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

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 x 10(7) s(-1)) than [Mn(3,9-PC2A)] (k(ex)(298) = 1.26 x 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 Mn-52 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 Mn-52 at elevated temperatures, yet at 37 degrees 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.

Automated summary

A new ligand derivative was synthesized to improve the dissociation kinetics of the Mn(II) complex. The ligand exhibited lower basicity but maintained its stability. The exchange rate of the ligand was lower compared to other ligands. These differences were confirmed by calculations and experiments. Additionally, the ligand showed good stability in rat/human serum. However, under certain conditions, some ligand exchange/metal ion exchange occurred.