The Synthesis and Characterization of a Series of Novel Macrocyclic and Picolylamine Manganese(II) Complexes for Use as Potential MRI Contrast Agents

<p>The synthesis and characterization of two distinct sets of Manganese(II) based magnetic resonance imaging (MRI) contrast agents (CAs) are reported. The first set is comprised of a series of cyclen-based derivatives. Included in this series is a new, mixed pendant-arm macrocyclic ligand, 1,4,7,10-tetraazacyclododecane-1,7-bis(acetate)-4,10-bis(acetamide). HXDO2A(X-2)+, HXDO2AMX+, HXDO2A2AM(X-2)+ and their Mn(II) derivatives are characterized by solution state infrared spectroscopy. Full crystallographic details are reported for [Mn(DO2AM)(H2O)](Cl1.34)(Br0.66)·2H2O (triclinic, <em>P</em>1 ; <em>a</em>=7.68140(10), <em>b</em>=8.80980(10),<em> c</em>=16.6027(2) Å; <em>α</em>=103.7880(10)˚, <em>β</em>=97.2190(10)˚, <em>γ</em>=100.9880(10)˚; Z=2) and [Mn(DO2A2AM)](NH4Cl)·3.5H2O (triclinic, <em>P</em>1 ; <em>a</em>=8.4976(5), <em>b</em>=9.5396(2), <em>c</em>=15.6492(8) Å;<em> α</em>=94.139(3)˚, <em>β</em>=103.306(5)˚, <em>γ</em>=90.393(3)˚; Z=2), which are seven- and six-coordinate, respectively. Binding constants for five macrocyclic Mn(II) complexes are reported at 37˚C, along with pH dependent <em>r</em>1 relaxivity measurements. Finally, a temperature dependent study of the 17O transverse relaxivity of the three complexes is used to determine the number of bound waters (<em>q</em>) in each complex: [Mn(HXDO2A)]X+ (<em>q</em>=0), [Mn(DO2AM)]2+ (<em>q</em>=1), and [Mn(HXDO2A2AM)]X+ (<em>q</em>=0).</p> <p>The second set is comprised of two tris-pyridine amine carboxylic acid derivatives. The synthesis of the two ligands, TPAMA and TPADA, is reported. p<em>K</em>a values for the ligands and binding constants for their Mn(II) complexes are determined by potentiometry at 37˚C. The pH dependent relaxivity profiles are reported and <em>r</em>1 values at physiological pH are compared with other pyridine derived Mn(II) complexes.</p>