Brief Article pubs.acs.org/jmc
Complementary Strategies for Developing Gd-Free High-Field T1 MRI Contrast Agents Based on MnIII Porphyrins Weiran Cheng,†,‡ Inga E. Haedicke,†,‡ Joris Nofiele,∥,⊥ Francisco Martinez,# Kiran Beera,§ Timothy J. Scholl,*,#,∞ Hai-Ling Margaret Cheng,*,∥,⊥ and Xiao-an Zhang*,†,‡,§ †
Department of Chemistry, University of Toronto, Toronto, Ontario, M5S 3H6, Canada Department of Physical and Environmental Sciences and §Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, Ontario, M1C 1A4, Canada ∥ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1X8, Canada ⊥ Physiology and Experimental Medicine, The Research Institute, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada # Imaging Research Laboratories, Robarts Research Institute, The University of Western Ontario, 100 Perth Drive, London, Ontario, N6A 5K8, Canada ∞ Department of Medical Biophysics, The University of Western Ontario, London, Ontario, N6A 5C1, Canada ‡
S Supporting Information *
ABSTRACT: MnIII porphyrin (MnP) holds the promise of addressing the emerging challenges associated with Gd-based clinical MRI contrast agents (CAs), namely, Gd-related adverse effect and decreasing sensitivity at high clinical magnetic fields. Two complementary strategies for developing new MnPs as Gd-free CAs with optimized biocompatibility were established to improve relaxivity or clearance rate. MnPs with distinct and tunable pharmacokinetic properties can consequently be constructed for different in vivo applications at clinical field of 3 T.
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incidence of nephrogenic systemic fibrosis (NSF), a rare but severe adverse effect associated with the administration of GBCAs to patients with renal dysfunction, has been increasingly reported. This suggests that the release and accumulation of toxic GdIII ions may occur in vivo if rapid clearance of GBCAs is impeded.4 In addition, the clinical MRI scanners are progressively replaced by 3 T instruments to gain higher sensitivity and resolution, whereas the contrast enhancement efficiency (measured as T1 relaxivity or r1) of typical GBCAs decreases at increased magnetic fields. Several chemical strategies have been developed to improve the r1 of GBCAs. High r1 at high clinical field could be achieved successfully when multiple molecular parameters are finely tuned to match their optimal ranges.5 To address these challenges and to introduce molecular diversity to the field, we decided to explore fundamentally different chemical platforms for developing safer and more efficient Gd-free T1 CAs, particularly suitable for applications at high clinical magnetic field of 3 T. Toward this goal, manganese(III) porphyrin (MnP) came in to our view as a superior candidate.
INTRODUCTION Magnetic resonance imaging (MRI) is a high-resolution, noninvasive, and versatile 3D imaging modality widely applied in clinical diagnosis to obtain internal anatomical and functional information of living objects. Conventional MRI typically relies on the 1H NMR signal mainly from water, the most abundant molecule in vivo. By administration of a paramagnetic contrast agent (CA), which can catalytically shorten the longitudinal (T1) or transverse (T2) nuclear spin relaxation time of surrounding water protons, the sensitivity and contrast of MR image can be significantly improved. This enhances the visualization of a wide range of otherwise undetectable pathologies and certain physiological functions, such as blood flow.1 Since the first clinical MRI CA, Gd-DTPA, was published in 1984,2 the development of effective and safe Gd-based CAs (GBCAs) has made indispensable contributions to the success of MRI in diagnostic medicine. During the past 3 decades, a wide variety of paramagnetic chelates have been devised as T1 CAs based on GdIII, which has the largest possible number of seven unpaired electrons (S = 7/2) to generate a large magnetic moment. Currently, GBCAs have been applied in >40% of MRI scans, playing a crucial and dominant role in contrast enhanced MRI studies.3 Challenges emerge recently, however, as the © 2013 American Chemical Society
Received: July 24, 2013 Published: December 12, 2013 516
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Scheme 1. Synthesis of 3a
It was first reported in mid-1980s that a water-soluble MnP, MnIII meso-tetra(4-sulfonatophenyl)porphine (MnTPPS) exhibited an “anomalously” high r1 (10.4 mM−1 s−1) at 0.47 T (20 MHz for 1H Larmor frequency), given that there are only four unpaired electrons (S = 2) in MnIII compared to seven in GdIII.6 More interestingly, as the magnetic field strengths increase beyond 1 MHz, the r1 of MnTPPS increases, unlike that of typical small GBCAs, such as Gd-DTPA.7 In addition to this valuable but largely unexplored relaxation property, the MnP platform has other advantages, including high thermodynamic and kinetic stability against Mn dissociation,8 lower toxicity of Mn (a micronutrient) than Gd, two water coordination sites,9 rigid backbone, and the adaptability of porphyrins for other imaging or therapeutic functions (i.e., fluorescence imaging or photodynamic therapy). Despite these advantages, limited efforts have been made to optimize and utilize MnPs for in vivo MRI studies.10 Here, we report two complementary chemical strategies to design new MnPs with optimized biocompatibilities and desired pharmacokinetic properties for different clinical applications. The first strategy is to increase r1 and thus reduce the dose needed for in vivo imaging. The second strategy is to increase the in vivo clearance rate of the CA, thereby minimizing its retention in the body.
