Synthesis and characterization of a stable and inert MnII-based ZnII responsive MRI probe for molecular imaging of glucose stimulated zinc secretion (GSZS)

Abstract

A new potential Zn^II responsive Mn^II-based MRI CA candidate derived from pyclen-3,9-diacetate (3,9-PC2A) has been synthesized and it possesses a di-(2-picolyl)amine (DPA) moiety as an active arm. The PC2A-DPA ligand was found to form a thermodynamically stable complex with Mn^II (log K_MnL = 15.87(6) which translates into a pMn of 8.79) which also possesses outstanding inertness towards Zn^II ion triggered transmetallation (t_1/2 at pH = 6.0 is 64.5 h). The [Mn(PC2A-DPA)] complex has a relatively high relaxation rate (3.11 s⁻¹ at 1.41 T and 37 °C for a 0.96 mM complex) which is not affected by the Zn^II concentration directly, yet in the co-presence of 0.7 mM human serum albumin (HSA) the relaxation rate values (both R₁ and R₂) increased significantly (9.08 s⁻¹ at 1.41 T and 37 °C, for a 0.748 mM complex) owing to the efficient binding of the complex to the protein (log K_aff = 3.5 ± 0.1 M⁻¹). The increase is large enough to visualize it by MR imaging using phantoms in vitro while preliminary in vivo MRI experiments confirmed that the glucose stimulated Zn^II secretion (GSZS) can be visualized in the prostate of a healthy mouse.