and Ln-DOTAm-F12 Are Effective Paramagnetic ... - ACS Publications

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Fe- and Ln-DOTAm-F12 Are Effective Paramagnetic Fluorine Contrast Agents for MRI in Water and Blood Kriti Srivastava,† Evan A. Weitz,† Katie L. Peterson,§ Małgorzata Marjańska,‡ and Valérie C. Pierre*,† †

Department of Chemistry and ‡Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota, Minneapolis, Minnesota 55455, United States S Supporting Information *

ABSTRACT: A series of fluorinated macrocyclic complexes, MDOTAm-F12, where M is LaIII, EuIII, GdIII, TbIII, DyIII, HoIII, ErIII, TmIII, YbIII, and FeII, was synthesized, and their potential as fluorine magnetic resonance imaging (MRI) contrast agents was evaluated. The high water solubility of these complexes and the presence of a single fluorine NMR signal, two necessary parameters for in vivo MRI, are substantial advantages over currently used organic polyfluorocarbons and other reported paramagnetic 19F probes. Importantly, the sensitivity of the paramagnetic probes on a per fluorine basis is at least 1 order of magnitude higher than that of diamagnetic organic probes. This increased sensitivity is due to a substantialup to 100-fold decrease in the longitudinal relaxation time (T1) of the fluorine nuclei. The shorter T1 allows for a greater number of scans to be obtained in an equivalent time frame. The sensitivity of the fluorine probes is proportional to the T2/T1 ratio. In water, the optimal metal complexes for imaging applications are those containing HoIII and FeII, and to a lesser extent TmIII and YbIII. Whereas T1 of the lanthanide complexes are little affected by blood, the T2 are notably shorter in blood than in water. The sensitivity of Ln-DOTAm-F12 complexes is lower in blood than in water, such that the most sensitive complex in water, HoIIIDOTAm-F12, could not be detected in blood. TmIII yielded the most sensitive lanthanide fluorine probe in blood. Notably, the relaxation times of the fluorine nuclei of FeII-DOTAm-F12 are similar in water and in blood. That complex has the highest T2/T1 ratio (0.57) and the lowest limit of detection (300 μM) in blood. The combination of high water solubility, single fluorine signal, and high T2/T1 of M-DOTAm-F12 facilitates the acquisition of three-dimensional magnetic resonance images.

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frequency (400 MHz at 9.4 T) to that of 19F (376 MHz at 9.4 T).10 A negligible biological fluorine level and short T2 relaxation times of fluorines present in the body eliminates background interference and ensures that signal intensity is proportional to the concentration of the contrast agent. Lastly, the promulgation of ratiometric imaging agents is aided by the large chemical shift range (>300 ppm) of fluorine nuclei. Ratiometric agents can be developed that independently monitor two discrete signals. This approach overcomes the nonuniform biodistribution of the imaging agent and enables quantification of in vivo analytes.11,12 Even with these advantages, further advancement of 19F imaging is reliant on increasing the sensitivity of detection. Currently, diamagnetic 19 F contrast agents need to be used in very high concentrations, typically between 10 and 50 mM, suffer from poor signal-tonoise ratios (SNR), and require long image acquisition times.13,14 Increased application of 19F contrast agents in MRI thus requires the development of novel probes with increased sensitivity on a per fluorine basis. The signal intensity for spin−echo MRI is dependent on the number of nuclei in the volume being imaged and their

INTRODUCTION The three-dimensional (3D) in vivo imaging capability and noninvasive nature of magnetic resonance imaging (MRI) has rendered it one of the preferred techniques for diagnostics in clinical medicine and biomedical research. MRI contrast agents further increase the power and utility of this imaging technique by increasing the contrast between regions where the probe accumulates and the background tissues. The development of contrast agents has extended beyond extracellular fluid and blood-pool contrast agents to targeted and responsive probes.1 However, the imaging by these responsive 1H gadoliniumbased and magnetic iron oxide nanoparticle contrast agents is negatively affected by the ambiguity introduced by the high background of the bulk water signal, interfering physiological anions,2−6 or nonlinear responses to analytes.7,8 More importantly, such agents have limited use in vivo due to their inability to generate ratiometric responses to their biological analytes.9 Development of 19F MRI and fluorinated contrast agents represents an attractive alternative approach. Fluorine-based MRI has several key advantages over standard 1 H MRI that make it an attractive alternative for in vivo imaging of specific molecular targets. The fluorine nuclei (19F, I = 1/2) is 100% abundant and has a similar sensitivity to the proton (83% of 1H). Fluorine images can be collected on 1H MRI scanners if the radiofrequency coil is tuned from the 1H © XXXX American Chemical Society

Received: November 1, 2016

A

DOI: 10.1021/acs.inorgchem.6b02631 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry

