A New Oxygen Containing Pyclen-Type Ligand as a Manganese(II) Binder for MRI and 52Mn PET Applications: Equilibrium, Kinetic, Relaxometric, Structural and Radiochemical Studies
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of the Ligand
2.2. Equilibrium Studies
2.3. Relaxivity of the Mn(II) Complex
2.4. 17. O and NMRD Measurements
2.5. Kinetic Studies
2.6. Radiochemistry
2.7. DFT Calculations
3. Summary/Conclusions
4. Materials and Methods
4.1. General Methods
4.2. Synthesis and Characterization of New Compunds
4.3. Equilibrium Studies
4.4. Relaxation Properties
4.5. Kinetic Studies
4.6. H- and 17O-NMR Relaxometry
4.7. Computational Details
4.8. Radiochemistry
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
List of Abbreviations
MRI | Magnetic Resonance Imaging |
PET | Positron Emission Tomography |
CAs | Contrast Agents |
GBCAs | Gadolinium-Based Contrast Agents |
NSF | Nephrogenic Systemic Fibrosis |
BFCs | Bifunctional Chelators |
EMA | European Medicines Agency |
FDA | US Food and Drug Administration |
HSA | Human Serum Albumin |
DFT | Density Functional Theory |
KPhth | Potassium Phthalimide |
TsCl | 4-Methylbenzene-1-sulfonyl Chloride |
DMF | N,N-Dimethylformamide |
DIPEA | N,N-Diisopropylethylamine |
TEA | Triethylamine |
TFA | Trifluoroacetic Acid |
HEPES | N-(2-Hydroxyethyl)piperazine-N′-(2-Ethanesulfonic Acid) |
mAb | Monoclonal Antibody |
MBO | Mayer Bond Orders |
MBV | Mayer Bonded Valence |
MFV | Mayer Free Valence |
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Equivalent Amount of Compound 8 | O-pyclen (7) tR = 2.77 min | 3-OPCAOEt (11) tR = 4.74 min | 3,9-OPC2AOEt (9) tR = 7.86 min |
---|---|---|---|
0.4 | 52.1% | 47.9% | - |
0.8 | 17.5% | 66.7% | 15.8% |
1.2 | - | 54.1% | 45.9% |
1.6 | - | 16.2% | 83.8% |
2.0 | - | 1.9% | 98.1% |
H23,9-OPC2A | H23,9-PC2A a | H23,6-PC2A a | H21,4-DO2A b | H21,7-DO2A b | H21,7-O2DO2A c | |
log K1H | 7.73(2) | 12.25 | 10.72 | 11.44 | 11.69 | 8.05 |
log K2H | 7.66(1) | 5.97 | 8.37 | 9.51 | 9.75 | 7.43 |
log K3H | 2.13(1) | 3.47 | 3.81 | 4.14 | 3.97 | 2.06 |
log K4H | - | 1.99 | 1.26 | 1.55 | 2.68 | - |
Σlog Κ2H | 15.39 | 18.22 | 19.09 | 20.95 | 21.44 | 15.48 |
H23,9-OPC2A | H23,9-PC2A a | H23,6-PC2A a | H21,4-DO2A b | H21,7-DO2A b | H21,7-O2DO2A c | ||
Σlog Κ2H | 15.39 | 18.22 | 19.09 | 20.95 | 21.44 | 15.48 | |
Mg2+ | log KMnL | 7.02(1) | 9.84;(8.4) d | 8.11 | - | - | 3.91 |
log KMnHL | - | 5.91 | 5.87 | - | - | - | |
Ca2+ | log KMnL | 8.27(1) | 9.92;(10.0) d | 9.57 | 8.62 | 8.86 | 6.96 |
log KMnHL | - | 5.08 | 5.27 | - | - | - | |
Mn2+ | log KMnL | 13.03(1) | 17.09 | 15.53 | 15.68 | 14.64 | 9.38 |
log KMnHL | 2.40(2) | 2.14 | 3.06 | 4.15 | 4.40 | - | |
log KMnLOH | 11.49(1) | - | - | - | - | 12.38 | |
pMn e | 8.69 | 8.64 | 8.09 | 7.27 | 6.52 | 6.67 | |
Zn2+ | log KMnL | 14.81(1) | 19.49 | 20.37 | 18.03 | 18.86 | 10.55 |
log KMnHL | 2.08(3) | 2.74 | 2.36 | 3.58 | 4.23 | - | |
log KMnLOH | 10.95(2) | - | - | 1.65 f | 1.78 f | 11.40 | |
Cu2+ | log KMnL | 18.41(4) g | 23.58 g | 24.09 g | 24.43 g | 24.24 | 14.56 |
log KMnHL | 1.92(4) g | 2.12 g | 2.37 g | 2.95 | 3.06 | 2.46 | |
log KMnLOH | 10.50(5) | - | - | - | - | 11.95 |
H23,9-OPC2A (25 °C/37 °C) | H23,9-PC2A a | H23,6-PC2A a | H21,4-DO2A b | H21,7-DO2A b | H21,7-O2DO2A c | ||
0.49 T | r1p | 3.13(2)/2.54(1) | 2.91 | 2.72 | 2.10 | 1.50 | 2.86 |
