Expanding the Ligand Classes Used for Mn(II) Complexation: Oxa-aza Macrocycles Make the Difference

Abstract

We report two macrocyclic ligands based on a 1,7-diaza-12-crown-4 platform functionalized with acetate (tO2DO2A2−) or piperidineacetamide (tO2DO2AMPip) pendant arms and a detailed characterization of the corresponding Mn(II) complexes. The X−ray structure of [Mn(tO2DO2A)(H2O)]·2H2O shows that the metal ion is coordinated by six donor atoms of the macrocyclic ligand and one water molecule, to result in seven-coordination. The Cu(II) analogue presents a distorted octahedral coordination environment. The protonation constants of the ligands and the stability constants of the complexes formed with Mn(II) and other biologically relevant metal ions (Mg(II), Ca(II), Cu(II) and Zn(II)) were determined using potentiometric titrations (I = 0.15 M NaCl, T = 25 °C). The conditional stabilities of Mn(II) complexes at pH 7.4 are comparable to those reported for the cyclen-based tDO2A2− ligand. The dissociation of the Mn(II) chelates were investigated by evaluating the rate constants of metal exchange reactions with Cu(II) under acidic conditions (I = 0.15 M NaCl, T = 25 °C). Dissociation of the [Mn(tO2DO2A)(H2O)] complex occurs through both proton− and metal−assisted pathways, while the [Mn(tO2DO2AMPip)(H2O)] analogue dissociates through spontaneous and proton-assisted mechanisms. The Mn(II) complex of tO2DO2A2− is remarkably inert with respect to its dissociation, while the amide analogue is significantly more labile. The presence of a water molecule coordinated to Mn(II) imparts relatively high relaxivities to the complexes. The parameters determining this key property were investigated using 17O NMR (Nuclear Magnetic Resonance) transverse relaxation rates and 1H nuclear magnetic relaxation dispersion (NMRD) profiles.

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

“…This correlates well with the structural difference of the ligand (i.e., the replacement of the secondary amino group by an ether -O-atom), which can affect the number and the exchange rate of the coordinated water (see later, the Section dealing with the 17 O and NMRD measurements). Similar relaxivity improvement has been previously observed, when applying similar modifications to the structurally related cyclen-based [Mn(1,7-DO2A)] (which does not possess a metal-bound water molecule [12]), while the [Mn(1,7-O2DO2A)] complex possesses a metal-bound water molecule [20].…”

“…Based on these values, the H 2 3,9-OPC2A ligand possesses the lowest basicity (considering the sum log K 1 H + log K 2 H , although H 2 3,9-OPC2A and its analogs possess more protonation constants). A similar decrease in the protonation constants/ligand basicity has been evidenced for the H 2 1,7-DO2A derivative H 2 1,7-O2DO2A ligand, and was rationalized by the replacement of two nitrogen donor atoms in the cyclen backbone for oxygen atoms [20]. The overall basicity of the series of structurally related ligands follows the trend H 2 1,7-DO2A > H 2 1,4-DO2A > H 2 3,6-PC2A > H 2 3,9-PC2A > H 2 1,7-O2DO2A ≈ H 2 3,9-OPC2A.…”

“…It is achieved by the replacement of one amine nitrogen in the macrocycle for an etheric oxygen atom. This structural modification can also positively affect the hydration number of the Mn(II) ion in the complexes, in a similar manner that was observed for the diacetate of 1,4-diaza-7-oxacyclononane (9-membered 1,4,7-triazacyclononane derivative ligand), or for [Mn(1,7-O2DO2A)] in relation to [Mn(1,7-DO2A)]-the former complex possesses one metal ion bound water molecule, while none are present in [Mn(1,7-DO2A)] (Figure 1) [20,21].…”

“…The given value is similar to that of macrocyclic Mn(II) complexes possessing 0.9 [(Mn(1,4-DO2A)]), i.e., one coordinated water molecule (q = 1) in their inner coordination sphere (i.g. [Mn(3,6-PC2A)], [Mn(3,9-PC2A)], or [Mn(1,7-O2DO2A]), and they were higher than the relaxivity of complexes with q = 0 (typically 1.4-1.6 mM −1 s −1 as observed for [Mn(DO3A)] − or [Mn(PCTA)] − [12,16,20,21]. Lowering the pH below pH = 4.0, resulted in a sharp relaxivity increase, reaching the r 1p value of 6.51 mM −1 s −1 (at 1.41 T and 25 • C) near pH = 1.8.…”

“…The pyclen macrocycle and its derivatives (triacetate derivative H 3 PCTA, for instance) exhibit a rather unique protonation sequence: the first protonation occurs at the nitrogen atom positioned trans to the pyridine ring, while, during the second protonation step (involving one cis-N-atom), the first proton shifts to the second cis-nitrogen atom for a better charge separation [29]. Therefore, the replacement of the amine -NHgroup by an etheric -O-atom is expected to affect not only the protonation constant values (as it is observed on going form H 2 1,7-DO2A ligand towards the H 2 1,7-O2DO2A chelator), but the protonation sequence as well, since the most basic N-atom of the pyclen is missing in O-pyclen [20]. As it can be seen from the data presented in Table 2, the highest protonation constant for the H 2 3,9-OPC2A ligand is log K 1 H = 7.73, while the second protonation can be characterized by a nearly identical constant (log K 2 H = 7.66).…”