Table 1. 19F Chemical Shift (δ), Lanthanide-Induced Shift (LIS, ΔδF), T1 and T2 Relaxation Times, and MRI SNR of MDOTAm-F12 Complexes in Water at B0 μeff/μBa DOTAm-F12e La-DOTAm-F12 Eu-DOTAm-F12 Gd-DOTAm-F12 Tb-DOTAm-F12 Dy-DOTAm-F12 Ho-DOTAm-F12 Er-DOTAm-F12 Tm-DOTAm-F12 Yb-DOTAm-F12 FeII-DOTAm-F12

Bleaney constantc

3.40−3.51 7.94 9.7 10.6 10.6 9.6 7.6 4.5 ∼5.2b

4.0 0 −87 −100 −39 32 53 22

δd (ppm)

ΔδFd

T1d (ms)

T2d (ms)

T2/T1d

SNRf,g

−72.7 −72.1 −72.4 −72.0 −54.1 −52.4 −61.8 −76.5 −83.3 −75.9 −70.1

0 −0.3 +0.1 +18.0 +19.7 +10.3 −4.4 −11.2 −3.8 +2.0

880 570 360 12 6.3 5.9 7.6 14 26 130 5.7

680h 400h 41h 0.14i 1.3h 2.2h 5.4h 8.8h 16h 55h 5.6h

0.77 0.70 0.11 0.01 0.21 0.37 0.71 0.63 0.61 0.42 0.98

n.d. 4.7 6.6 ∼1 6.5 6.6 32 14 20 23 28

Conditions: ref 13. bμeff for FeII complex of 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane from ref 41. cReferences 13 and 76. B0: 7.0 T, T = 25 °C, D2O, DPO42−/D2PO4− buffer, pD 7.4. eNMR in deuterated methanol. fM-DOTAm-F12 = 5 mM, B0: 9.4 T, T = 33 °C, TR = 5 ms. gSNR were obtained at the optimum chemical shift for each complex using images shown in Figure 2B: La-DOTAm-F12 (3), −78 ppm; EuDOTAm-F12 (4), −78 ppm; Gd-DOTAm-F12 (5), −73 ppm; Tb-DOTAm-F12 (6), −73 ppm; Dy-DOTAm-F12 (7), −62; Ho-DOTAm-F12 (8), −62; Er-DOTAm-F12 (9), −78 ppm; Tm-DOTAm-F12 (10), −86 ppm; Yb-DOTAm-F12 (11), −86 ppm; Fe-DOTAm-F12 (12), −78 ppm. h Measured according to the CPMG sequence. iMeasured from the width at half peak. a

d

longitudinal and transverse relaxation time (T1 and T2) according to the following equation (eq 1):15,16 ⎡ ⎛− T − ⎛ −TE ⎞⎢ R ⎜ I ≈ N (F )exp⎜ ⎟⎢1 − 2exp⎜ ⎜ T1 ⎝ T2 ⎠⎢ ⎝ ⎣

(

⎤ ⎛ −TE ⎞⎥ + exp⎜ ⎟⎥ ⎝ T1 ⎠⎥ ⎦

TE 2

stitution of the chelate with the trifluoroaryl moiety provided complexes with insufficient water solubility for biological MRI.33 Despite the pseudo-C4 symmetry of tetra-trifluoroethyl-substituted Ln-DOTMP complexes ([Ln-F-DOTPME]−), the fluorine signal intensity was reduced due the existence of multiple stereoisomers in solution.35 Stereoisomers arising from different configurations of the macrocyclic ring or arrangement of the pendant arms have also been observed with other fluorinated DOTA (tetraazacyclododecane-1,4,7,10-tetraacetic acid)- or DOPA (ethyl [(4,7-di{[ethoxy(methyl)phoshoryl]methyl}-10-({[2-(trifluoromethyl)phenyl]carbamoyl}methyl)1,4,7,10- tetraazacyclodecan-1-yl)methyl](methyl)phosphinate)-based metal complexes designed for 19 F MRI.36,37 For MRI applications, complexes that exist as multiple isomers in solution diminish the overall signal intensity at the imaging frequency and negatively affect the observed SNR. It is apparent from these studies that the symmetry of the complex as well as the rate of interconversion between isomers are important considerations in the design of paramagnetic fluorine probes. Optimizing the sensitivity of 19F MRI contrast agents requires an understanding of the dependence of longitudinal (R1) and transverse (R2) relaxation rate constants of 19F nuclei on parameters including the rotational correlation time (τR) of the complex, the effective magnetic moment (μeff) of the metal ion, and its distance (d) from 19F nuclei, at a given temperature and magnetic field strength.33 Here, the synthesis and physical characterization of water-soluble, paramagnetic 19F MRI contrast agents featuring a highly fluorinated chelate are presented. Additionally, the potential of these imaging agents for use in 19F MRI is evaluated in water and rat blood. The ligand DOTAm-F12 consists of a trifluoroethylacetamidesubstituted macrocycle that features 12 chemically equivalent fluorine nuclei. At first approximation, since the ligand is kept constant, d and τR vary little throughout the series according to the lanthanide contraction.38 The differences in relaxation times are thus primarily a consequence of the effective magnetic moment (μeff) of the metal ion (Table 1). We studied M-DOTAm-F12 complexes containing LaIII, EuIII, GdIII, TbIII, DyIII, HoIII, ErIII, Tm III, YbIII, and FeII (Figure 1). These complexes are sufficiently soluble in water (>100