a
Reagents and conditions: (a) Pd(PPh3)2Cl2, TBAF, H2O/THF, rt, 85%; (b) conc H2SO4, 80 °C, 98%; (c) Mn(OAc)2, NH4Ac buffer, pH 6.8, 90 °C, 97%.
small and highly polar MnP. It was reported that MnTPPS exhibited a dual hepatic and renal excretion and a relatively long in vivo retention after iv injection in mice.10e The slow clearance rate shared among MnPs is possibly due to the hydrophobic nature of most porphyrin derivatives. No effort, however, has been previously reported to improve clearance rate of MnP. Mn tetracarboxylporphyrin, MnTCP (6) (Scheme 2), was thus designed as a smaller and more polar version of
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RESULTS AND DISCUSSION Commonly used approaches to improve r1 include (a) incorporating multiple paramagnetic metal centers into one molecule and (b) optimizing molecular parameters that govern the relaxation process, such as increasing its rotational correlation time (τR),5d which have been proven to be effective for GBCAs. The relaxation behavior of MnTPPS is very different from that of small GBCAs. The classic Solomon− Bloembergen−Morgan (SBM) model,11 which works well for most of the Gd agents, returned seemingly unreasonable molecular parameters when it was applied to fit the NMRD profiles of MnPs.7 The unique field-dependent relaxivity of MnPs has been proposed to be due to the configuration and relaxation behaviors of electron spin.10c,12 An increase in τR is expected to improve the r1 at high fields, where the fielddependent electron relaxation becomes slower in contrast to the low magnetic field scenarios. A MnP dimer, MnP2 (3) (Scheme 1), was therefore designed. Covalently coupling the rigid aromatic backbone in MnTPPS is an effective approach to increase τR, offering a unique advantage over flexible ligand frameworks in most Gd complexes. The internal motion of macromolecular GBCAs can significantly compromise the r1, owing to the conformational flexibility of aliphatic linkers. In contrast, the two porphyrin planes of 3 adopt a relatively rigid, staggered orientation, originating from the restricted rotation between phenyl−porphyrin and phenyl−phenyl rings. This conformation in combination with the large 2D surface of TPP can significantly slow rotation. To develop an efficient synthesis for 1, a high yielding PdII catalyzed homolytic coupling reaction13 was successfully employed for the first time for porphyrin dimerization (Scheme 1). Water solubilizing sulfonate groups were then installed by reacting 1 with concentrated H2SO4 at 80 °C.14 Highly regioselective sulfonation at the para-position of six peripheral benzene rings, but not on the bridging biphenyl unit, was achieved with high yield. Mn insertion was performed on sulfonated 2 to generate the final product 3. Our second strategy was to accelerate the clearance rate and thereby minimize the retention of the CAs in vivo by creating a
Scheme 2. Synthesis of 6a
Reagents and conditions: (a) BF3OEt2, CH2Cl2, rt, 10%; (b) MnCl2· 4H2O, DMF, reflux, 85%; (c) ethanol, NaOH, reflux, 85%. a
MnP. The four sulfonate-PhSO3− arms in MnTPPS were replaced by smaller carboxylates at the meso positions for water solubility and polarity. 6 was synthesized for the first time from a base-catalyzed hydrolysis of the tetraethyl ester precursor15 5 (Scheme 2). Under the same condition, direct hydrolysis of 4 gives the diamagnetic apo form of 6, which was confirmed by NMR (see Supporting Information). Indeed, 6 exhibits a significantly higher solubility in aqueous solution in contrast to MnTPPS8a and can diffuse rapidly across the 1 kDa cutoff membrane of the dialysis system, which is barely observable for MnTPPS, confirming the smaller effective size of 6. To investigate the field-dependent relaxation properties of 3 and 6, the NMRD profiles were acquired with a fast field cycling NMR relaxometer16 covering magnetic fields from 0.23 mT to 1 T as shown in Figure 1. Mn atomic absorption spectroscopy (AAS) was used to calibrate the concentration of the MnPs. Among all four compounds tested (MnTPPS and Gd-DTPA used as reference controls), the dimeric 3 exhibits the highest r1 per Mn at fields above ∼0.03 T. The r1 peak of 3 (20.9 mM−1 s−1 per Mn) occurs close to 1 T, and this broad 517
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Figure 1. NMRD profiles of Gd-DTPA (◇), MnTPPS (●), 3 (▽), and 6 (□) from 0.2 mT to 1 T at 25 °C, fitted with the SBM model (parameters shown in Table S1).
