NOTA Complexes with Copper(II) and Divalent Metal Ions: Kinetic and

Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

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NOTA Complexes with Copper(II) and Divalent Metal Ions: Kinetic and Thermodynamic Studies Vojtěch Kubíček,*,† Zuzana Böhmová,† Romana Ševčíková,‡ Jakub Vaněk,‡,§ Přemysl Lubal,*,‡,§ Zuzana Poláková,† Romana Michalicová,‡ Jan Kotek,† and Petr Hermann† †

Department of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 40 Prague 2, Czech Republic Department of Chemistry, Masaryk University, Kotlárš ká 2, 611 37 Brno, Czech Republic § Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic ‡

S Supporting Information *

ABSTRACT: H3nota derivatives are among the most studied macrocyclic ligands and are widely used for metal ion binding in biology and medicine. Despite more than 40 years of chemical research on H3nota, the comprehensive study of its solution chemistry has been overlooked. Thus, the coordination behavior of H3nota with several divalent metal ions was studied in detail with respect to its application as a chelator for copper radioisotopes in medical imaging and therapy. In the solid-state structure of the free ligand in zwitterionic form, one proton is bound in the macrocyclic cavity through a strong intramolecular hydrogen-bond system supporting the high basicity of the ring amine groups (log Ka = 13.17). The high stability of the [Cu(nota)]− complex (log KML = 23.33) results in quantitative complex formation, even at pH Na(I) > K(I)). Thus, H3nota shows high selectivity for small metal ions. The [Cu(nota)]− complex is hexacoordinated at neutral pH, and the equatorial N2O2 interaction is strengthened by complex protonation. Detailed kinetic studies showed that the Cu(II) complex is formed quickly (millisecond time scale at cCu ≈ 0.1 mM) through an out-of-cage intermediate. Conversely, conductivity measurements revealed that the Zn(II) complex is formed much more slowly than the Cu(II) complex. The Cu(II) complex has medium kinetic inertness (τ1/2 46 s; pH 0, 25 °C) and is less resistant to acid-assisted decomplexation than Cu(II) complexes with H4dota and H4teta. Surprisingly, [Cu(nota)]− decomplexation is decelerated in the presence of Zn(II) ions due to the formation of a stable dinuclear complex. In conclusion, H3nota is a good carrier of copper radionuclides because the [Cu(nota)]− complex is predominantly formed over complexes with common impurities in radiochemical formulations, Zn(II) and Ni(II), for thermodynamic and, primarily, for kinetic reasons. Furthermore, the in vivo stability of the [Cu(nota)]− complex may be increased due to the formation of dinuclear complexes when it interacts with biometals.

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INTRODUCTION

radioisotope bound in a thermodynamically stable and kinetically inert complex. Macrocycles are the most commonly used ligands for complexation because complexes of open-chain ligands are usually kinetically labile. However, most macrocyclic ligands undergo slow complexation, which is an important setback for their radiopharmaceutical applications. Several copper radioisotopes are used in nuclear medicine, including 60Cu, 61Cu, and 64Cu, which are emerging PET radioisotopes. 64Cu and 67Cu are β− emitters which can be used for radiotherapy. Copper radioisotopes are produced from neighboring elements, Zn and Ni, which are simultaneously daughter elements of their radioactive decay. Therefore,

Positron emission tomography (PET) is one of the most commonly used medical imaging techniques. PET imaging enables the observation of metabolic processes in the body using positron-emitting radioisotopes. The positron travels a short distance through the tissue (usually 1−20 mm), depending on its kinetic energy, and undergoes electron annihilation. Annihilation yields two collinear photons, which are detected by a PET scanner. Consequently, differences in photon intensity allow the 3D image reconstruction of the radioisotope distribution in the body. Several suitable PET radioisotopes are metal radioisotopes. However, metal radioisotopes cannot be applied in the “free” form (as simple salts) because their injection into the body leads to nonspecific deposition of radioisotopes. The desired biodistribution and pharmacokinetics require a metal ion/ © XXXX American Chemical Society

Received: November 16, 2017

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DOI: 10.1021/acs.inorgchem.7b02929 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

Ni(II)27 and the acid-assisted decomplexation kinetics of the H3nota complex with Mn(II)26 have been investigated. Other solution studies have involved EPR and UV−vis spectroscopy of complexes with paramagnetic metal ions,19,29,31 NMR studies of complexes with diamagnetic metal ions,23,29,32 and IR and electrochemical analysis of complexes with Mn(II), Fe(II) and Ni(II).17 The exchange rate of “free” (aqua ion) Cu(II) and Cu(II) complexed with H3nota, H4dota, and H4teta (Chart 1) has been studied using 64Cu, and the slowest exchange was found for the H3nota complex.33,34 Complexes of tetraaza macrocycles are usually considered highly kinetically inert.35 Thus, even higher resistance of the H3nota complex to transmetalation is surprising. These unexpected findings are difficult to explain with the current knowledge on the behavior of H3nota complexes. Thus, in this study, we investigated the thermodynamic and kinetic properties of H3nota complexes with divalent metal ions to bridge the gap in knowledge and to collect further data that may help explain the behavior of 64Cu-nota radiopharmaceuticals and that may be useful in designing ligands for metal radioisotopes. Complementarily, solid-state structures of H3nota complexes with a number of divalent metal ions are described and discussed in an accompanying paper.36