) ⎞⎟ ⎟⎟ ⎠

(1)

where I is the intensity of the image, N(F) is the 19F nuclei density detectable by NMR, and TR and TE are the repetition time and echo times of the pulse sequence, respectively. Image intensity can be augmented by incorporating additional chemically equivalent 19F nuclei and by increasing 19F longitudinal relaxation rates. Linear polymers,17−20 dendrimers,21−25 hyperbranched or star polymers,16,26−28 and nanoparticle-based29−31 probes have been reported that maximize local 19F spin density and facilitate reduced fluorine relaxation times via the slow molecular tumbling. However, when relaxation is modulated by increasing the rotational correlation time (τR), the concomitant decrease in T2 negatively effects signal intensity. Optimizing signal intensity, thus, requires decreasing T1 as much as possible while minimizing the effect on T2 so as to achieve a T2/T1 value near 1. Paramagnetic metals are well-known to decrease relaxation times of nearby nuclei by up to 2 orders of magnitude, with the relative decrease in T2 versus T1 being influenced by the nature of the metal and its complex.13,32,33 We postulated that this approach, with careful consideration of the complex’s structure, can afford highly water-soluble fluorine contrast agents, which can, in principle, further be exploited in the design of responsive imaging agents. Recent progress in the field of molecular paramagnetic 19F imaging agents has suggested the possibility of exploiting this approach for biological imaging. A DyIII triphosphonate complex with a trifluoroaryl-substituted amide arm ([DyDOPA-arCF3]) is soluble in water and increases SNR 13-fold compared to diamagnetic analogues.34 Unfortunately, efforts to increase the number of equivalent 19F nuclei via tetrasubB


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Inorganic Chemistry

arm 1. This arm is then coupled to the cyclen backbone to afford the ligand DOTAm-F12 (2) in decent yield. The lanthanide complexes Ln-DOTAm-F12 are generated from equimolar amounts of the ligand and the respective lanthanide halide salt in aqueous solution at neutral pH by heating at 75 °C for ∼4 d. The FeII complex was formed under inert atmosphere from iron(II) trifluoromethanesulfonate using slight modification in conditions reported by Morrow.33,40 Notably, all the complexes demonstrate high water solubility (>100 mM) despite their high fluorine content (>25% by mass). Structure of M-DOTAm-F12. The structures of the MDOTAm-F12 complexes were evaluated by 1H and 19F NMR; the Tm complex was further investigated by X-ray crystallography and density functional theory (DFT) calculations. 1H NMR spectra of the complexes illustrate paramagnetism (Figures S1−S9 in Supporting Information). Importantly, 19F NMR of each complex in D2O revealed one single fluorine resonance (Figure 2). The presence of a single peak illustrates

Figure 1. Chemical structure of M-DOTAm-F12. M = LaIII (3), EuIII (4), GdIII (5), TbIII (6), DyIII (7), HoIII (8), ErIII (9), Tm III (10), YbIII (11), and FeII (12).

mM) for MRI applications and produce one fluorine resonance peak. Although prior studies on paramagnetic fluorine probes have focused entirely on lanthanide ions,13,32,33 we postulate that iron(II), being also paramagnetic with a high magnetic moment, could also yield sensitive fluorine probes with short T1 and high T2/T1 ratio. Indeed, work by Morrow has illustrated that FeII macrocyclic complexes are air-stable for days and inert to Fe dissociation,39,40 supporting the use of such complexes for in vivo MRI applications. The properties of FeII complexes previously studied as paramagnetic chemical exchange saturation transfer MRI agents39−41 and reported NMR studies of fluorinated iron complexes42−45 also encouraged us to evaluate FeII-DOTAm-F12 as 19F MRI contrast agent. In addition, iron complexes are anticipated to be less toxic to patients suffering from chronic and acute renal insufficiencies due to intrinsic iron homeostatic mechanisms and iron-binding proteins, such as transferrin, that can regulate the concentration of iron in the blood.