r2p | 5.15(3)/4.17(4) | 3.96 | 3.49 | - | - | - | |
1.41 T | r1p | 2.72(2)/2.06(1) | 2.24 | 2.40 | - | - | - |
r2p | 9.90(5)/7.37(3) | 4.82 | 4.20 | - | - | - |
Parameter | [(Mn(3,9-OPC2A)] | [Mn(3,9-PC2A)] a | [Mn(1,4-DO2A)] b | [Mn(1,4-DO2AMMe2)]2+ c | [Mn(1,7-O2DO2A)] d |
r129820 MHz/mM−1s−1 | 3.09 | 2.91 | 2.1 | 2.5 | 2.86 |
kex298/107s−1 | 5.3 ± 0.4 | 12.6 | 113 | 11.5 | 5.3 |
ΔH‡/kJmol−1 | 28.5 ± 1.7 | 37.5 | 29.4 | 36.9 | 29.7 |
ΔS‡/JK−1mol−1 | −1.9 ± 0.8 | – | – | - | 2.8 |
τR298/ps | 40.0 ± 1.1 | – | 46 | 53 | 46.7 |
ER/kJmol−1 | 14.8 ± 0.6 | – | 19.1 | 19.1 | 20 e |
Δ2/1018s−2 | 17.8 ± 3.6 | – | 481 | 510 | 111 |
τv298/ps | 19.3 ± 3.0 | – | 4.4 | 5.5 | – |
q e | 1 | 1 | 0.87 | 0.87 | 1 |
[Mn(3,9-OPC2A)] | [Mn(3,9-PC2A)] a | [Mn(3,6-PC2A)] a | [Mn(1,4-DO2A)] b | [Mn(1,4-DO2AMMe2)]2+ c | [Mn(1,7-O2DO2A)] d | |
k0 (s−1) | (8.6 ± 1.1) × 10−6 | – e | – e | – e | – e | – e |
k1 (M−1s−1) | 2.81 ± 0.07 | 221 | 70 | 99 | 8.7 | 85 |
k2 (M−2s−1) | - | - | 1.5 × 105 | 1.4 × 106 | - | 3.0 × 106 |
k3 (M−1s−1) | - | 3.6 × 10−2 | 2.6 × 10−2 | - | - | - |
KMnL x H | - | 3.6 × 103 | 1.15 × 103 | - | - | - |
KML x Cu | 7 ± 4 | 26 | 16 | - | - | - |
t1/2 (h) at pH = 7.4 | 21.9 f 1625 | 21.0 | 63.2 | 48 | 556 | 56.8 |
[Mn(3,9-PC2A)] | [Mn(3,9-OPC2A)] | |||
Bond | R | MBO | R | MBO |
Mn–N1 | 2.041 | 0.56 | 2.041 | 0.56 |
Mn–N3 | 2.610 | 0.24 | 2.692 | 0.22 |
Mn–N6/O6 | 2.077 | 0.48 | 2.190 | 0.26 |
Mn–N9 | 2.101 | 0.48 | 2.067 | 0.50 |
Mn–O3 | 2.252 | 0.19 | 2.099 | 0.26 |
Mn–O9 | 2.051 | 0.45 | 2.016 | 0.44 |
Mn–O1w | 2.114 | 0.35 | 2.151 | 0.34 |
[Mn(3,9-PC2A)] | [Mn(3,9-OPC2A)] | |||||
atom | q | MBV | MFV | q | MBV | MFV |
Mn | 0.297 | 3.46 | 1.50 | 0.434 | 3.19 | 1.77 |
N1 | −0.118 | 3.15 | 0.00 | −0.108 | 3.15 | 0.00 |
N3 | −0.238 | 2.97 | 0.00 | −0.254 | 2.97 | 0.00 |
N6/O6 | −0.019 | 3.22 | 0.00 | −0.277 | 2.07 | 0.00 |
N9 | −0.086 | 3.24 | 0.00 | −0.081 | 3.31 | 0.00 |
O3 | −0.520 | 1.85 | 0.00 | −0.516 | 1.87 | 0.00 |
O9 | −0.464 | 1.89 | 0.00 | −0.456 | 1.92 | 0.00 |
O1w | −0.447 | 2.08 | 0.00 | −0.455 | 2.05 | 0.00 |
Solvent A (MeCN) | Solvent B (Aqueous 5 mM TFA Solution) | |
---|---|---|
0.0 min | 0% | 100% |
15.0 min | 90% | 10% |
16.0 min | 0% | 100% |
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Csupász, T.; Szücs, D.; Kálmán, F.K.; Hollóczki, O.; Fekete, A.; Szikra, D.; Tóth, É.; Tóth, I.; Tircsó, G. A New Oxygen Containing Pyclen-Type Ligand as a Manganese(II) Binder for MRI and 52Mn PET Applications: Equilibrium, Kinetic, Relaxometric, Structural and Radiochemical Studies. Molecules 2022, 27, 371. https://doi.org/10.3390/molecules27020371
Csupász T, Szücs D, Kálmán FK, Hollóczki O, Fekete A, Szikra D, Tóth É, Tóth I, Tircsó G. A New Oxygen Containing Pyclen-Type Ligand as a Manganese(II) Binder for MRI and 52Mn PET Applications: Equilibrium, Kinetic, Relaxometric, Structural and Radiochemical Studies. Molecules. 2022; 27(2):371. https://doi.org/10.3390/molecules27020371
Chicago/Turabian StyleCsupász, Tibor, Dániel Szücs, Ferenc Krisztián Kálmán, Oldamur Hollóczki, Anikó Fekete, Dezső Szikra, Éva Tóth, Imre Tóth, and Gyula Tircsó. 2022. "A New Oxygen Containing Pyclen-Type Ligand as a Manganese(II) Binder for MRI and 52Mn PET Applications: Equilibrium, Kinetic, Relaxometric, Structural and Radiochemical Studies" Molecules 27, no. 2: 371. https://doi.org/10.3390/molecules27020371