| Summary: | A new pyclen-3,9-diacetate derivative ligand (H<sub>2</sub><b>3,9-OPC2A</b>) was synthesized possessing an etheric O-atom opposite to the pyridine ring, to improve the dissociation kinetics of its Mn(II) complex (pyclen = 3,6,9,15-tetraazabicyclo(9.3.1)pentadeca-1(15),11,13-triene). The new ligand is less basic than the N-containing analogue (H<sub>2</sub><b>3,9-PC2A</b>) due to the non-protonable O-atom. In spite of its lower basicity, the conditional stability of the [Mn(<b>3,9-OPC2A</b>)] (pMn = −log(Mn(II)), c<sub>L</sub> = c<sub>Mn(II)</sub> = 0.01 mM. pH = 7.4) remains unaffected (pMn = 8.69), compared to the [Mn(<b>3,9-PC2A</b>)] (pMn = 8.64). The [Mn(<b>3,9-OPC2A</b>)] possesses one water molecule, having a lower exchange rate with bulk solvents (<i>k</i><sub>ex</sub><sup>298</sup> = 5.3 ± 0.4 × 10<sup>7</sup> s<sup>−1</sup>) than [Mn(<b>3,9-PC2A</b>)] (<i>k</i><sub>ex</sub><sup>298</sup> = 1.26 × 10<sup>8</sup> s<sup>−1</sup>). These mild differences are rationalized by density-functional theory (DFT) calculations. The acid assisted dissociation of [Mn(<b>3,9-OPC2A</b>)] is considerably slower (<i>k</i><sub>1</sub> = 2.81 ± 0.07 M<sup>−1</sup> s<sup>−1</sup>) than that of the complexes of diacetates or bisamides of various 12-membered macrocycles and the parent H<sub>2</sub><b>3,9-PC2A</b>. The [Mn(<b>3,9-OPC2A</b>)] is inert in rat/human serum as confirmed by <sup>52</sup>Mn labeling (nM range), as well as by relaxometry (mM range). However, a 600-fold excess of EDTA (pH = 7.4) or a mixture of essential metal ions, propagated some transchelation/transmetalation in 7 days. The H<sub>2</sub><b>3,9-OPC2A</b> is labeled efficiently with <sup>52</sup>Mn at elevated temperatures, yet at 37 °C the parent H<sub>2</sub><b>3,9-PC2A</b> performs slightly better. Ultimately, the H<sub>2</sub><b>3,9-OPC2A</b> shows advantageous features for further ligand designs for bifunctional chelators.
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