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RESULTS AND DISCUSSION Synthesis. The ligand DOTAm-F12 was synthesized in two steps and readily forms metal complexes from their respective halides as shown in Scheme 1. In a first step, 2,2,2trifluoroethylamine is coupled to bromoacetyl bromide in the presence of triethylamine in solvent CH2Cl2 to get the pendant

Scheme 1. Synthesis of M-DOTAm-F12a

Figure 2. 19F NMR of M-DOTAm-F12 complexes (377 MHz, D2O, DPO42−/D2PO4− buffer, pD 7.4). Note that in the spectra of FeIIDOTAm-F12 (12) the peak at δF = −78.6 ppm corresponds to the trifluoromethanesulfonate counterion.

that any rotation of the trifluoromethyl arm occurs faster than the NMR time scale. This represents a major advantage over the isomeric mixtures of other 19F contrast agents, such as [LnF-DOTPME]13,35 and DOTA-based complexes with aryl trifluoromethyl groups,32,33,37 which were characterized by up to eight 19F peaks at different relative intensities. Fluorine probes with nonequivalent 19F nuclei that have small frequency difference between the 19F resonances can overlap in an MR scan, resulting in blurry images.46 The NMR spectra give further information with regard to the solution structures of the complexes. In the case of lanthanide

Reagents and conditions: (a) Et3N, CH2Cl2, 0 °C-rt, 6 h, 80%; (b) cyclen, Cs2CO3, CH3CN, reflux, 28 h, 60 °C, 61%; (c) LnX3, NaOH(aq), CH3OH/H2O, 75 °C, 80−103 h, 81%−97%; (d) Fe(OSO2CF3)2, CH3CN/CH3OH, 65 °C, 30 h, 56%. a

C


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the chemical shift of the 17O resonance of water in aqueous solution of Dy-DOTAm-F12 verified the presence of one innersphere water molecule q on the DyIII complex (Figure S10 in Supporting Information). This agrees with previous reports of one bound water molecule in DOTA-tetramide complexes containing pendant amine, N-methyl, N-dimethyl, and N-aryl substituted arms.33,53,54 Occupation of the ninth coordination site of Dy-DOTAm-F12 with a water molecule is also consistent with the outward positioned pendant arms that place the fluorines equatorially and provide solvent access to the lanthanide metal. The structure of Tm-DOTAm-F12 was also investigated with X-ray crystallography. In the crystalline state, Tm-DOTAm-F12 adopts a slightly distorted square-antiprismatic (SAP) geometry55,56 consistent with an observed interplanar angle between the oxygen and nitrogen planes of 41.6° (Figure 3). The crystal

ions, the shift in a nuclei’s resonance caused by the paramagnetic metal is defined as the lanthanide-induced shift (LIS). For the fluorine nuclei, we define 19F LIS as ΔδF = δF· paramagnetic − δF· diamagnetic. The chemical shift of the fluorine nuclei of the diamagnetic lanthanum compound La-DOTAmF12 (3) is used as the reference (δF· diamagnetic). Since the 19F−M distances (d) in DOTAm-F12 complexes are greater than 5 Å, the contact shift δc is assumed to be negligible, and the observed LIS results from the pseudocontact component δpc. Under these conditions, the 19F LIS is described by the McConnell−Robertson equation (eq 2):13 19

F LIS = C D

β 2 (3 cos2 θ − 1) 0 B2 60(kT )2 d3

(2)

where d is the 19F−LnIII distance, θ is the angle between the principal magnetic dipolar axis of the LnIII ion and 19F nuclei, B20 is the second-order crystal field coefficient that is dependent on LnIII coordination environment, and CD is the Bleaney constant for the specific lanthanide. Both the direction and magnitude of the shift are dependent on the identity of the lanthanide ion, allowing lanthanides to be ranked by their relative pseudocontact shift (PCS) strength according to their Bleaney constants (Table 1).13 For every lanthanide complex of DOTAm-F12, the direction of the shift matches the sign of the Bleaney constant: TbIII, DyIII, and HoIII have a negative CD, and the 19F resonance is shifted downfield, while the coefficients for EuIII, ErIII, TmIII, and YbIII are positive, and their resonances are shifted upfield (Table 1). This provides insights to the location of the fluorine atoms around the metal center and thus the solution structures of the lanthanide complexes. 19F nuclei positioned equatorially, within a cone aligned with the principle magnetic axis, would shift downfield if the Bleaney coefficient is negative and upfield if it is positive. Conversely, axially positioned nuclei, which are perpendicular to the principle magnetic axis, would be shifted in the opposite direction. Indeed, opposing directions of 19F LIS are observed by Kim et al. for axial and equatorial positioned 19F nuclei.35 The fact that the 19F LIS observed matches the sign of the Bleaney constant indicates (1) that all of the lanthanide complexes share a common structure in solution and (2) that in each case the 19F nuclei are located equatorially to the principle magnetic axis. It can thus be inferred that the fluorines do not collapse as a hydrophobic cap on top of the macrocycle but rather remain independently solvated on the equator of the complex. Do note that although this approach to gaining information on the position of the CF3 groups with respect to the magnetic axis of the complexes applies qualitatively to DOTA-like systems, it is not necessarily applicable to other geometries of lanthanide complexes.47 Interestingly, the chemical shift of the fluorine nuclei of the metal complexes are independent of both temperature and pH. As can be seen in Figures S12 and S13, no shift is observed for the 19F of both Tm-DOTAm-F12 (10) and FeII-DOTAm-F12 (12) between 25 and 33 °C. Similarly, the 19F signal of both Tm-DOTAm-F12 (10) and Tb-DOTAm-F12 (6) remain constant between pH 5.4 and 8.4 (Figures S14 and S15). This is unlike other lanthanide-based fluorine probes for which the chemical shift of the fluorine nuclei does vary with both temperature and pH.18,33,48 Similarly, although δ19F of many diamagnetic fluorine probes do not change,14 some do.49−51 This conclusion is further backed by 17O NMR of the DyIII complex. According to the method of Peters,52 evaluation of

