As Mn(II) complexes attract continuous interest as alternatives to Gd-based contrast agents (CAs) in clinical magnetic resonance imaging (MRI), we synthesized two monosubstituted derivatives of the 15-membered pyridine-based macrocycle 15-pyN3O2 bearing either a 2-pyridylmethyl (L2) or a 2-benzimidazolylmethyl pendant arm (L3) and characterized their Mn(II) complexes MnL2 and MnL3 in the context of MRI contrast agent development. Their X-ray molecular structures confirmed a coordination number of seven and a pentagonal bipyramidal geometry with one coordination site available for inner-sphere water. Protonation constants of L2 and L3, and stability constants with selected divalent metal ions were determined using potentiometry. MnL2 and MnL3 complexes are fully formed at pH 7.4; however, they both display low kinetic inertness due to a significant spontaneous dissociation of the nonprotonated complex. The presence of one inner-sphere water molecule in the Mn(II) complexes was confirmed by 17O NMR and 1H NMRD measurements. The water exchange rate constants are very low (kex298 = 0.46 × 107 and 0.23 × 107 s-1 for MnL2 and MnL3, respectively), but typical for Mn(II) complexes of 15-pyN3O2 derivatives. The relaxivities are in good agreement with monohydrated small-molecular-weight Mn(II) chelates (r1 = 2.49 and 2.77 mM-1 s-1 at 20 MHz, 25 °C, for MnL2 and MnL3, respectively).

• Publication type
• Journal Article MeSH

The five-step synthesis of a polydentate building block combining a cyclen-based macrocycle (DO3A) with N-(2-aminoethyl)propane-1,3-diamine, which are linked through the xylylen moiety as a rigid C-spacer is described. These two molecular parts were coupled by subsequent bromine atom substitution in 1,4-bis(bromomethyl)benzene. First, N-(2-aminoethyl)propane-1,3-diamine was protected by phthaloyl moieties and then it was reacted with 1,4-bis(bromomethyl)benzene to form (2-phthalimidoethyl)(3-phthalimido-prop-1-yl)(4-bromomethylbenzyl)amine (2). This compound underwent a substitution reaction with DO3A in the form of its tert-butyl esters leading to the intermediate 1-{4-[(2-phthalimidoethyl)(3-phthalimidoprop-1-yl)aminomethyl]phenylmethyl}-4,7,10-tris(t-butoxy-carbonylmethyl)-1,4,7,10-tetraazacyclododecane (3). The phthaloyl as well as the t-butyl protecting groups were removed in the next two reaction steps to form the final product 1-{4-[(2-aminoethyl)(3-aminoprop-1-yl)aminomethyl]phenylmethyl}-4,7,10-tris(carboxy-methyl)-1,4,7,10-tetraazacyclododecane (5). The intermediates 1-4 as well as the final product 5 were characterized by elemental analysis, mass spectrometry, and multinuclear (1H and 13C) and two-dimensional NMR spectroscopy. The final product 5 could serve as a potential building block in subsequent syntheses of binuclear complexes of lanthanides and/or transition metals.

• MeSH
• Heterocyclic Compounds, 1-Ring chemistry   MeSH
• Heterocyclic Compounds chemical synthesis   chemistry   MeSH
• Mass Spectrometry MeSH
• Magnetic Resonance Spectroscopy MeSH
• Polyamines chemistry   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid MeSH Browser
• Heterocyclic Compounds, 1-Ring MeSH
• Heterocyclic Compounds MeSH
• Polyamines MeSH