Abstract
<jats:p>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder whose prevalence is rising with the aging of the global population. Among the proposed pathological hallmarks, the amyloidbeta (Aβ) peptide aggregates and soluble Aβ oligomers are established biomarkers and remain valuable diagnostic targets. While positron emission tomography (PET) imaging agents dominate AD diagnostic imaging, there are no FDA-approved MRI agents for AD. Herein, we report five bifunctional chelators built on the 2,11-diaza[3.3](2,6)pyridinophane framework, and which were evaluated as chelators for Mn2+-based MRI contrast agents. Based on in vitro studies, including thermodynamic stability and kinetic inertness measurements, T1 relaxivity and 17O transverse relaxivity measurements to extract hydration numbers and water-exchange parameters, we obtained a clear structure-activity correlation for the corresponding bifunctional chelators: anionic 2 picolinate and acetate arms increase thermodynamic stability and kinetic inertness, while the benzothiazolyl-phenol arm accelerates water exchange. Importantly, a high hydration number alone is insufficient, as a rapid water exchange is also needed for an appreciable contrast. Moreover, we show both the bifunctional chelators and and their Mn2+ complexes exhibit appreciable affinity for Aβ aggregates, both in vitro and in 5xFAD mouse brain sections. [Mn(TE-8)], the most kinetically inert complex with favorable relaxivity, log D, and Aβ affinity, was advanced to in vivo MRI studies. Unlike MnCl2, which accumulates non-specifically, [Mn(TE-8)] cleared through renal and hepatobiliary routes and produced measurable brain contrast enhancement. Together, these results establish the diazapyridinophane scaffold as a viable firstgeneration platform for blood-brain-barrier-permeable Mn2+ MRI contrast agents.</jats:p>