Figure 3. Molecular structure of [Tm-DOTAm-F12]3+ (10, ORTEP, 50% probability level). Hydrogen and chlorine atoms omitted for clarity.

structure was found to belong to the centrosymmetric Cmca space group. The complex is not enantiopure, as the 12membered cyclen ring exhibits both the δδδδ and λλλλ configurations together with the associated helicity of the pendant arms, which can be either left-handed (Λ) or righthanded (Δ). The related [Dy-DTMA]3+ with pendant Nmethyl amide arms is also SAP and has both the enantiomers present in the unit cell.53 The C2-symmetric structure of TmDOTAm-F12 contains only six nonequivalent fluorine atoms that are positioned between 5.28 and 6.76 Å from the TmIII, with an average 19F−TmIII distance of 6.26 Å (Table 2). The angle θ is defined by the 19F−TmIII vector and the principle magnetic axis of the metal that extends through the center of the plane formed by the four nitrogen atoms of the cyclen backbone (Figure 4). The average θ value for Tm-DOTAmD


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The short F−F distance of 2.76 Å is less than the sum of the van der Waals radii (2.94 Å); contacts of this type are rare and, in most cases, a consequence of dense packing.59 These interactions (H−Cl and F−F) link the molecules together in a dimeric, “top-to-top” fashion (Figure S11). Additional crystal structure data, atomic coordinates, and displacement parameters are provided in Tables S1−S4 (see Supporting Information). The crystal structure of Tm-DOTAm-F12 together with the solution NMR data enabled us to test our predicted structure of macrocyclic lanthanide complexes by solution-phase DFT calculations using polarizable continuum model (PCM) implicit solvation models. Water was used as a solvent. Calculations were performed using Gaussian0960 with a B3LYP functional, the 6-31G(d) basis set, and the quasirelativistic effective core potential (RECP) of Dolg et al. and the related valence basis set [5s4p3d]-GTO for the TmIII. This RECP accommodates 46 + 4fn electrons in the core for the lanthanide, and the outermost 11 electrons are treated explicitly.61−63 The optimized geometry of Tm-DOTAm-F12 (Figure 4) obtained by DFT calculations is congruent with the crystal structure (Figure 3 and Table 2). The average 19F−TmIII distance (6.22 Å) and angle θ (81°) are in agreement with the orientation of the 19F nuclei observed in the crystal structure (Table 2). Furthermore, the SAP geometry is confirmed with an interplanar angle of 36.8° between the N4 and O4 planes. Overall, NMR spectroscopy, X-ray crystallography, and DFT calculations are in agreement; they confirm the SAP conformation of the complexes, the equatorial position of the trifluoromethyl groups, and the presence of one bound water molecule. Proton NMR spectroscopy of the FeII-DOTAm-F12 reveals significantly shifted resonances that verify the presence of a paramagnetic, high-spin FeII (Figure S9 in Supporting Information). This is in agreement with previous reports that illustrate stabilization of the +2 oxidation state of iron by amide pendant groups.64 By 19F NMR, the complex displays a single resonance (δF = −70.1 ppm), indicating a C4 symmetric complex (Figure 3). Morrow also observed C4 symmetry and one diastereomeric form of Fe-DOTAm complexes by 1H NMR, which suggests coordination of all four carbonyls.40,41 Compared to the lanthanide complexes (with the exception of EuIII, isotropic GdIII, and diamagnetic LaIII), FeII-DOTAm-F12 yields a smaller 19F paramagnetic-induced pseudocontact shift (+2.0 ppm). Paramagnetic Relaxation Enhancement in Water. The sensitivity of the M-DOTAm-F12 complexes is higher than that of all previously reported fluorine probes, including the only water-soluble 19F−Ln complex that has been evaluated as an MRI contrast agent.34,65,66 Part of this higher sensitivity is due to the presence of 12 19F nuclei, which are chemically equivalent. The presence of nonequivalent fluorines not only decreases the sensitivity of a fluorinated probe but also complicates substantially image acquisition and can lead to artifacts.67 Moreover, a greater component to the increased sensitivity of the water-soluble complexes comes from the paramagnetic nature of the metals. Paramagnetic relaxation enhancement (PRE) can decrease T1 by 2 orders of magnitude (from 1 s to 3)71 is extrapolated as 280 μM for the FeII complex and 430 μM for the TmIII derivative. 19 F Relaxation in Blood. The media highly influences the relaxivity of the fluorine nuclei of each metal complex. Consequently, which paramagnetic ion yields the highest SNR may not necessarily be the same in different media. The difference in the behavior of the metal complexes in water versus blood could arise from the different viscosity of the two media. Moreover, it was anticipated that the hydrophobic trifluoromethyl groups of the M-DOTAm-F12 complexes would likely interact with proteins present in blood, such as serum albumin, the most ubiquitous protein found in the mammalian bloodstream. Serum albumin has previously been reported to bind hydrophobic molecules such as perfluorocarbons.72,73 Binding to large proteins such as albumins is anticipated to affect the rotational correlation time τR of the complex. As is apparent from eqs 3, 4, and 7 and from Figures 6 and 7, the rotational correlation times influence T1 and T2 differently, with higher τR (larger macromolecules) affecting T2 noticeably more than T1. The T2/T1 ratio of the fluorine nuclei

