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

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