A versatile fluorinated azamacrocyclic chelator enabling ¹⁸F PET or ¹⁹F MRI: a first step towards new multimodal and smart contrast agents

Abstract

Macrocyclic chelators play a central role in medical imaging and nuclear medicine owing to their unparalleled metal cation coordination abilities. Their functionalization by fluorinated groups is an attractive design, to combine their properties with those of ¹⁸F for Positron Emission Tomography (PET) or natural ¹⁹F for Magnetic Resonance Imaging (MRI), and access potential theranostic or smart medical imaging probes. For the first time, a compact fluorinated macrocyclic architecture has been synthesized, based on a cyclen chelator bearing additional pyridine coordinating units and simple methyltrifluoroborate prosthetic groups. This ligand and its corresponding model Zn(II) complex were investigated to evaluate the ¹⁸F-PET or ¹⁹F MRI abilities provided by this novel molecular structure. The chelator and the complex were obtained via a simple and high-yielding synthetic route, present excellent solvolytic stability of the trifluoroborate groups at various pH, and provide facile late-stage ¹⁸F-radiolabeling (up to 68% radiochemical yield with high activity) as well as a satisfying detection limit for ¹⁹F MRI imaging (low mM range).

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Introduction

Fluorine is a ubiquitous element in medical imaging with its two main isotopes, natural ¹⁹F and radioactive ¹⁸F, that allow Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET), respectively. On the one hand, ¹⁸F is the most used and readily available radionuclide for PET, with a wide range of radiolabeling strategies currently available,^1,2 as it has the advantages of a biologically relevant radioactive half-life (t_1/2 = 110 min), low radiotoxicity and low positron (β⁺) emission energy resulting in high resolution images. On the other hand, ¹⁹F-MRI presents the intrinsic advantages of the natural abundance of ¹⁹F (100%) and its good sensitivity compared to other nuclei (second best behind ¹H used in MRI). Moreover, the lack of in vivo background owing to the absence of fluorine in the body soft tissues allows direct quantitative detection of the tracer, in opposition to conventional ¹H MRI that relies on the water content of the body.^3,4 However this also leads to a low overall sensitivity of the ¹⁹F MRI technique that is currently tackled by two distinct strategies when it comes to molecular probes: high fluorine content of the tracer (ex: perfluorinated alcanes)⁴ or combination with paramagnetic metals or lanthanides that lower the relaxation time of the sensors.⁵

Concurrently, in the field of molecular probes for medical imaging and therapy, saturated polyazamacrocycles, such as cyclen (1,4,7,10-tetraazacyclododecane), cyclam (1,4,8,11-tetraazacyclotetradecane) and tacn (1,4,7-triazacyclononane) are cornerstone for the complexation of metallic and lanthanide cations for MRI,⁶ PET,^7,8 Single-Photon Emission Computed Tomography (SPECT)⁹ or internal Radiotherapy,^7,8 owing to their exceptional coordination properties and in vivo inertness of their complexes. In that context, fluorinated azamacrocycles are highly attractive as they can combine, within a single molecular architecture, the properties of metals or radiometals coordinated within their cavity with the ones of ¹⁹F or ¹⁸F. In particular, two major applications have been targeted recently: (i) complexes combining radiometals (α or β⁻ emitters) for radiotherapy and prosthetic ¹⁸F-radiolabeled units for diagnosis, leading to so-called theranostic tracers that merge therapeutic and diagnostic modalities in a single molecule and provide identical biodistribution in vivo; and (ii) complexes of paramagnetic cations with natural ¹⁹F pendants as sensitive or responsive ¹⁹F MRI probes.

