Methylated tetra‐amide derivatives of paramagnetic complexes for magnetic resonance biosensing with both BIRDS and CEST

• Published in: NMR in biomedicine 2022-06, Vol.35 (6), p.e4687-n/a
• Main Authors: Zakaria, Abul B. M., Huang, Yuegao, Coman, Daniel, Mishra, Sandeep K., Mihailovic, Jelena M., Maritim, Samuel, Rojas‐Quijano, Federico A., Jurek, Paul, Kiefer, Garry E., Hyder, Fahmeed
• Format: Article
• Language: English
• Subjects: Amides; Biological products; biosensing; Biosensing Techniques - methods; Biosensors; Birds; Chelates; Chelating Agents; Contrast Media - chemistry; Hydrophobicity; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Magnetic Resonance Spectroscopy; methyl protons; molecular imaging; paramagnetic contrast agents; pH effects; Probes; Protons; Resonance; temperature; Thulium
• ISSN: 0952-3480; 1099-1492
• DOI: 10.1002/nbm.4687

Paramagnetic agents that utilize two mechanisms to provide physiological information by magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) are described. MRI with chemical exchange saturation transfer (CEST) takes advantage of the agent's exchangeable protons (e.g., ‐OH or ‐NHx, where 2 ≥ x ≥ 1) to create pH contrast. The agent's incorporation of non‐exchangeable protons (e.g., ‐CHy, where 3 ≥ y ≥ 1) makes it possible to map tissue temperature and/or pH using an MRSI method called biosensor imaging of redundant deviation in shifts (BIRDS). Hybrid probes based upon 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetate chelate (DOTA4−) and its methylated analog (1,4,7,10‐tetraazacyclododecane‐α, α′, α″, α‴‐tetramethyl‐1,4,7,10‐tetraacetate, DOTMA4−) were synthesized, and modified to create new tetra‐amide chelates. Addition of several methyl groups per pendent arm of the symmetrical chelates, positioned proximally and distally to thulium ions (Tm3+), gave rise to favorable BIRDS properties (i.e., high signal‐to‐noise ratio (SNR) from non‐exchangeable methyl proton peaks) and CEST responsiveness (i.e., from amide exchangeable protons). Structures of the Tm3+ probes elucidate the influence of methyl group placement on sensor performance. An eight‐coordinate geometry with high symmetry was observed for the complexes: Tm‐L1 was based on DOTA4−, whereas Tm‐L2 and Tm‐L3 were based on DOTMA4−, where the latter contained an additional carboxylate at the distal end of each arm. The distance of Tm3+ from terminal methyl carbons is a key determinant for sustaining BIRDS temperature sensitivity without compromising CEST pH contrast; however, water solubility was influenced by introduction of hydrophobic methyl groups and hydrophilic carboxylate. Combined BIRDS and CEST detection of Tm‐L2, which features two high‐SNR methyl peaks and a strong amide CEST peak, should enable simultaneous temperature and pH measurements for high‐resolution molecular imaging in vivo. We synthesized three new thulium‐based methylated probes and we investigated the possibility of using them as pH and temperature sensors for dual detection with Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) and Chemical Exchange Saturation Transfer (CEST). The temperature and pH sensitivities depend on the number and position of methyl groups and the overall charge of the complex. Combining BIRDS and CEST modalities allows simultaneous temperature and pH measurements