peak is extended to higher fields up to 3 T with a moderate decrease, favoring high r1 at high magnetic fields. Similar relaxivities at high clinic fields have been achieved in a few intermediate size GBCAs with finely tuned parameters.17 Notably, a hydroxypyridonate (HOPO) based Gd chelate conjugated with water-soluble dendrimer showed a very similar NMRD profile with comparable r1 maxima at similar high field strength between 1 and 3 T. With similar molecular weight as MnP2, this Gd complex contains a single paramagnetic metal ion.17a Even though 6 has a slightly lower r1 than MnTPPS at clinical field strengths, its r1 is still substantially higher than that of Gd-DTPA. Importantly, the r1 of 6 decreases only moderately at fields above 0.2 T. To further assess the r1 of the novel MnPs at high clinical field of 3 T, phantom imaging experiments were conducted. The four CAs, at various concentrations, were imaged with a 3 T clinical MRI scanner (Figure S4). Both r1 and r2 values were quantitatively derived (Table S1). Of the four CAs, 3 exhibits the highest signal intensity on T1 weighted images (r1 = 14.1 mM−1 s−1 per Mn). As expected, 6 (r1 = 7.9 mM−1 s−1) shows significantly higher signal than Gd-DTPA, even though their molecular size is similar (Mw 535 for MnTCP, Mw 546 for Gd-DTPA). The low r2/r1 ratios of both 3 and 6 favor positive contrast enhancement (brightening effect) because the interference from T2 effect (darkening) is relatively small. Overall, in vitro characterizations suggest that both new MnPs are efficient T1 agents and are potentially valuable for high field clinical applications at 3 T. To demonstrate that the new MnPs are efficient T1 CAs for in vivo applications, 3 and 6 were administered to rats with subsequent MRI studies on a 3 T clinical scanner, again using MnTPPS and Gd-DTPA as reference compounds. A relatively low dose, 0.05 mmol of Mn or Gd/kg (typical dose for clinical Gd-based CAs is ∼0.1 mmol Gd/kg), was chosen based on the in vitro r1 values described above. All MnPs exhibited significant T1 contrast enhancements in vivo after iv injection, allowing the pharmacokinetic properties of MnPs, including tissue distribution, metabolic pathway, and clearance rate to be analyzed from the in vivo MRI data. As shown in the whole body images of the rats (Figure 2), the small and polar 6 rapidly accumulated in the kidney and the bladder within 10 min postinjection and the majority of kidney enhancement was quickly relocated into the bladder in 1 h, which then fully
Figure 2. T1-weighted spin-echo whole body MRIs of rats at 3 T. The location of the left kidney is highlighted in the yellow circle, while that of the bladder, from separate bladder MRI slices, is delineated within the blue circle.
