Pyridinophane Ligands: An Attractive Chelator Platform for Mn-Based Imaging Agents

Magnetic resonance imaging (MRI) is a widely used diagnostic tool, yet it exhibits inherent low sensitivity that necessitates the use of contrast agents to improve the quality of MRI scans. Gadolinium-based contrast agents, and more recently manganese-based agents, have been used in pre-clinical and clinical applications due to their relaxation properties. Herein, we report a series of chelators based on the 2,11-diaza[3.3](2,6)pyridinophane macrocycle, which was chosen since its rigidity was hypothesized to favorably enhance the relaxivity of the Mn2+ complexes. The synthesized chelators were used to probe the effect of coordination number and choice of pendant arms on the efficiency of the corresponding Mn MRI contrast agents, and two lead compounds, [Mn(TE-1)]+ and [Mn(TE-4)], were identified. [Mn(TE-1)]+ has a relaxivity of 3.6 mM-1 s-1 (1.4 T, 33 ºC), comparing well to clinically established Gd-based contrast agents. By employing the 52Mn radioisotope, a positron emission tomography (PET) radiotracer, in vivo PET imaging experiments, along with T1-weighted MRI studies, reveal that [Mn(TE-4)] shows rapid clearance with significant contrast enhancement in the kidney and bladder, indicating primarily renal clearance. By comparison, the lipophilicity of [Mn(TE-1)]+ promotes a mixed, biliary-renal excretion. Importantly, both compounds show no appreciable degradation in urine metabolites. Overall, the in vivo performance of [Mn(TE-4)] lends promise to its potential development either as an MRI contrast agent or PET imaging agent. The hepatobiliary clearance of [Mn(TE-1)]+ provides opportunities for blood pool imaging via MRI, with low-temperature radiolabeling conditions compatible with a range of biologics and potential use for immuno-PET imaging.