suitable ligands should exhibit high selectivity for Cu(II) over Ni(II) and Zn(II) ions. Suitable ligands for copper radioisotope binding have been sought for a long time.1−5 The first ligands successfully used for copper radioisotope binding were cyclam derivatives. Although cyclam derivatives are very thermodynamically selective for Cu(II), they have several unsuitable properties: e.g., the susceptibility of their complexes to reduction to Cu(I) and the subsequent release of copper radioisotopes. Thus, other ligand families have been investigated and used: e.g., improved cyclam derivatives6−9 or sarcophagin-based ligands.10 Among these ligands, H3nota (Chart 1) and its derivatives stand out as Chart 1. Structures of the Ligands Discussed in the Text

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RESULTS AND DISCUSSION H3nota in the Solid State. Crystals of zwitterionic H3nota suitable for X-ray analysis were collected from the synthesized bulk material (the synthesis is described in detail in the Supporting Information). In the molecule, one proton is located on the ring nitrogen atom N1 (Figure 1). The proton is the ligands of choice in recent years11 due to their fast copper radioisotope incorporation and reasonable in vivo stability. Furthermore, their advantages for antibody labeling have also been shown.12 However, the underlying chemical reasons for these convenient properties are not fully understood and, surprisingly, no detailed study on the chemistry of H3nota complexes with Cu(II) has been published thus far. H3nota was the first macrocyclic polyamino-polycarboxylate ligand synthesized.13,14 Since then, this ligand has been thoroughly investigated, mostly in complexes with trivalent metal ions15,16 because the relatively small and preorganized ligand cavity of H3nota is perfectly suited for transition-metal ions requiring octahedral or twisted-trigonal-prismatic arrangements. H3nota hexacoordination has been observed in solidstate complexes with divalent metal ions, including Fe(II),17 Ni(II),18 Cu(II),19−21 and Zn(II).22 Furthermore, the H3nota ligand is pentadentate in the [Cu(Cl)(H2nota)] complex, wherein two carboxylate groups are protonated and one of the groups remains uncoordinated.18 Surprisingly, divalent metal complexes have been rarely studied in solution. Protonation constants have been determined several times.18,23−29 However, the protonation constants were determined mostly in the presence of sodium(I) ions, which significantly interact with H3nota.28 The stability constants of H3nota complexes with divalent metal ions have only been reported for alkaline-earth-metal ions,18,24,29 Mn(II),26 Zn(II),29 and Cu(II).24,29 Stability constants were also determined by polarography for some other metal ions.13 However, the reported stability constants lack the necessary confidence for a detailed description of the solution behavior of H3nota and its complexes with metal ions.30 Kinetic data for complexes of divalent metal ions are also rather sparse because only the formation kinetics of the H3nota complex with

Figure 1. Solid-state structure of H3nota. Carbon-bound hydrogen atoms are omitted for clarity.

strongly bound in the macrocyclic cavity as the center of the hydrogen bonds between all three nitrogen atoms (dN1···N4 2.719 Å, dN1···N7 2.752 Å, ∠N1−H···N4 117°, ∠N1−H···N7 116°) and the nonprotonated carboxylate (dN1···O112 2.634 Å, ∠N1−H···O112 120°). The remaining two protons are bound to carboxylic acid groups and participate in the intermolecular hydrogen bond network. The parameters of all hydrogen bonds are outlined in Table S1. The structure clearly shows the preorganized nature of the ligand with all pendant arms toward the same side of the triaza cycle. The last proton is usually shared among all ring amine groups of 1,4,7-triazacyclononane B


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Inorganic Chemistry

Figure 2. Distribution diagrams of H3nota (A), Cu(II)−H3nota (B), Zn(II)−H3nota (C), Ni(II)−H3nota (D), Pb(II)−H3nota (E), and Li(I)− H3nota (F) systems (cM = cL = 4 mM, I = 0.1 M (NMe4)Cl, 25 °C). The circles show the relative abundances of free Cu(II) ion (green) and the sum of the complexed Cu(II) ion species (red) assessed by UV−vis spectroscopy (B) or the sum of free Zn(II) ion (red) and Zn(II)−H3nota complex (green) species assessed by 1H NMR (C). The dashed line shows the sum of the concentrations of Cu(II)−H3nota species (B).