disappeared after 24 h, similar to Gd-DTPA. The desired rapid clearance of 6 via renal filtration was further confirmed by urine sample analysis (Figure S5). The concentrations of MnPs can be accurately quantified by UV−vis and Mn AAS. Both the high concentration (318 μM) of 6 detected in urine 90 min after injection and the absence of 6 in urine collected at ∼24 h postinjection suggested rapid renal clearance. In contrast, the reference compound MnTPPS has a significantly slower renal clearance rate, as confirmed by MRI and urine sample analysis (Figure S5). The kidney MRI enhancement remained at high levels rather than fully relocating to the bladder within 60 min postinjection. The MRI enhancement in the liver, which was absent for 6, became significant after 24 h for MnTPPS (Figure 2). This is consistent with the literature which reports the dual hepatic and renal clearance of MnTPPS. For the dimeric 3, no bladder enhancement was detected over the 3 days of the entire experimental period and no MnP signal was found by either Mn AAS or UV−vis in urine over 72 h postinjection. The significant liver enhancement and the decrease in contrast over 3 days (data not shown) suggest that 3 was accumulated and mainly metabolized by the liver. Noticeably, 3 exhibited relatively long-lasting strong enhancement in the blood vessels and in the heart, a property desired for blood pool imaging. For the current study, the same concentration of the four CAs was administered. In the future, lower dose of 3 can be used for adequate contrast enhancement due to its significantly higher r1. Nevertheless, all the rats were found to be healthy after the in vivo studies, which were carried out in duplicate, suggesting good biocompatibility of the new MnPs. Detailed toxicity studies will follow to evaluate their safety for future use in comparison with the parent compound MnTPPS.18 Overall, these observations demonstrated the great potential of 3 as a blood-pool CA and a tissue-selective agent for liver imaging. On the other hand, 6 may be used for most applications involving conventional extracellular small GBCAs. 518
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(21 mg, 0.12 mmol) were mixed. The reaction was allowed to run for 16 h at 90 °C with stirring in ammonium acetate buffer solution at pH 6.8 (3 mL). The crude product was filtered and dialyzed using a 3500 MWCO membrane to remove bulk excess salt. The dialyzed solution was concentrated and loaded onto an RP-18 column, which was then rinsed with water to remove free inorganic salt residual, and then pure methanol was used to elute the porphyrin product. The product was run through an Amberlite IR120, Na+ form, to give 10 mg of dark green product (97%) as sodium salt. ESI MS found m/z = 451.5048 ([M]4−), calcd for C88H48N8O18S6Mn24−, m/z = 451.5047. UV−vis (HEPES buffer): λabs = 382, 402, 421, 469, 569, 602 nm, λmax = 469 nm, ε = 205 000 M−1 cm−1. [5,10,15,20-Tetrakis(carboxy)porphyrinato]manganese(III) (6). Ethanol (10 mL) and 2 M NaOH (10 mL) were added to a solution of 515 (14 mg, 21.9 μmol) in 6 mL of THF. The mixture was refluxed for 12 h followed by neutralization with 3 M H2SO4 (aq). Purification by Sephadex LH-20 chromatography with water gave the desired product in 85% yield. ESI MS found m/z = 539.0032 ([M]+), calcd for C24H12MnN4O8+, m/z = 539.0030. UV−vis (HEPES buffer): λabs = 325, 377, 397, 421, 465, 561, 592 nm, λmax = 465 nm, ε = 68 000 M−1cm−1. IR (neat): ν = 3378 (carboxylic O−H), 1567 (sp2 CO, carbonyl), 1383, 1319 (sp3 C−O, carboxylic acid) cm−1.
CONCLUSION In summary, we report two seemingly opposite molecular strategies to design highly efficient Gd-free MRI CAs based on water-soluble MnP. The synthesis of two novel targets, 3 and 6, was described, and their characterization in vitro and in vivo was determined in parallel and compared to MnTPPS and GdDTPA. The MnP dimer 3 exhibits a high r1 of 20.9 mM−1 s−1 per Mn or 41.8 mM−1 s−1 per molecule at 1 T and shows extended high relaxivities up to 3 T, comparable to the state-ofart GBCAs designed for high-field applications. This new CA has achieved an unprecedented high molar r1 at high fields among all MnP-based CAs,19 allowing decrease of the required dose for in vivo applications. On the contrary, the smaller 6 demonstrated a rapid renal clearance, which is the first MnP with similar pharmacokinetics as a typical extracellular CA, thereby reducing the exposure time in the body. These results suggest that the size, geometry, and polarity of MnPs can be systematically modified to optimize their relaxivities and pharmacokinetic properties, including tissue specificity, diffusion rate, metabolic pathway, and clearance rate. Hence, by building on each strategy or by combining them, a library of MnPs can potentially be tailored for different clinical applications, such as tissue (or disease) targeted imaging, magnetic resonance angiography, or dynamic contrast enhanced MRI.
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ASSOCIATED CONTENT
S Supporting Information *
General methods, extra synthetic procedures, original spectra for structural characterization, additional figures and tables. This material is available free of charge via the Internet at http://pubs.acs.org.
