Pyridinophane Ligands: An Attractive Chelator Platform for Mn-Based Imaging Agents
Tarek El Sayed, Karna Terpstra, Jennifer Whetter, Kerui Xu, Lingyang Zhu, Sagnik Chakrabarti, Axia Marlin, Andrew Wessel, Shreyan Majumdar, Bradley P. Sutton, Eszter Boros, Liviu M. Mirica*
Manganese-based magnetic resonance imaging (MRI) contrast agents were developed using chelators derived from the 2,11-diaza[3.3](2,6)pyridinophane macrocycle to enhance Mn2+ relaxivity. The synthesized chelators were assessed to determine how coordination number and pendant arm selection affect the efficiency of the resulting Mn-based MRI contrast agents. Two compounds demonstrated significant potential: [Mn(TE-1)] exhibited relaxivity comparable to clinical gadolinium-based agents (3.6 mM–1 s–1 at 1.4 T), while [Mn(TE-4)] displayed rapid renal clearance and strong contrast enhancement in the kidney and bladder. In vivo PET imaging with 52Mn confirmed that [Mn(TE-4)] undergoes renal excretion, supporting its further development as an MRI or PET imaging agent. The lipophilic [Mn(TE-1)] exhibited both biliary and renal excretion, indicating its suitability as a blood pool MRI agent and for potential immuno-PET applications.
Sayed, T. E.; Terpstra, K.; Whetter, J.; Xu, K.; Zhu, L.; Chakrabarti, S.; Marlin, A.; Wessel, A.; Majumdar, S.; Sutton, B. P.; Boros, E.; Mirica, L. M. Pyridinophane Ligands: an attractive chelator platform for MN-Based imaging agents. Journal of Medicinal Chemistry2026, 69 (9), 10448–10462. https://doi.org/10.1021/acs.jmedchem.5c03597.
Evaluation of Anti-Alzheimer's Potential of Azo-Stilbene-Thioflavin-T derived Multifunctional Molecules: Synthesis, Metal and Aβ Species Binding and Cholinesterase Activity
Monika Rana, Karna Terpstra, Citlali Gutierrez, Kerui Xu, Hemant Arya, Tarun K. Bhatt, Liviu M. Mirica*, and Anuj K. Sharma*
Inhibition of amyloid β (Aβ) aggregation and cholinesterase activity are two major therapeutic targets for Alzheimer's disease (AD). Multifunctional Molecules (MFMs) specifically designed to address other contributing factors, such as metal ion-induced abnormalities, oxidative stress, toxic Aβ aggregates etc., are very much required. Several multifunctional molecules have been developed using different molecular scaffolds. Reported herein is a new series of four MFMs based on ThT, Azo-stilbene, and metal ion chelating pockets. The synthesis, characterization, and metal chelation ability for [Cu2+ and Zn2+] are presented herein. Furthermore, we explored their multifunctionality w.r.t. to their (i) recognition of Aβ aggregates and monomeric form, (ii) utility in modulating the aggregation pathways of both metal-free and metal-bound amyloid-β, (iii) ex vivo staining of amyloid plaques in 5xFAD mice brain sections, (iv) ability to scavenge free radicals, and (v) ability to inhibit cholinesterase activity. Molecular docking studies were also performed with Aβ peptides and acetylcholinesterase enzyme to understand the observed inhibitory effect on activity. Overall, the studies presented here establish the multifunctional nature of these molecules and qualify them as promising candidates for furthermore investigation in the quest for finding Alzheimer's disease treatment.
Rana, M.; Terpstra, K.; Gutierrez, C.; Xu, K.; Arya, H.; Bhatt, T. K.; Mirica, L. M.; Sharma, A. K. Evaluation of Anti‐Alzheimer’s Potential of Azo‐Stilbene‐Thioflavin‐T derived Multifunctional Molecules: Synthesis, Metal and Aβ Species Binding and Cholinesterase Activity. Chemistry - a European Journal 2024, 31 (2), e202402748. https://doi.org/10.1002/chem.202402748.