Table 1. Stability (log K) or Dissociation (pKa) Constants of the H3nota Complexes Studied equilibriuma M + L = [M(L)] [M(HL)] = [M(L)] + H [M(H2L)] = [M(HL)] + H [M(L)] + H2O = [M(L)(OH)] + H [M(L)] + L = [M(L)2] Mg(II)c M + L = [M(L)] a

Mn(II)b

Co(II)

Ni(II)

Cu(II)

Zn(II)

Cd(II)

Pb(II)

16.30 2.87

20.13

19.24

22.32

17.87 2.54

18.18 2.76

12.56

12.29

23.33 2.65 1.04 12.15

10.97 b

12.66

Ca(II)c

Sr(II)

Ba(II)

Li(I)

Na(I)

4.43 K(I)

10.32

8.14

6.76

5.24

3.55

2.37

c

Charges are omitted. From ref 26. From ref 40.

solution, wherein two protons are presumably bound to ring amines.23 Equilibrium Studies. Dissociation/protonation constants of H3nota have been previously determined,18,23−26 albeit mostly in the presence of alkali-metal ions. These ions may interact with the fully deprotonated anion, forming weak complexes (similarly to H4dota-like ligands),30,38,39 which leads to a decrease in the value of the first protonation constant. Thus, we redetermined the H3nota protonation constants in

(tacn) derivatives. However, the H3nota structure is rather unique because the pendant arm is also involved in the hydrogen-bond network. A similar intramolecular hydrogen bond system has been observed only in the bis(2-methylpyridine) derivative of tacn.37 The hydrogen bond network is more compact than that of cyclen derivatives, which explains the high value of the first protonation constant (see Equilibrium Studies).26 However, the solid-state protonation scheme assessed differs from that suggested for the same species in C


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Inorganic Chemistry

previously.17 In the presence of excess ligand, only Pb(II) forms [M(nota)2]4− species, although the second ligand is weakly coordinated. Surprisingly, alkali-metal ions show relatively strong interactions with H3nota, and they form [M(nota)]2− complexes, under alkaline conditions. The stability constants of the [Na(nota)]2− complex are similar to the values recalculated on the basis of literature data (Table S2). It should be noted that the stability constant of the [Li(nota)]2− complex is among the highest reported for this cation in aqueous solution. The size of first-row transition-metal ions fits the H3nota cavity almost perfectly, as shown in the solid-state structures of their complexes,36 thus explaining the high thermodynamic stability of these complexes. First-row transition-metal ions do not form protonated complexes, except in the Cu(II)−H3nota system, wherein mono- and diprotonated species (maximum abundance at pH 1.8 and 0.6, respectively) were identified in acidic solutions. Accordingly, in the solid state, differently protonated [Cu(nota)]− species were isolated, although only the oxonium salt of [Ni(nota)]− was identified.18,36 The titration results showed only low H3nota selectivity for Cu(II) over Zn(II) and Ni(II) ions, in this order, which are the two most common metallic impurities found in solutions of copper radionuclides. The stability of the Co(II) complex was slightly higher than that of the Ni(II) complex, most likely due to the higher affinity of divalent cobalt for oxygen donors. The constants assessed in this study were mostly higher than those reported in the literature (Table S4)13,24,44 because we used a higher first protonation constant in our calculations. Large metal ions, such as Cd(II) and Pb(II), are unable to fit in the small H3nota cavity. Therefore, H3nota complexes with these ions are less thermodynamically stable than those with first-row transition-metal ions (Table 1). Furthermore, large ions may have a coordination number higher than 6. Thus, if the coordination sphere of [M(nota)]− is not saturated, a second ligand molecule may also be involved in the complex, as observed in the Pb(II)−H3nota system; however, the value of the second consecutive stability constant indicates very weak binding. In this case, the small H3nota cavity also explains the modest selectivity of H3nota for Mg(II) over Ca(II)18,24,40 and for Ca(II) > Sr(II) > Ba(II) and Li(I) > Na(I) > K(I). H3nota interaction with alkali-metal ions is significant and similar to that of H4dota.38 The small ligand cavity of H3nota is suitable for small metal ions, but it is also reasonably flexible to accommodate large metal ions, as shown when the structures of solid-state complexes are compared.36 The Cu(II)−H3nota system stands out. The d9 electronic configuration of the Cu(II) ion induces a Jahn−Teller distortion, and thus, the ion does not fit well the octahedral cavity of H3nota, which results in an irregular coordination sphere. Therefore, solid-state species with both octahedral and distorted-trigonal-antiprismatic geometry were isolated and characterized.36 In addition, only the weak coordination of the axial donor atoms could lead to their relatively easy protonation, thereby facilitating the formation of protonated species. The addition of up to two protons leads to thermodynamically stable protonated species, and their solution structures may be similar to those characterized in the solid state, wherein both mono- and diprotonated complexes were observed.36 Changes in geometry could explain the solution UV−vis spectra. Spectra of protonated species were assessed by curve-fitting analysis of spectrophotometric titration data. Spectra of fully deprotonated species were measured at pH 4 (Figure S5). The fully deprotonated [Cu(nota)]− species