Several fluorinated polyazacycloalcane scaffolds have thus been described for these two distinct objectives in recent years. First, azamacrocycles were used in ¹⁸F-PET as an alternative to conventional ¹⁸F-labeling (via C–F bonds formation)^10,11 for the tagging of biomolecules. In this case, the macrocyclic cavity of tacn-based chelators was used to accommodate metal-¹⁸F synthons: with Al(III) over a decade ago (AlF-NOTA, Scheme 1),^12–14 and lately with Ga(III) and Fe(III).^15–18 Linear ligands, such as ResCa and analogues, have also been reported since to allow such radiolabeling at low temperature (<37 °C).^19–23 However in those cases, the chelating cavity is occupied by innocent metal cations bearing no additional property. Only very recently Boros et al. went a step further and developed the corresponding theranostic version, using the Sc(III)–F synthon that can allow the ⁴⁷Sc (β⁻ radiotherapy)/¹⁸F (PET imaging) theranostic couple.²⁴ Nevertheless, the scope of this strategy is limited in terms of possible metal cations and corresponding radiometals as the strength of the M–F interaction is not sufficient with most relevant metallic cations, as already observed for instance with lanthanides.^25,26

Scheme 1 Fluorinated azamacrocyclic complexes for ¹⁸F-PET imaging and theranostics.

In a second strategy, the well-known DOTA chelator ((1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid), that can coordinate a wide range of metal cations and ¹⁷⁷Lu (β⁻ emitter) in particular, has been functionalized by branched side chains allowing grafting on a targeting moiety and installation of fluoroborate or fluorosilane prosthetic groups.^27,28 These are particularly attractive in this context, as they allow easy late-stage ¹⁸F-labeling via¹⁹F/¹⁸F isotopic exchange processes (Scheme 1),^29–31 as an alternative to sometimes tedious C–¹⁸F bond forming reactions.^10,11 However, the organic frameworks attached to the chelator in this case require challenging multistep syntheses, and result in large branched structures that can be detrimental to the recognition properties of the targeting unit and biodistribution of the radiopharmaceuticals. Therefore, more compact architecture are highly desirable.

Concerning the ¹⁹F MRI modality, small trifluoromethyl units have been efficiently used in sensitive or responsive probes based on azamacrocyclic complexes. First, trifluoromethylated cyclen-based chelators (Scheme 2) have proven excellent to coordinate paramagnetic lanthanide cations (Tb³⁺, Dy³⁺, Ho³⁺, Er³⁺ in particular) that decrease ¹⁹F relaxation times and drastically enhance the probes sensitivity.^5,32–34 Similarly, CF₃-appended cyclam chelators (Scheme 2) have been used with nickel(II) cations as sensitive probes,^35,36 or as on–off responsive sensors with redox-active cations (Co²⁺, Cu²⁺) that can modulate the ¹⁹F MRI signal upon modification of their oxidation state by external stimuli.^37,38 However, the lipophilic nature of such trifluoromethylated groups can be detrimental to applications in aqueous media and in vivo in particular.³²

Scheme 2 Fluorinated azamacrocyclic complexes as sensitive or responsive probes for ¹⁹F-MRI imaging, and versatile Do2py2BF₃ ligand presented in this work.

Therefore, we report in this study a novel compact cyclen-based architecture, bearing methyltrifluoroborate units directly supported by the macrocyclic amines (Do2py2BF₃, Scheme 2), to target two different applications with the same molecular topology: (i) allow easy ¹⁸F-radiolabeling via¹⁹F/¹⁸F isotopic exchange to allow future theranostic combinations with relevant radiometals; and (ii) present suitable ¹⁹F MRI signal, which has never been explored in the case of trifluoroborates, that could be used in responsive or sensitive imaging agents upon coordination with relevant non-radioactive paramagnetic cations. Noteworthy in the field (see AlF-NOTA or ScF-mptacn, Scheme 1), the chemistry of such chelators is first developed without the introduction of grafting functions and targeting molecules that will be necessary for future in vivo targeted applications. Therefore, the bispyridyl-cyclen scaffold has been selected in this proof-of-concept study for its ease of preparation and ubiquitous coordination properties.^39–41 Herein, the synthesis and characterization of this novel ligand architecture is presented, as well as the corresponding zinc(II) complex, a convenient diamagnetic model complex that allowed easy NMR characterizations and simple stability studies. The ability of the scaffold to undergo ¹⁸F-labeling, as known for other types of trifluoroborates, was investigated on this new structure. Then the potential of BF₃ units as ¹⁹F MRI reporters was also investigated for the first time on the model Zn(II) complex. Finally, a particular focus was given to the study of the solvolytic stability of the new trifluoroborated scaffolds in water at different pH, which is a crucial parameter to envisage future applications for this new type of chelators.