Figure 5. MRI phantom images of M-DOTAm-F12 in water at 5.0 mM. B0 = 9.4 T, T = 33 °C. (A) 1H 3D gradient-echo images, TR = 10 ms, TE = 1.78 ms, 20°, FOV: 20 mm × 40 mm × 20 mm, matrix: 128 × 256 × 128, resolution: 0.156 mm isotropic. (B) 19F gradient-echo images, TR = 5 ms, TE = 1.34 ms, 90°, field of view (FOV): 32 mm × 32 mm, matrix: 64 × 64, slice thickness = 10 mm, number of averages (na) = 64. Images are shown with the same intensity scale after 2D zero-padding. Transmitter offset for 19F images: −122 ppm KF; −86.7 ppm TmIII; −79 ppm YbIII, ErIII; −73.7 ppm GdIII, LaIII, EuIII; −63.1 ppm FeII, HoIII, DyIII, TbIII. SNR for 19F images: Yb-DOTAm-F12 (11), 23, Tm-DOTAm-F12 (10), 20; Fe-DOTAm-F12 (12), 28; LaDOTAm-F12 (3), 4.7; Er-DOTAm-F12 (9), 14; Eu-DOTAm-F12 (4), 6.68; Tb-DOTAm-F12 (6), 6.5; Gd-DOTAm-F12 (5), 1; HoDOTAm-F12 (8), 32; Dy-DOTAm-F12 (7), 6.6.

32. Notably, none of the lanthanide ions are as efficient as FeII. Indeed, FeII has the highest T2/T1 ratio of 0.98 and also the highest SNR of 28, which is 6 times greater than the diamagnetic LaIII complex. Comparison of the SNR of the MR image of solutions of the diamagnetic LaIII complex with that obtained with the HoIII complex demonstrates the strength of using a paramagnetic metal ion. Both of these complexes have similar T2/T1 value of 0.7. However, the T1 of the fluorines of the paramagnetic HoIII complex is 75 times shorter than that of the diamagnetic LaIII complex. This enables the acquisition of 75 times more scans in a same amount of time with the HoIII complex than with the LaIII one. As a result, exchanging LaIII by HoIII results in a sixfold increase in SNR. A T2/T1 value near 1 signifies that the effect of T1 is maximized compared to the negative effect of line broadening induced by a short T2. Comparison with other published lanthanide-based 19F complexes indicates that although the trend between T2/T1 and SNR holds, the lanthanide ion that yields the most sensitive probe is not necessarily the same for all ligands. ErIII was reported to be a good metal for the previously reported DOTA- and DOPA-based system.32,34 In the case of DOTAm-F12, however, it yields an SNR value 3 times lower than HoIII in water. The extent to which a same lanthanide ion influences the sensitivity of a fluorine probe depends substantially on the ligand. With the aryl trifluoromethyl-substituted Ln-DOTA complexes studied by Chalmers et al., HoIII increases the sensitivity 2.4 times over the

Figure 6. Longitudinal relaxation rate of 19F nuclei of Tm-DOTAmF12 (10) as a function of the applied magnetic field B0 and the rotational correlation time τR. The analysis is based on eq 2 and is done at 37 °C using the mean Tm−19F distance determined from Xray crystallography (6.26 Å), assuming a magnetic moment μeff of 7.6 μB and an electronic relaxation time τe of 0.20 ps, values typical of TmIII complexes. G


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Inorganic Chemistry

Figure 8. MRI phantom images of M-DOTAm-F12 in rat blood at 5.0 mM. B0 = 9.4 T, T = 33 °C. 19F gradient-echo images, TR = 10 ms, TE = 1.34 ms, 90°, FOV: 32 mm × 32 mm, matrix: 64 × 64, slice thickness = 10 mm, na = 64. Images are shown with the same intensity scale after 2D zero-padding. Transmitter offset for 19F images: −86 ppm Yb, Tm; −73 ppm Fe; −62 ppm of Ho. SNR for 19F images: YbDOTAm-F12 (11), 6.1, Tm-DOTAm-F12 (10), 10; Fe-DOTAm-F12 (12), 16.3; Ho-DOTAm-F12 (8), ∼1.