the presence of the noncomplexing (NMe4)+ cation, and the NMR titration clearly showed that the first protonation constant is rather high.26 The log K1 > 13 value in the presence of noncomplexing cations has also been suggested by Geraldes et al. on the basis of NMR titration measurements.28 When studying the Cu(II)−H3nota system, we noted that complex formation occurs even in very acidic solutions, thus requiring assessment of the very low ligand protonation constants. Because the values are clearly out of the range of standard potentiometric titrations (usually conducted in the pH range 1.5−11.8), the NMR titration was performed in the pH range 0−1.5, and the curve-fitting analysis of the 1H/13C{1H} NMR chemical shift as a function of pH (Figure S1) gave a value of log Ka = 0.70. Thus, the full set of consecutive protonation constant values (log K1−5) of H3nota is 13.17, 5.74, 3.22, 1.96, and 0.70 (for comparison with literature data, see Table S2). The speciation diagram of H3nota is shown in Figure 2. The stability constants of H3nota complexes with divalent metal ions and monovalent alkali-metal ions were determined and are outlined in Table 1 (for the calculated overall constants with SDs, see Table S3). The corresponding distribution diagrams are shown in Figure 2 and Figure S2. A comparison with previously reported values of stability constants is outlined in Table S4.18,24−26,40,41 The metal ions showed fast complexation, and titrations were performed using the in-cell method (it should be noted that only Mg(II) complexation was slow, thus requiring the use of the out-of-cell method in this case).40 Titrations were conducted at 1:1 and 2:1 ligand to metal ion ratios to assess the coordination of the second ligand molecule. In Cu(II)− and Zn(II)−H3nota systems, complexation started in very acidic solutions and, therefore, determination of the stability constants is just at the limit of potentiometry. Therefore, other methods were used to confirm the potentiometric results and/or to collect more data on these complexes. UV−vis spectra of the Cu(II)−H3nota system (Figure S3) showed that the complex is fully formed even at pH 0. The linear increase of the dissociation rate in the studied region indicates that the [Cu(H3nota)]2+ complex is the main kinetically active species and that it is decomposed in the rate-determining step. The proposed reaction mechanism is shown in Scheme 2. This reaction can be described using the following general rate law given by eq 9:51

(i.e., log Kp3 < −1 for the experimental conditions used in this study) and, therefore, eq 9 can be simplified to eq 10. kd,obs = dkK p3[H+] = dkH[H+]

(10) d

d

Thus, only the overall dissociation constant kH = kKp3 was calculated by fitting the experimental data using eq 10 (Figure 4 and Table S5). The rate constant (dkH = 0.0151(4) M−1 s−1 at 25 °C, I = 3.0 M (H,Na)ClO4) and the decomplexation half-life at pH 0 and 25 °C (τ1/2 = 46 s) can be compared with the values of complexes of cyclen-based ligands (cyclen52 kH = 2.54 × 10−4 M−1 s−1, τ1/2 = 54.2 min; trans-H2do2a50 kH = 5.63 × 10−7 M−1 s−1, τ1/2 = 30.4 h; H3do3a35 kH = 1.68 × 10−6 M−1 s−1, τ1/2 = 17.9 h; H4dota35 kH = 2.06 × 10−7 M−1 s−1, τ1/2 = 31.9 h). [Cu(nota)]− is clearly the least inert complex of all complexes with these macrocyclic ligands. However, the [Cu(nota)]− complex is still significantly more inert than the [Cu(edta)]2− complex (τ1/2 = 0.02 ms, I = 0.5 M KCl).53 Zn(II), in a large excess, may compete with Cu(II) for H3nota at pH >2 (Figure S16). This allows measuring decomplexation kinetics at pH values higher than those commonly used for acid-assisted decomplexation. Similar measurements are commonly used to assess the decomplexation of Gd(III) complexes used as MRI contrast agents.47 Experiments were conducted in the pH range 2.0−3.1 (the reaction was very slow at higher pH) and in the presence of 10−250 equiv of Zn(II). Surprisingly, the observed values of G


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Inorganic Chemistry the rate constant Znkd,obs decreased with an increase in Zn(II) concentration (Figure 5 and Figure S17). Three different

