Development of Lanthanide metal complxes as contrast agents for magnetic resonance imaging (MRI).

摘要

This work describes work related to the search for new and improved MRI contrast agents. It isuda focused study that describes the synthesis and characterization of three novel macrocyclicudligands, two of which incorporates a pendant β-amino alcohol (cyclohexyl) arm for complexationudwith Eu3+ and Gd3+. The target products were synthesized successfully in quantitatively highudyields and confirmed using general analytical characterization techniques including NMR, ESIMS,udFTIR and in some cases X-ray crystallography.udCrystal structures of two of the N-substituted cyclen based ligands, namely molecules 2 and 3 areudreported. They both formed in the monoclinic crystal system and found to be in the P21/c andudP21/n space group, respectively. Although 2 crystallized as a free base, 3 formed a complex withudsodium with iodide as a counter ion. In addition, three lanthanide crystal structures are reportedudand each adopts a distorted capped square anitiprismatic geometry. Molecule 2 formed crystalsudwith both Eu3+ and Gd3+ to give molecule 5 and 6, respectively. They both formed in theudtriclinic and orthorhombic crystal system and found to be in the P-1 and Pcca space group,udrespectively. Efforts to grow lanthanide crystals with 7 failed, however its Eu3+ complex wasudsatisfactorily synthesized. For comparative purposes molecule 9 was synthesized and the crystaludstructure is reported.udIn an effort to elucidate the solution structure of these new Eu3+ complexes in the absence andudpresence of KHP, their interaction with the metal center and ligand were studied further usingudluminescence and UV-visible analyses to determine pKas spectroscopically. Comparing the pKaudfor the hydrolysis of water in 5 and 9 in MCB with KHP, it was observed that the pKa for 5 isudlarger. This increase is attributed to the compression induced by the cyclohexyl moiety whichudconsequently causes an overall decrease in bond distance between the metal center and amidicudoxygen donors as shown in the solid-state data. Furthermore, the hydrophobic nature of theudcyclohexyl side arm which replaces one of the acetamide arms in 9 also contributes to the overalluddecrease in pKa observed. Comparing the pKa for the hydrolysis of water in 5 and 7 in MCBudexcluding KHP, again it was observed that the pKa for 5 is larger. The coordinated water in 5 appears to be more acidic than for 7, possibly due to the weaker inductive effect of 7 whichudpossess arms that are of a sp3 nature and impossible to deprotonate.udIn addition, the number of coordinated water molecules (q) to the metal center were determinedudusing luminescent lifetime measurements and corrected for the estimation according to structuraludfunctionalities innate to the complexes in this study. In solution, the q values obtained agreedudwell with the proposition that the phthalate moiety coordinates with the central Eu3+ ion in audunidentate fashion and maintains a nine coordination number. The q values also agree withudluminescent spectroscopic data which shows two valid spectroscopic pKas; the deprotonation ofudthe phthalate carboxylate and the deprotonation of the water molecule coordinated to the metaludcenter. The mean pKa values were found to be pK1 = 4.67 ± 0.06 and pK2 = 8.69 ± 0.12,udrespectively. The q values obtained for 5 in MCB with KHP from pH 4.710 and 9.484 rangedudfrom 1.77 to 0.70 using Equation 3.1 and from 1.79 to 0.72 using Equation 3.2, respectively. Itudis proposed that the due to the coordination of the phthalate moiety the hydroxyl group of theudcyclohexyl moiety no longer coordinates itself to the metal center. The q values obtained for 5 inudwater from pH 4.375 and 8.645 ranged from 0.94 to 0.55 using Equation 3.1 and from 0.95 toud0.56 using Equation 3.2, respectively. The slight increase in the q value is attributed to theudhydrogen bonding the cyclohexyl group is involved in with water molecules in the secondudcoordination sphere which is very close to 0.5.udFinally, the electrochemical behavior of complex 5 and 9 across the pH range were investigatedudusing CV. Only a single electrochemically active species exists for both complexes. The resultsudfor 5 show that the metal is encapsulated between pH 3 to 10 (E1/2 = -0.83 V), however above pHud11 the complex is demetalated (E1/2 = -1.02 V). The results for 9 show that the metal isudencapsulated between pH 3 to 10 (E1/2 = -0.83 V), however below pH 11 the complex shows auddecrease in overall current (E1/2 = -0.90 V). This result shows that complex 9 is more resistant toudoxidation as compared to complex 5, meaning that having four acetamide arms at higher pH isudbetter than having three. This difference can also be related to the role and tautomeric effect ofudthe amidic arms in stabilizing the complex. In addition, the standard rate constant wasuddetermined for electron transfer and is close to 1.0 for both complexes investigated, which meansudthe reductions in both complexes are not diffusion controlled but the electrochemically active species are adsorbed on the electrode surface. The above electrochemical results show that theudmetal remains encapsulated for most of the pH range and only becomes toxic free metal aboveudpH 11. This vast pH range of complex intactness is a favorable attribute if it were to beudconsidered in its application as a potential MRI agent.udKey words: MRI, europium(III), gadolinium(III), polyazamacrocycles, luminescence, cyclicudvoltammetry, MRI contrast agent.