Results & discussion

Synthesis and characterization

Ligand H₂Do2py2BF₃ was prepared from previously described Do2py,⁴⁰ through a 2-step synthetic procedure adapted from Perrin et al. for the installation of methyltrifluoroborate functional groups via fluorination of a pinacolborane intermediate with potassium bifluoride (Scheme 3).⁴²

Scheme 3 Synthesis of H₂Do2py2BF₃ ligand and Zn(Do2py2BF₃) complex.

The new macrocycle was fully characterized by means of High-Resolution Mass Spectrometry (HRMS) and multinuclear NMR. In 1 : 1 D₂O/CD₃CN (pH 4), the ligand exhibits broad singlets in ¹⁹F (δ = −135.6 ppm) and ¹¹B (δ = 2.44 ppm) NMR and a diagnostic quadruplet for the α-methylene group in ¹H NMR (δ = 1.80 ppm, ³J_H–F = 5.2 Hz) (see ESI† for spectral data). In ¹³C NMR, this methylenic carbon could not be directly observed owing to multiplicity and broadness induced by neighboring boron and fluorine nuclei, but was assigned thanks to 2D ¹H–¹³C HSQC NMR (47.8 ppm). Single crystals were grown from a water/acetonitrile mixture (1 : 1, pH 4) revealing the neutral H₂Do2py2BF₃ ligand with both nitrogen atoms holding the BF₃ pendants (N2 and N4, Fig. 1a) that are protonated.⁴³ This feature is classical for cyclen-based ligands at this pH, as two amines in trans N1–N3 positions generally have pK_as above 9.⁴⁴

Fig. 1 X-Ray diffraction structures of (a) H₂Do2py2BF₃ ligand at pH 4, (b) H₄Do2py2BF₃ at pH 1 and (c) Zn(Do2py2BF₃) complex (c). Ellipsoids are drawn with 50% probability. H atoms omitted for clarity, except on ammonium groups of H₂Do2py2BF₃ and H₄Do2py2BF₃.

Single crystals were also grown from an acidic aqueous solution (pH 1), revealing a different structure with the ligand under the form H₄Do2py2BF₃²⁺ displaying additional protonation of the two pyridine units (H5 and H6, Fig. 1b) creating a H-bonding network with fluorine atoms (F3 and F4) from both trifluoroborate pendants (d_F4–H5 and d_F3–H6 of 1.89 and 1.91 Å respectively). This constrained geometry is also present in solution at acidic pH, as evidenced by a set of 3 broad signals on the ¹⁹F spectrum from −136 to −140 ppm (D₂O, pH 1), close to the sole chemical shift observed at pH 4 (−135.6 ppm). Similarly, ¹H NMR spectrum reveals the different symmetry of the molecule with a complex multiplet centered at 4.16 ppm accounting for the four methylenic pyridyl protons (vs. sharp singlet at 4.49 ppm at pH 4), different multiplicity of the aromatic protons and a set of three broad signals between 1.90 and 2.30 ppm for the methylenic protons linked to the trifluoroborate units.