constant calculated considering cZn = 0 M, and it is formally equivalent to the rate constant kd,obs of eq 10. The two sets of constants calculated from Zn(II)- and acid-assisted experiments match each other very well (Figure S19), which confirms the proposed mechanism of Zn(II)-assisted dissociation. The values of dkZn are pH dependent (Table S6 and Figure S18). This indicates that the dinuclear complex is protonated before the transmetalation step. In the pH range tested, this transmetalation is 2−3 times slower than acid-assisted dissociation. Therefore, the formation of the dinuclear {Zn[Cu(nota)]}+ complex explains the inhibitory effect of Zn(II) on [Cu(nota)]− decomplexation. The Zn(II) ion coordination in the dinuclear species did not cause any considerable change in the coordination sphere of the Cu(II) ion because only minor changes in the UV−vis spectra of the complex are observed with the increase in Zn(II) concentration at pH 2. The values of the conditional stability constant of the dinuclear complex, log KZn*, are pH and temperature independent (log KZn* ≈ 2−2.5; Tables S6 and S7). These values lie between the stability constants of Zn(II)−glycinate (log KZnL = 4.96) or Zn(II)−malonate (log KZnL = 3.0) and those of Zn(II)−acetate (log KZnL = 1.07) complexes.55 Thus, assuming strong N2O2 equatorial coordination of H3nota complexes with Cu(II), which is present in solid-state protonated complex species,36 the Zn(II) ion may be out-ofcage-coordinated by carboxylate oxygen atoms of a noncoordinated pendant arm involving the adjacent ring amine group originally present in the axial position of the [Cu(nota)]− species. Such interaction suppresses the direct protonation of the Cu(II)-bound ring amine groups, which starts Cu(II) decoordination. Consequently, formation of the dinuclear complex decreases the overall dissociation rate and, thus, it could be considered the “dead-end complex”. Such transmetalation behavior, i.e., decomplexation inhibition in the presence of other metal ions, has been observed in complexes of macrocyclic ligands for the first time. Similar interactions with other metal ions may explain the in vivo stability of the [Cu(nota)]− complex and the surprisingly slow exchange of Cu(II) bound in the [Cu(nota)]− complex with free 64Cu(II) in comparison with analogous data on [Cu(dota)]2− and [Cu(teta)]2− complexes.33,34

Figure 5. Examples of curves of the pseudo-first-order rate constant of decomplexation of [Cu(nota)]− as a function of Zn(II) concentration at different acidities (cCuL = 0.1 mM, t = 60 °C, I = 0.1 M KCl). The experimental data were fitted using eq 11. The corresponding parameters are outlined in Tables S6 and S7.

pathways can be considered for the transmetalation process (Scheme 3): (i) spontaneous (acid-assisted) dissociation Scheme 3. Possible Pathways for Zinc(II)-Assisted Decomplexation: Spontaneous (Acid-Assisted) Dissociation Followed by Complexation of Zn(II) with the Free Ligand (Top), Direct Transmetalation (Middle), or Formation of a Dinuclear Complex as an Intermediate (Bottom)a

a

The number of protons associated with the complex species and their charges are omitted for clarity.

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followed by Zn(II) coordination with the free ligand, (ii) direct transmetalation, and/or (iii) formation of a dinuclear complex as an intermediate. The decrease in transmetalation rate with the Zn(II) concentration indicates fast formation of the dinuclear complex as the reaction intermediate (the stopped-flow measurements gave a formation rate constant of the dinuclear species (kobs) of ∼0.57 s−1 at 60 °C, cZn = 2 mM, cCuL = 0.1 mM, pH = 2.6) and excludes direct transmetalation. In addition, the rate constants measured at large Zn(II) excess are pH dependent (Figure 5 and Figure S18), suggesting the rate law (eq 11)54

CONCLUSIONS Despite lengthy research on H3nota complexes, this study is the first detailed thermodynamic assessment and kinetic study of H3nota complexes with divalent metal ions, specifically Cu(II) and Zn(II) ions. H3nota shows selectivity for small metal ions because its ligand cavity is small. This ligand forms rather stable complexes, even with alkali-metal ions. Unlike other transitionmetal ions, Cu(II) does not have a regular octahedral arrangement in the complex. Consequently, thermodynamically stable protonated complexes are formed in acidic media. Although thermodynamic data suggest a lower H3nota selectivity for Cu(II) over Ni(II) and Zn(II) ions in comparison to that found, e.g., in cyclam derivatives, formation kinetics data indicate a significantly faster Cu(II) complex formation in comparison to that of the other two metal ions, and H3nota complexation with Cu(II) could be considered immediate. The [Cu(nota)]− complex shows high thermodynamic stability and fast formation, which is not affected by the presence of Zn(II) and Ni(II) ions, the most common metallic impurities in radiocopper solutions. These properties are desired for any application of copper radioisotopes in nuclear

* [Zn 2 +] k 0 + dk ZnKZn * [Zn 2 +] 1 + KZn

d Zn

kd,obs =

* [Zn 2 +] k 0,H[H+] + dk Zn,H[H+]KZn * [Zn 2 +] 1 + KZn

d

= d

(11)

d

where k0 and kZn are the pH-dependent rate constants of each pathway (i.e.: dk0 = dk0,H[H+] and dkZn = dkZn,H[H+]) and KZn* is the conditional stability constant of the dinuclear complex. The experimental data were fitted using eq 11 (Figure 5, Figure S17, and Tables S6 and S7). The constant dk0 is the rate H


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Inorganic Chemistry medicine. The [Cu(nota)]− complex shows medium resistance against acid-assisted dissociation. However, its lifetime is prolonged in the presence of other metal ions due to the formation of stable dinuclear complexes. The data reported here support using H3nota derivatives for conjugation with biological targeting vectors and their labeling with copper radioisotopes. However, the [Cu(nota)]− properties are still suboptimal for this application, especially considering the low kinetic inertness of its Cu(II) complex. Therefore, complexes with higher kinetic inertness and ligands with better thermodynamic selectivity for Cu(II) over other metal ions in comparison to that of H3nota and/or with even better kinetic selectivity for Cu(II) might be still required to apply copper radioisotopes to nuclear medicine.

