A New Oxygen Containing Pyclen-Type Ligand as a Manganese(II) Binder for MRI and (52)Mn PET Applications: Equilibrium, Kinetic, Relaxometric, Structural and Radiochemical Studies

A new pyclen-3,9-diacetate derivative ligand (H(2)3,9-OPC2A) 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(2)3,9-PC2A) due to the non-protonable O-atom. In spite of its lower basicity, the conditional stability of the [Mn(3,9-OPC2A)] (pMn = −log(Mn(II)), c(L) = c(Mn(II)) = 0.01 mM. pH = 7.4) remains unaffected (pMn = 8.69), compared to the [Mn(3,9-PC2A)] (pMn = 8.64). The [Mn(3,9-OPC2A)] possesses one water molecule, having a lower exchange rate with bulk solvents (k(ex)(298) = 5.3 ± 0.4 × 10(7) s(−1)) than [Mn(3,9-PC2A)] (k(ex)(298) = 1.26 × 10(8) s(−1)). These mild differences are rationalized by density-functional theory (DFT) calculations. The acid assisted dissociation of [Mn(3,9-OPC2A)] is considerably slower (k(1) = 2.81 ± 0.07 M(−1) s(−1)) than that of the complexes of diacetates or bisamides of various 12-membered macrocycles and the parent H(2)3,9-PC2A. The [Mn(3,9-OPC2A)] is inert in rat/human serum as confirmed by (52)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(2)3,9-OPC2A is labeled efficiently with (52)Mn at elevated temperatures, yet at 37 °C the parent H(2)3,9-PC2A performs slightly better. Ultimately, the H(2)3,9-OPC2A shows advantageous features for further ligand designs for bifunctional chelators.