem. Commun., 2015, 51, 2918--2920
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