Figure 7. Transverse relaxation rate of 19F nuclei of Tm-DOTAm-F12 (10) as a function of the applied magnetic field B0 and the rotational correlation time τR. The analysis is based on eq 3 and is done at 37 °C using the mean Tm−19F distance determined from X-ray crystallography (6.26 Å), assuming a magnetic moment μeff of 7.6 μB and an electronic relaxation time τe of 0.20 ps, values typical of TmIII complexes.

a TR of 10 ms and a center frequency corresponding to the chemical shift of each complex (Figure 8). Under these conditions, and as a consequence of the short T2, the SNR of the TmIII derivative drops by almost half in blood (10) versus water (18.1). Similarly, the SNR obtained with the YbIII in blood is 25% lower than that observed in water. The HoIII complex is affected the most by blood. Whereas in water it is one of the most sensitive complexes with an SNR of 32, in blood, the signal could not be detected, likely as a consequence of the too-short T2 (Figure S17 in Supporting Information). Likewise, De Luca et al. could not detect a chitosan polymer substituted with fluorinated HoIII complexes in mice with an imaging time of 1 h.74 It is possible that more recent imaging sequences, such as SWIFT,75 which could alleviate the effects of a short T2 if it is not too short, could enable more sensitive 19F MRI with the lanthanide complexes. FeII-DOTAm-F12, unlike its lanthanide counterparts, remained an efficient contrast agent in blood with a sensitivity that is barely affected by blood components. The SNR for the image obtained with the FeII complex was 16, which is 57% of that obtained in water. The limit of detection of the FeII and TmIII complexes in blood was estimated from 19F gradient-echo images of blood samples containing increasing concentrations of either complex (Figure 9). Note that in Figure 9 the image intensity of the TmIII complex has been increased by a factor of 2 versus that of FeII. Using the linear relationship between the SNR and the complex concentration, FeII-DOTAm-F12 is estimated to have a limit of detection of 300 μM in blood. However, the SNR of the TmIII complex is not proportional to the concentration. Three-dimensional 19F MRI phantoms of M-DOTAm-F12 complexes at 5 mM were collected in blood with a resolution of 0.5 mm × 0.5 mm × 1 mm (Figure S18 in Supporting Information). Signal from three complexes was observed in the number of slices to acquire this 3D acquisition over 33 min (YbIII, TmIII, and FeII). The signal of Fe complex has the highest signal intensity and was observed in largest number of slices. Together, the resolution and sensitivity obtained with FeII-DOTAm-F12 suggest that the Fe(II) complex provides a good starting point for the development of paramagnetic fluorine probes for in vivo applications.

for the different metal ions is thus expected to be different in blood than in water, and as such so would their sensitivity. Experimentally, fluorine T1 values in blood were found to be comparable to those measured in water (Table 3). As predicted, Table 3. 19F T1 and T2 Relaxation Times, T2/T1 Ratio, and MRI SNR of Select M-DOTAm-F12 Complexes in Rat Venous Blood at 37 °C La-DOTAm-F12 Ho-DOTAm-F12 Tm-DOTAm-F12 Yb-DOTAm-F12 FeII-DOTAm-F12

T1a (ms)

T2a (ms)

T2/T1a

SNRb,c

700 10 36 170 7.7

29 2.7 6.4 12 4.4

0.041 0.26 0.18 0.071 0.57

n.d. ∼1d 10 6.1 16.3

a

Conditions: B0 = 7.0 T, rat venous blood. b[M-DOTAm-F12] = 5 mM, B0: 9.4 T. cSNR were obtained at the optimum frequency for each complex using images shown in Figure 3B: Ho-DOTAm-F12 (8), −62 ppm; Tm-DOTAm-F12 (10), −86 ppm; Yb-DOTAm-F12 (11), −86 ppm; Fe-DOTAm-F12 (12), −73 ppm. d19F MRI signal could not be observed.

unfortunately, the fluorine transverse relaxation times T2 are substantially shorter in blood than in water. For the HoIII complex, the fluorine T2 in blood is decreased twofold to 2.7 ms, resulting in a T2/T1 value of barely 0.26a third of that found in waterand thus significant signal loss. The T2/T1 ratio of the TmIII complex similarly decreases over threefold to 0.18 as its T2 decreases from 16 to 6.4 ms. Similar reduction of fluorine T2 in vivo compared to in vitro was observed recently with a 19F−DyIII chitosan polymer.74 In the current study, the FeII complex behaves substantially better in rat blood than any of its lanthanide counterparts. The fluorine T1 relaxation time of the FeII-DOTAm-F12 surprisingly became longer by 2 ms, whereas the T2 relaxation time decreased by only 1 ms. As a result, the T2/T1 ratio dropped from 0.98 in water to only 0.57 in blood. It therefore appears, based on fluorine relaxation times alone, that the FeII-DOTAm-F12 complex would be more appropriate for in vivo 19F MRI. Gradient-echo MR images obtained at 9.4 T illustrate the relative strength of the M-DOTAm-F12 complexes in rat blood (Figure 8 and Table 3 for SNR). Each image was collected with