The corresponding zinc(II) complex was then prepared, from an equimolar mixture of H₂Do2py2BF₃ and zinc(II) perchlorate in acetonitrile at 60 °C, with potassium carbonate as a base, and purified by crystallization in a water/acetonitrile mixture (3 : 7). Owing to its limited solubility in water at high concentrations, NMR analysis was carried out in a 1 : 1 D₂O/CD₃CN mixture (pH 6). At RT, the ¹H spectrum presents very broad signals for the macrocyclic protons, that could however be resolved at 333 K (Fig. S11, ESI†), and ¹⁹F NMR reveals a broad singlet at −137.4 ppm, very close to that of free ligand, as a first indication of the innocent nature of the trifluoroborate pendants upon coordination of the metal. More insight was gained by the structure revealed by X-ray diffraction analysis on single crystals of the complex grown in CH₃CN/H₂O (7 : 3) solution (Fig. 1c). Zinc(II) cation lies slightly above the cyclen plane (distance with N1–N2–N3–N4 centroid = 0.999 Å, Fig. S13, ESI†) and adopts a distorted trigonal prismatic geometry similar to the Zn(Do2py)²⁺ complex reported in the literature,⁴⁰ highlighting again the innocent behaviour of the trifluoroborated groups in the coordination sphere of the metal. Only the Zn–N bonds with cyclen nitrogen atoms are somewhat longer in this complex (by up to 0.07 Å, Fig. S13, ESI†), probably owing to the different steric bulk on two nitrogen atoms from the ring (N–CH₂–BF₃vs. NH in Do2py).

Solvolytic stability

The main limitation of trifluoroborate prosthetic groups for practical use in [¹⁸F]-PET radiotracers can be their lack of stability towards solvolysis, via the release of free fluoride and formation of boronic acid derivatives, which has been well-documented by Perrin et al.^45,46

The solvolytic stability of the new azamacrocyclic motifs was thus investigated for the free ligand and the Zn complex by ¹⁹F NMR, at a concentration of 3 × 10⁻² M in buffered aqueous solutions at pH 2.0, 7.3 and 9.7 (Fig. S15–S20, ESI†). In these conditions, Do2py2BF₃ demonstrated exceptional robustness with no degradation observed in any of the three pH conditions, after up to 3 days at 25 °C (Table 1). In particular, this observation is in contrast with the closest reported ammonium-based structure (Et₂NH⁺CH₂BF₃) that displays a half-life of 66 hours at physiological pH.⁴⁶ This enhanced stability in Do2py2BF₃ is probably due to the higher basicity of the cyclen tertiary amines providing a poorly labile ammonium proton stabilizing the zwitterionic structure with the trifluoroborate group. On the zinc(II) complex, the stability is slightly different, owing to the loss of the ammonium protons to accommodate the metallic cation. First, at pH 2.0, a fast decoordination of the cation was evidenced by ¹⁹F NMR (t_1/2(Zn) < 5 min, Fig. S18, ESI†), which is common with such highly basic polyamines at acidic pH. However, no degradation of the BF₃ units was observed as only the ¹⁹F signals of the free ligand were recovered. At neutral and basic pH, no release of the metal occurred, demonstrating the strong coordination ability of the ligand. However, very slow solvolysis of the BF₃ groups appeared (Fig. S19–S20,† ESI). As previously discussed in the literature by Perrin and others,^45,47 the kinetics of solvolysis follow a pseudo-first order kinetic rate, with a rate-determining step corresponding to the loss of the first fluoride ion, and the other intermediates towards fully hydrolyzed boronic acid being fast-lived. Very long half-lives (985 and 400 hours at pH 7.3 and 9.7 respectively) could be calculated here for the new BF₃ pendants, that are perfectly suited to consider further use in the context of ¹⁸F PET imaging when compared to the radioactive half-life of ¹⁸F (110 min) or the biodistribution and clearance of radiotracers (from minutes to a few days). Indeed, the stability of these pendants even surpasses the one of the most stable similar trifluoroborate functions described so far in the literature in these pH ranges (366 h for AMBF₃ groups at pH 7.5).