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constants of the metal hydroxido complexes involved in the data analysis were retrieved from the literature.55,62 Full sets of determined overall concentration constants (with their standard deviations directly given by the program) are provided in Table S3 in the Supporting Information. NMR and UV−Vis Titrations. Samples of these titrations were prepared as those of out-of-cell titrations (final cL = 0.004 M, final sample volume 1 mL).60 To determine the lowest ligand protonation constant, 15 samples in the formal pH range 0.1−1.5 were prepared from the ligand and aqueous HCl (0.2 M or 1.0 M) stock solutions without ionic strength corrections. The proton concentrations of the samples were calculated from the added quantity of the strong acid. The 1H and 13C{1H} NMR spectra were recorded on a Bruker Avance III 600 system using a capillary as external standard (tBuOH in D2O, δH 1.25 ppm, δC 30.3 ppm). The samples used in ligand−metal ion system titrations (Zn(II) or Cu(II)) were prepared with the same concentrations as those used for potentiometry (M:L 1:1): formal pH range 0.1−1.5, 15 samples, with 0.2 M or 1 M aqueous HCl stock solutions, with a final sample volume of 1 mL. The 1H NMR spectra were recorded on a Bruker Avance III 600 system using a capillary as external standard (tBuOH in D2O). UV−vis spectra were recorded on a Specord 50 Plus system (Analytic Jena) in the 500−800 nm range. The stability constants of Cu(II) species were determined by simultaneous analysis of potentiometric and UV−vis data using the OPIUM software package.61 Formation and Dissociation Kinetics. The formation kinetics of the Cu(II) complex was studied by absorption spectroscopy (pH 1.0− 3.5, cCu = 0.1−5 mM, cL = 0.1−0.2 mM, cZn = 0.1−10 mM) conducted at 25.0 ± 0.1 °C and I = 0.10 M (KCl). The conductometric study of the formation of Cu(II) and Zn(II) complexes (cM = cL = 1 mM) was conducted in ligand solution with low buffer capacity (cH = 1−5 mM) without ionic strength corrections (I → 0 M). The final pH of the solutions changed no more than 0.05 unit. The protonation constants of H3nota were recalculated to I = 0 M from those calculated at I = 0.1 M using the Debye−Hückel equation. The wavelength of 265 nm (and in some cases, also visible region wavelengths) was chosen to monitor the course of the formation/dissociation on a HP 8453A (Agilent) or CARY BIO 50 (Varian) diode-array spectrophotometer. The fast formation was measured by stopped-flow spectrometry (SX 20, Applied Photophysics) by UV absorption or by conductometric detection. During the formation experiments, a pH range up to 1−4 was used, approximately, depending on the Cu(II) excess over the ligand. All experimental data from kinetic experiments were processed by nonlinear regression using Excel and/or the ProK-II software (Applied Photophysics) with similar results. The acid-assisted decomplexation kinetics of the [Cu(nota)]− complex (prepared as stock solution with cCuL = 0.15 mM and pH ∼5.5) was followed in the 0.50−3.00 M proton concentration range, 15.0−35.0 (±0.1) °C temperature range, and I = 3.00 M (H,Na)ClO4. The Zn(II)-assisted dissociation of the [Cu(nota)]− complex was studied by spectrophotometry in the pH range 2.0−3.1 adjusted using hydrochloric acid, with various Zn(II) concentrations (cZn = 1−30 mM), at I = 0.1 M (K,H)Cl and in the 25.0−75.0 (±0.1) °C temperature range.

