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.