Table 1 Solvolysis data of Do2py2BF₃ ligand and Zn(Do2py2BF₃) complex

Compound	pH	t	% intact BF3	t 1/2
Do2py2BF3	2.0	72 h	100%	—
	7.3	72 h	100%	—
	9.7	72 h	100%	—
Zn(Do2py2BF3)^2+	2.0	8 days	100% (90% Zn release)	—
	7.3	22 h	89%	985 h
		13 days	77%
	9.7	18 h	90%	400 h
		11 days	63%

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¹⁸F-radiolabeling

Furthermore the ability of the new molecule for easy ¹⁸F-radiolabeling was evaluated on both H₂Do2py2BF₃ ligand and Zn(Do2py2BF₃) (Scheme 4). Radiosyntheses were carried out on a TRACERlab FXFN module (GE) (Fig. S21, ESI†). At the end of bombardement (EOB), the [¹⁸F] fluoride produced by the cyclotron was delivered to the automate and trapped on a pre-conditioned QMA Sep-Pak cartridge to remove [¹⁸O]–water. The elution of the activity (30 GBq at EOB) into the reactor was performed with a solution of TBABr (16 mg in 0.5 ml H₂O) to form [¹⁸F]tetrabutylammonium fluoride ([¹⁸F]TBAF). Acetonitrile was added for the azeotropic evaporation under vacuum and helium flow. Solutions containing 1 mg of H₂Do2py2BF₃ in acetonitrile or Zn(Do2py2BF₃) in DMSO were added into the reactor for a 30 min incubation at 80 °C. It is worth noting that these solvents are not desired for further application in vivo, but were used herein as the ligand and complex are not fully soluble in water. However, solubility in aqueous media should be achieved for future applications upon grafting on water soluble biomolecules, and aqueous ¹⁸F-labelling of trifluoroborates has been well documented.^48,49

Scheme 4 ¹⁸F-radiolabeling of H₂Do2py2BF₃ and Zn(Do2py2BF₃) in acetonitrile, and corresponding HPLC (UV) and radioHPLC traces for H₂Do2py2BF₃.

RadioChemical Yields (RCY) were subsequently measured via radioHPLC analyses, with UV traces of the “cold” ligand or zinc complex as references (Fig. S22–S23, ESI†). In these conditions, highly satisfactory RCY of up to 68% was obtained for the ligand H₂Do2py2BF₃. RCY for the Zn(Do2py2BF₃) complex is somewhat lower, probably owing to its lower solubility in the reaction medium, but is acceptable to envisage future applications in the field. Indeed, these RCY are excellent when compared to analogous isotopic exchange with trifluoroborates in similar conditions (15–30%)^42,50 or labeling via metal-fluoride synthons (30–45% with Al,⁵¹ 65% with Sc (ref. 24)). In addition to these conversions, labeled compounds could also be easily purified on semi-preparative HPLC with a Gemini C₁₈ Column and formulated as injectable aqueous solutions after solubilization in NaCl solutions on C₁₈ Sep-Pak cartridges within the automated system, which is one of the main advantages of such facile isotopic exchange on BF₃ units. For the H₂Do2py2BF₃ radiolabeling, 30.6 GBq μmol⁻¹ at the injection time were associated to the desired product whereas 7.8 GBq μmol⁻¹ were obtained for the radiolabeled Zn(Do2py2BF₃). These results on the molar activities are good enough for further in vivo studies and consistent with the reference publications (around 40–110 GBq μmol⁻¹ for high specific activity).⁴⁸