EXPERIMENTAL SECTION

General Considerations. All chemicals were purchased (Merck, Fluka, CheMatech, or Aldrich). The NMR experiments (1H and 13 C{1H}) were run on a Bruker Avance III 600 instrument with a cold probe. UV−vis characterization and titration experiments were conducted on a Specord 50Plus spectrophotometer (Analytic Jena, Germany). Throughout the paper, pH means −log [H+]. H3nota was prepared from 1,4,7-triazacyclononane trihydrochloride according to the previously published alkylation procedure with bromoacetic acid with modifications (see the Supporting Information).56 Crystal Structure Determination. A suitable single crystal was chosen from the bulk sample resulting from ligand synthesis (see the Supporting Information). The selected crystal was mounted on a glass fiber in a random orientation, and diffraction data were collected using graphite-monochromated Mo Kα radiation on an Enraf-Nonius KappaCCD diffractometer at 150(1) K (Cryostream Cooler, Oxford Cryosystem) and analyzed using the HKL DENZO software package.57 Data were corrected for absorption effects using the multiscan method (SADABS). All structures were solved by direct methods (SHELXS97)58 and refined using full-matrix least-squares techniques (SHELXL2014).59 All non-hydrogen atoms were refined anisotropically. The hydrogen atoms were found in the electron density difference map, whereas the carbon atoms were fixed in theoretical positions using the riding model with Ueq(H) = 1.2[Ueq(C)] to keep the number of refined parameters low. The atoms bound to nitrogen and oxygen atoms were fully refined, affording a somewhat longer O−H bond (1.01 Å) due to its involvement in short intermolecular hydrogen bonds (dO···O = 2.52 Å). The corresponding experimental data are outlined in Table S8. The crystallographic information file has been deposited with the Cambridge Crystallographic Data Centre with registration number CCDC-1570023. Potentiometric Titrations. Potentiometry was performed according to the previously published procedure: for stock solution preparation and further details on chemicals, equipment, electrode system calibration, titration procedures and data treatment, see refs 38 and 60. Protonation and stability constants were determined in 0.1 M (NMe4)Cl at 25.0 °C with pKw = 13.81. The stock solution of the ligand was prepared by dissolving H3nota in water and adding a known amount of standard (NMe4)OH solution. The lowest ligand protonation constant was determined here (see below), and the others were retrieved from the literature;26 however, identical values of the constants (log K2, log K3, and log K4) were obtained in “confirmation” titrations performed during this study (cL = 0.004 M). The stability constants of the divalent metal ion complexes were determined by in-cell titrations from data collected in the pH range 1.6−12 with ∼40 points per titration and four parallel titrations for each M to L ratio (cL = 0.004 M, cM = 0.004, 0.002 M). For titration with alkali-metal ions, the M:L ratio was 10:1 with an appropriately lower quantity of (NMe4)Cl to maintain a 0.1 M background electrolyte concentration. Titration data were analyzed using the OPIUM61 software, and the chemical models proposed were chosen on the basis of chemical feasibility and fitting statistics. The stability

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b02929. Parameters and data of the reported crystal structure, consecutive protonation constants, 1H and 13C{1H} NMR titration, stability constants of complexes, distribution diagrams of complexes, spectral changes of the Cu(II)−H3nota system, changes in 1H NMR spectra of the Zn(II)−H3nota system, electronic spectra of Cu(II) species, conditional stability constants of the H3nota, H4dota, and H4teta complexes, changes in UV−vis spectra in the course of complexation and decomplexI