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EXPERIMENTAL SECTION
The purity of the final products was analyzed and determined to be ≥95% pure using Mn flame AA and analytical high performance liquid chromatography (HPLC), an Agilent 1100 system equipped with an Agilent 1100 series diode array UV/vis detector, and an Eclipse C-18 reverse phase column (4.6 mm × 150 mm, 5 μm). General methods, detailed experimental procedures, and original spectra can be found in the Supporting Information. 4,4′-Bis(5,10,15-triphenylporphin-20-yl)biphenyl (1). TPPBPin20 (74.6 mg, 0.099 mmol), Pd(PPh3)2Cl2 (9.0 mg, 0.013 mmol), and tetrabutylammonium fluoride (35 mg, 0.111 mmol) were added to a reaction flask. Then a 1:4 water and THF solvent mixture (10 mL) was added and allowed to stir at room temperature and opened to the air. After 5.5 h, the reaction was stopped and the mixture dried in vacuo. The solid product was washed with hexane/ chloroform 7:3 and diethyl ether to remove impurities. Filtration was performed, and the purple crystals were rinsed with cold CHCl3. An amount of 52 mg of dark purple solid was obtained (85%). 1H NMR (500 MHz, CDCl3): δ = 9.06 (4 H, d, J = 4.7 Hz, por-β), 8.94 (4 H, d, J = 4.7 Hz, por-β), 8.88 (8 H, s, por-β), 8.47 (4 H, d, J = 8.1 Hz, Ph), 8.35 (4 H, d, J = 8.1 Hz, Ph), 8.30−8.21 (12 H, m, Ph), 7.84−7.72 (18 H, m, Ph), −2.71 (4 H, s, NH). ESI MS found m/z = 1227.439 ([M + H]+), 614.2452 ([M + 2H]2+), calcd for C88H59N8+, m/z = 1227.4863, C88H60N82+, m/z = 614.2470. 4,4′-Bis(5,10,15-tris(4-sulfonatophenyl)porphin-20-yl)biphenyl (2). 1 (30 mg, 0.0245 mmol) was allowed to react in 2 mL of concentrated sulfuric acid at 80 °C for 9 h. After the reaction, the porphyrin solution was carefully poured into a beaker of ice (CAUTION: heat release), diluted, and slowly neutralized with 1.0 M NaOH until the solution turned deep red. The porphyrin solution was dialyzed using a 3500 MWCO membrane to remove the excess salt. An amount of 44 mg (98%) of red solid product was obtained. 1H NMR (500 MHz, DMSO-d6): δ = 9.06 (4 H, d, J = 4.6 Hz, por-β), 8.98 (4 H, d, J = 4.6 Hz, por-β), 8.87 (8H, s, por-β), 8.55 (4 H, d, J = 8.0 Hz, Ph), 8.51 (4 H, d,, J = 8.0 Hz, Ph), 8.25−8.15 (12 H, m, Ph), 8.12−8.00 (12 H, m, Ph), −2.86 (4 H, s, NH). ESI MS found m/z = 283.4 ([M]6−), 340.3 ([M + H]5−), calcd for C88H52N8O18S66−, m/z = 283.4, C88H53N8O18S65−, m/z = 340.2. 4,4′-Bis(Manganese(III) 5,10,15-Tris(4-sulfonatophenyl)porphin-20-yl)biphenyl (3). 2 (10 mg, 5.40 μmol) and Mn(OAc)2
AUTHOR INFORMATION
Corresponding Authors
*T.J.S.: phone, 519-663-5777; e-mail,
[email protected]. *H.-L.M.C.: phone, 416-813-5415; e-mail, hai-ling.cheng@ sickkids.ca. *X.a.Z.: phone, +1-416-287-7202; e-mail, xazhang@utsc. utoronto.ca Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was mainly supported by NSERC through a Discovery Grant awarded to X-a.Z (Grant 489075). X-a.Z. is also grateful to the University of Toronto Scarborough, Canada Foundation for Innovation, and Ontario Research Fund. H.L.M.C. is supported by NSERC through a Discovery Grant and by the SickKids Foundation. T.J.S. acknowledges financial support from the Ontario Institute for Cancer Research (Investigator Award) and NSERC (Discovery Grant).
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ABBREVIATIONS USED AAS, atomic absorption spectroscopy; DTPA, diethylenetriaminepentaacetic acid; GBCA, gadolinium based contrast agent; HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; MnP, MnIII porphyrin; NMRD, nuclear magnetic relaxation dispersion; NSF, nephrogenic systemic fibrosis; MnTPPS, MnIII meso-tetra(4-sulfonatophenyl)porphine
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REFERENCES
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Brief Article
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