¹⁹F-magnetic resonance

To investigate the potential of trifluoroborate units as ¹⁹F MRI probes, relaxivity studies were carried out at a 7.1 T field, on a CH₃CN/H₂O (1 : 1) solution of Zn(Do2py2BF₃) at a concentration of 0.032 M in complex (i.e.¹⁹F concentration of 0.192 M owing to the 6 fluorine atoms per molecule). A single peak in ¹⁹F modality was detectable at −137 ppm. Longitudinal (T₁) relaxivity was measured with an inversion recovery sequence, while the transversal (T₂) relaxivity was measured with a CPMG sequence, leading to values of T₁ = 383.7 ± 0.01 ms and T₂ = 268 ± 0.02 ms. These are reasonably short relaxation times compared to corresponding ligands bearing trifluoromethyl groups (i.e. two to three times lower T₁ than cyclam methylene-CF₃ analogue with diamagnetic Cu(I) cation),^5,38 that allowed a large number of averages to be accumulated in a short time. Then a phantom was prepared with variable ¹⁹F concentrations ranging from 1 mM to 150 mM (Fig. 2). Samples with ¹⁹F concentration of 50, 100 and 150 mM were clearly detectable already after 10 min of acquisition (corresponding Zn(Do2py2BF₃) concentration of 8.3, 16.7 and 25 mM, respectively). After 45 min of acquisition, samples with 15 and 25 mM ¹⁹F were barely visible so a different phantom (25–150 mM) was used for detection limit measurement with 10, 45 and 60 minutes acquisition (Fig. 2). From these data, a detection limit between 50 and 75 mM in ¹⁹F was observed at t = 10 minutes, and of 40 mM in ¹⁹F (6.7 mM in complex) could be determined for acquisition times of 45 and 60 minutes. This value is clearly in the range of perfluorocarbons used in preclinical and clinical studies.⁵²

Fig. 2 ¹⁹F-Magnetic resonance of Zn(Do2py2BF₃) in acetonitrile/water (1 : 1) at 3.2 × 10⁻² M. Measurements were conducted at t = 10 min (panels a–c), 45 min (panels d–f) and 60 min (panels g–i). For each timepoint, control ¹H MR (H₂O signal) is displayed in left column, ¹⁹F signal in the center column, and overlay in the right column. ¹⁹F concentration (mM) is indicated next to the corresponding sample.

Conclusions

In conclusion, we have successfully prepared the first example of a small trifluoroborated macrocyclic chelator, through a practical synthetic procedure and easy purifications. This ligand presents suitable stability of the BF₃ units, which is the usual limitation of such functions for in vivo applications, and a spectator character of these groups upon coordination to Zn(II) in the corresponding model complex. This architecture subsequently allowed easy late-stage ¹⁸F radiolabeling through simple and fast isotopic exchange with great RCY, and trifluoroborates have also been used for the first time as ¹⁹F MRI reporters. These first results suggest that such BF₃-appended azamacrocycles are a new very promising class of chelators to envisage both theranostic applications with the ¹⁸F PET modality and suitable radiometal coordination design, and their use as sensitive or responsive contrast agents when using the ¹⁹F MRI modality. Following this first step, ligand optimization will now be tackled for the various metals and radiometals relevant for these two distinct applications.

Data availability

CCDC 2314190 (H₂Do2py2BF₃ ligand), 2314191 (H₄Do2py2BF₃²⁺ ligand) and 2314192 (Zn(Do2py2BF₃)) contain the ESI† for this paper. The datasets supporting this article have been uploaded as part of the ESI.† Additional data can be provided upon reasonable request to E-mail: Thibault.troadec@univ-brest.f.

Author contributions

Conceptualization and funding acquisition by TT; investigation by CS, TT, VM, NSM and FG; supervision by TT, RT, LT, ET; original draft by TT; review and editing by all authors.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work has been supported by CNRS, University of Brest, the “Fondation ARC pour la recherche sur le cancer” (program Macrofluor, TT) and ANR (JCJC program Smartfluor, TT). The authors would like to thank Cyril Colas from the “Fédération de Recherche” ICOA/CBM (FR2708)” for HRMS analysis and Muriel Escadeillas from CRMPO (Rennes) for elemental analysis.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, spectroscopic data for characterization and stability studies of the new compounds, and experimental details for ¹⁸F labeling and ¹⁹F magnetic resonance experiments. CCDC 2314190–2314192. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4sc02871f

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