Article

Inorganic Chemistry

chelators with phosphonate pendant arms. Dalton Trans. 2012, 41, 1938−1950. (c) Guo, Y.; Ferdani, R.; Anderson, C. J. Preparation and biological evaluation of 64Cu labeled Tyr3-octreotate using a phosphonic acid-based cross-bridged macrocyclic chelator. Bioconjugate Chem. 2012, 23, 1470−1477. (d) Jiang, M.; Ferdani, R.; Shokeen, M.; Anderson, C. J. Comparison of two cross-bridged macrocyclic chelators for the evaluation of 64Cu-labeled-LLP2A, a peptidomimetic ligand targeting VLA-4-positive tumors. Nucl. Med. Biol. 2013, 40, 245−251. (e) Zeng, D.; Ouyang, Q.; Cai, Z.; Xie, X.-Q.; Anderson, C. J. New cross-bridged cyclam derivative CB-TE1K1P, an improved bifunctional chelator for copper radionuclides. Chem. Commun. 2014, 50, 43−45. (f) Cai, Z.; Ouyang, Q.; Zeng, D.; Nguyen, K. N.; Modi, J.; Wang, L.; White, A. G.; Rogers, B. E.; Xie, X.-Q.; Anderson, C. J. 64Culabeled somatostatin analogues conjugated with cross-bridged phosphonate-based chelators via strain-promoted click chemistry for PET imaging: In silico through in vivo studies. J. Med. Chem. 2014, 57, 6019−6029. (g) Cai, Z.; Li, B. T. Y.; Wong, E. H.; Weisman, G. R.; Anderson, C. J. Cu(I)-assisted click chemistry strategy for conjugation of non-protected cross-bridged macrocyclic chelators to tumourtargeting peptides. Dalton Trans. 2015, 44, 3945−3948. (h) Dale, A. V.; An, G. I.; Pandya, D. N.; Ha, Y. S.; Bhatt, N.; Soni, N.; Lee, H.; Ahn, H.; Sarkar, S.; Lee, W.; Huynh, P. T.; Kim, J. Y.; Gwon, M.-R.; Kim, S. H.; Park, J. G.; Yoon, Y.-R.; Yoo, J. Synthesis and evaluation of new generation cross-bridged bifunctional chelator for 64Cu radiotracers. Inorg. Chem. 2015, 54, 8177−8186. (7) (a) Pandya, D. N.; Kim, J. Y.; Park, J. C.; Lee, H.; Phapale, P. B.; Kwak, W.; Choi, T. H.; Cheon, G. J.; Yoon, Y.-R.; Yoo, J. Revival of TE2A; a better chelate for Cu(II) ions than TETA? Chem. Commun. 2010, 46, 3517−3519. (b) Pandya, D. N.; Kim, J. Y.; Kwak, W.; Park, J. C.; Gawande, M. B.; An, G. I.; Ryu, E. K.; Yoo, J. A new synthesis of TE2Aa potential bifunctional chelator for 64Cu. Nucl. Med. Mol. Imaging 2010, 44, 185−192. (c) Pandya, D. N.; Bhatt, N.; Dale, A. V.; Kim, J. Y.; Lee, H.; Ha, Y. S.; Lee, J.-E.; An, G. I.; Yoo, J. New bifunctional chelator for 64Cu-immuno-positron emission tomography. Bioconjugate Chem. 2013, 24, 1356−1366. (d) Dale, A. V.; Pandya, D. N.; Kim, J. Y.; Lee, H.; Ha, Y. S.; Bhatt, N.; Kim, J.; Seo, J. J.; Lee, W.; Kim, S. H.; Yoon, Y.-R.; An, G. I.; Yoo, J. Non-cross-bridged tetraazamacrocyclic chelator for stable 64Cu-based radiopharmaceuticals. ACS Med. Chem. Lett. 2013, 4, 927−931. (8) (a) Kotek, J.; Lubal, P.; Hermann, P.; Císařová, I.; Lukeš, I.; Godula, T.; Svobodová, I.; Táborský, P.; Havel, J. High thermodynamic stability and extraordinary kinetic inertness of copper(II) complexes with 1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic acid): Example of a rare isomerism between kinetically inert penta- and hexacoordinated copper(II) complexes. Chem. - Eur. J. 2003, 9, 233−248. (b) Füzerová, S.; Kotek, J.; Císařová, I.; Hermann, P.; Binnemans, K.; Lukeš, I. Cyclam (1,4,8,11tetraazacyclotetradecane) with one methylphosphonate pendant arm: a new ligand for selective copper(II) binding. Dalton Trans. 2005, 2908−2915. (c) Havlíčková, J.; Medová, H.; Vitha, T.; Kotek, J.; Císařová, I.; Hermann, P. Coordination properties of cyclam (1,4,8,11tetraazacyclotetradecane) endowed with two methylphosphonic acid pendant arms in the 1,4-positions. Dalton Trans. 2008, 5378−5386. (d) David, T.; Kubíček, V.; Gutten, O.; Lubal, P.; Kotek, J.; Pietzsch, H.-J.; Rulíšek, L.; Hermann, P. Cyclam derivatives with a bis(phosphinate) or a phosphinato-phosphonate pendant arm: Ligands for fast and efficient copper(II) complexation for nuclear medical applications. Inorg. Chem. 2015, 54, 11751−11766. (9) (a) Lima, L. M. P.; Esteban-Gomez, D.; Delgado, R.; PlatasIglesias, C.; Tripier, R. Monopicolinate cyclen and cyclam derivatives for stable copper(II) complexation. Inorg. Chem. 2012, 51, 6916− 6927. (b) Lima, L. M. P.; Halime, Z.; Marion, R.; Camus, N.; Delgado, R.; Platas-Iglesias, C.; Tripier, R. Monopicolinate cross-bridged cyclam combining very fast complexation with very high stability and inertness of its copper(II) complex. Inorg. Chem. 2014, 53, 5269−5279. (c) Rodriguez-Rodriguez, A.; Garda, Z.; Ruscsák, E.; EstebanGómez, D.; de Blas, A.; Rodríguez-Blas, T.; Lima, L. M. P.; Beyler, M.; Tripier, R.; Tircsó, G.; Platas-Iglesias, C. Stable Mn2+, Cu2+ and Ln3+ complexes with cyclen-based ligands functionalized with

ation, conditional stability constant of the out-of-cage complex and rate formation constant during formation of the [Cu(nota)]− complex, mechanism of formation of the in-cage [Cu(nota)]− complex, pH dependence of the second-order formation rate constants, formation of the [Cu(nota)]− and [Zn(nota)]− complexes with conductometric detection, the second-order rate constant for formation of the [Cu(nota)]− and [Zn(nota)]− complexes with conductometric detection, dissociation rate constant of the [Cu(nota)]− complex, the complex dissociation rate constants, and rate and stability constants for dissociation of [Cu(nota)]− complex in the presence of Zn(II) ion excess (PDF) Accession Codes

CCDC 1570023 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail for V.K.: [email protected]. *E-mail for P.L.: [email protected]. ORCID

Vojtěch Kubíček: 0000-0003-0171-5713 Jan Kotek: 0000-0003-1777-729X Petr Hermann: 0000-0001-6250-5125 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the support from the Grant Agency of the Czech Republic (17-13721S), the Ministry of Education of the Czech Republic (CEITEC 2020 - LQ1601), and Masaryk University (MUNI/A/1237/2016). We also thank I. Cı ́sarǒ vá for the X-ray diffraction data collection and T. David for the NMR measurements (Charles University).

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REFERENCES

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NOTA Complexes with Copper(II) and Divalent Metal Ions: Kinetic and

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