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CONCLUSION A series of metal complexes of the C4 symmetric ligand, namely, DOTAm-F12, has been synthesized, and its potential as 19F MRI contrast agents has been evaluated. Nine paramagnetic lanthanide ions were studied, EuIII, GdIII, TbIII, DyIII, HoIII, ErIII, H


Inorganic Chemistry

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Article

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.6b02631. Experimental and synthetic details, 1H and 19F NMR characterization of metal complexes, determination of hydration number by 17O NMR, and X-ray crystallographic data (PDF) The crystal structure of Tm-DOTAm-F12 has been deposited in the Cambridge Crystallographic Data Centre (Deposition No. CCDC 981931) (CIF)

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AUTHOR INFORMATION

Corresponding Author

Figure 9. 19F gradient-echo images of (A) FeII-DOTAm-F12 (12) and (B) Tm-DOTAm-F12 (10) in rat blood at three concentrations (0.5 mM, 1 mM, 5 MM from left to right for Fe and 5 mM, 1 mM, 0.5 mM from left to right for Tm). B0 = 9.4 T, T = 33 °C, TR = 10 ms, TE = 1.34 ms, 90°, FOV: 32 mm × 32 mm, matrix: 64 × 64, slice thickness = 10 mm, na = 256 for Fe and 64 for Tm. Images are shown with the same intensity scale after 2D zero-padding. SNR for FeII-DOTAm-F12 (12): 5 mM, 31.6; 1 mM, 4.4; 0.5 mM, 2.4. SNR for TmIII-DOTAmF12 (10): 5 mM, 8.2; 1 mM, 5.3; 0.5 mM, 2.3.

*E-mail: [email protected]. ORCID

Valérie C. Pierre: 0000-0002-0907-8395 Present Address §

Department of Chemistry, Bemidji State University, Bemidji, MN 56601. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

TmIII, and YbIII, as well as the diamagnetic LaIII analogue. FeII, which is known to form stable complexes with macrocyclic polyaminocarboxamides, was also evaluated. As opposed to currently used organic polyfluorocarbons such as perfluoro 15crown-5 and other reported paramagnetic fluorine probes, the complexes of DOTAm-F12 are all highly soluble in water. These complexes are more sensitive than other fluorinated MR probes, in part due to the 12 fluorine nuclei that are chemically equivalent and thus appear as a single resonance by 19F NMR. Importantly, the sensitivity of these probes is further increased due to the paramagnetic nature of the metals, which shortens T1, thereby enabling more scans to be acquired in the same amount of time. Shorter longitudinal relaxation times were observed for those metals with the highest effective magnetic moment, μeff. SNR observed in MR images, however, are not proportional to T1 but to a combination of T1 and the T2/T1 ratio. Higher SNR were observed for complexes that were characterized with fluorine T2/T1 as close to unity as possible. In water, the HoIII and FeII complexes were the most sensitive, followed by TmIII and YbIII. In blood, however, the increase in viscosity of the medium and possible association of the probe with proteins resulted in a decrease in the transverse relaxation times of the fluorines for all the metal complexes. As a result, the HoIII complex could no longer be observed by MRI. The TmIII complex of DOTAm-F12 is the most sensitive lanthanide complex in blood. FeII-DOTAm-F12, which has a T2/T1 closer to unity, is the most sensitive fluorine contrast agent in blood with a limit of detection of 0.30 mM. Overall, the increased sensitivity of these highly water-soluble paramagnetic fluorine probes renders them attractive alternatives to standard proton imaging by MRI. The ease by which MRI scanners can be retuned to the frequencies of fluorine further facilitates the promulgation of these probes. The ability to perform multicolor MR imaging with fluorine probes and the possibility to alter the transverse and longitudinal relaxation rates of the fluorine nuclei as a function of the metal−19F distance and rotational correlation times open interesting opportunities for the design of ratiometric responsive MRI contrast agents.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Science Foundation Grant No. CAREER 1151665 and by the NIH Clinical and Translational Science Award at the Univ. of Minnesota (8UL1TR000114), the NIBIB (P41 EB015894 and P30 NS076408) of the National Institutes of Health, and the W. M. Keck Foundation. Support to E.A.W. through a Wayland E. Noland Fellowship from the Dept. of Chemistry of the Univ. of Minnesota and to K.L.P. from the NIH−CBITG (GM 08700) and through a Dosdall fellowship are gratefully acknowledged. We thank L. J. Clouston and V. G. Young Jr. for X-ray crystallography, including data collection and structure solution and refinement.

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Inorganic Chemistry (76) Bleaney, B. Nuclear magnetic resonance shifts in solution due to lanthanide ions. J. Magn. Reson. 1972, 8, 91−100.

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