1. Sandra C. Balanga, Maria Benavides, PhD Department of Natural Sciences www.uhd.edu/academic/colleges/Sciences/ns Abstract : This study focuses on determining the structures and molecular properties of three compounds currently used as ligands in the preparation of magnetic resonance imaging (MRI) contrast agents (DTPA-N-MA, DTPA-N’-MA, and DTPA-cs124). Calculations were performed using density functional theory (DFT) with B3LYP functional applied in combination with a basis set of (3-21G and 6-311G to obtain equilibrium geometries, vibration frequencies, and IR spectra for the chelates. The highest occupied molecular orbital (HOMO) – lowest occupied molecular orbital (LUMO) energy gap values for the three compounds range between 3.5 to 4.5 eV, suggesting that the ligands are chemically stable. The compounds exhibit dipole moments ranging between 4.5 to 7.8 Debye indicating they possess polar character. Introduction Over the past years MRI exams including the use of contrast agents has considerably increased. MRI has important clinical applications, and its successful use in radiology practice and medical diagnostics has revolutionized medicine as a whole. Gadolinium(III) ion is an element of choice in MRI due to its very unique magnetic properties. Gadolinium(III) ion is known to be a potential toxic metal ion, but when appropriate ligands are attached to it, they stay chelated in the body and are excreted intact 1. Thus active investigations in the chemical structure and stability of complex agents have to be thoroughly study. Previous studies have shown that DTPA form strong complexes with gadolinium for the period that the complex agent is in the body 1. The main focus of our study is to use computational process to predict the structures as well as the molecular properties of three potential gadolinium chelating agents (DTPA-N-MA, DTPA-N’-MA, DTPA- cs124), used in the preparation of MRI contrast agents. Methods The three compounds were modeled using GaussView 5.0 2. First, geometry optimization calculations were performed to obtain an optimized and most stable molecular structure along with the dipole moment values of the compounds. The optimized structures were then used to run frequency calculations to obtain harmonic frequencies with corresponding IR spectra. The frequency calculation serves as well to confirm that the optimized structure corresponds to the equilibrium geometry, which in turn corresponds to the most stable structure. The optimized geometries are considered as true equilibrium geometries of the compounds only when no imaginary frequencies are generated during the frequency calculation. All calculations were performed using Gaussian 09 codes 3 along with density functional theory (DFT) in combination with the B3LYP hybrid functional. Two basis sets (3-21G, and 6-311G ) were used to run optimization and frequency calculations for each compound. Results and Discussion A.Geometries The computed equilibrium geometries of DTPA-N-MA, DTPA-N’-MA, and DTPA- cs124 correspond to structures that have suitable orientations for binding to Gadolinium (III) (figures 1-3). B. Vibrational analysis According to a study conducted by Darras, et al 4, bands in the IR spectrum of DTPA corresponding to the C=O bending and stretching of CO 2 H are observed at 1730 and 1696 cm -1, and the bending of the OH group in CO 2 H is observed at about 1100cm -1. Under the 6-311G basis set, the computational frequency values corresponding to the C=O bending/stretching for the three ligands ranged between 1700 to 1705 cm -1 and 1716 to 1721 cm -1, and the experimental values were 1696 cm -1 and 1730 cm -1, respectively (Table 3). The computational frequencies corresponding to the vibration motion of OH in CO 2 H for the three compounds ranged in values between 1100.1 and 1110.4 cm -1.The ratio of the computational and experimental frequency of the ligands is near unity, indicating that our proposed models are good representations of the actual molecular structures. C. HOMO-LUMO energy gaps HOMO-LUMO energy gaps are excellent indicators of chemical stability; a value greater than 1 eV suggests a compound is chemically stable 5. HOMO- LUMO energy gaps resulting from calculations using 6-311G basis sets ranged between 3.5 to 4.5 eV, for all three compounds, indicating these molecules possess high chemical stability. D. Hydrogen Bonding Multiple hydrogen bonding are observed for DTPA-N-MA, DTPA-N’-MA, and DTPA-cs124 molecules. The hydrogen bonding appears mostly between the hydrogen attached to the nitrogen and the oxygen atoms of the carbonyl group. Hydrogen bonding between hydrogen attached to carbon atoms and the oxygen atoms of the carbonyl group is also observed. E. Dipole moments All three compounds exhibit large dipole moment values, ranging from 4.5 to 7.8 eV. This suggests all three compounds are highly polar in nature. This is consistent with the presence of various electronegative atoms such as O and N atoms and the fact that these compounds are not symmetrical. Interestingly, the DTPA-cs124 compound has the lowest dipole moment value among the three compounds which may be due to the presence of benzene rings and increased molecular weight. Conclusion The presence of multiple hydrogen bonding and large HOMO-LUMO energy gaps indicate that these ligands are highly chemically stable. The results indicate that these molecules possess the necessary chemical properties and molecular geometry to be used as chelating agents in the productions of MRI contrast agents. Future Work: In order to broaden the scope of this work, it would be of great interest to study other ligands. Acknowledgements : Special thanks to the Welch Foundation (grant no. BJ-0027)27). Thanks to my research advisor Dr. Maria Benavides for her valuable advices and endless support throughout this enriching research experience. References: 1.Caravan, P., Ellison, J. J., McMurry, T. J., & Randall, B. L. (1999). Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. Chemical Reviews, 99, 2293-2352. 2.Dennington, R., Keith, T., A., Millam, J. (2009). GaussView Version 5. Semichem, Inc., Shawnee Mission KS. 3.Frisch, M. E., et al. (2009). Gaussian 09, Revision A.01. Wallingford, CT: Gaussian, Inc. 4.Darras, V., Nelea, M., Winnik, F. M., & Buschmann, M. D. (2010). Chitosan Modified with Gadolinium Diethylenetriaminepentaacetic Acid for Magnetic Resonance Imaging of DNA/Chitosan Nanoparticles. Carbohydrate Polymers, 80, 1137-1146. 5.Aihara, J. (1999) Reduced HOMO-LUMO gaps as index of kinetic stability for polycyclic aromatic hydrocarbons. J. Phys. Chem. A. 103, 7487-7496. Figure 1: DTPA-N-MAFigure 2: DTPA-N’-MA Figure 3: DTPA-cs124 Basis Set Chelating Agent Dipole Moment (Debye) DTPA-N-MA DTPA-N’-MA DTPA-cs124 3-21G 5.0108 5.01086.38134.561 6-311G4.53487.83754.5022 Basis Set Chelating Agent HOMO-LUMO Energy Gap (eV) DTPA-N-MA DTPA-N-MA DTPA-N’-MA DTPA-cs124 3-21G5.1135.0233.476 6-311G4.5114.3443.568 Table 1: Calculated dipole moment of all chelating agent Table 2: HOMO-LUMO Energy Gap Table 3: Frequency data comparison for the carboxylic acid and hydroxyl group using 6-311G basis setCompound Computational Frequency (cm -1 ) Experimental Frequency (cm -1 ) Ratio Near Unity DTPA-N-MA Bending/Stretching COOH 1703.516961.00 1719.217301.00 Bending OH group Bending OH group1107.511000.99 DTPA-N’-MA Bending/Stretching COOH 1700.316961.00 1716.417300.99 Bending OH group Bending OH group1100.111000.99 DTPA-cs124 Bending/Stretching COOH 1705.916961.00 1721.917300.99 Bending OH group Bending OH group1110.411000.99 Figure 4: IR spectrum for DTPA-N-MAFigure 5: IR spectrum for DTPA-N’-MA Figure 6: IR spectrum for DTPA-cs124