Work

Singlet Oxygen-Responsive MRI Contrast Agents

Year: 2026

Type: article

Abstract: In vivo imaging detection of singlet oxygen (1O2) produced by photodynamic therapy remains a challenge. To address this unmet necessity, two Gd3+-based multicyclic magnetic resonance imaging (MRI) probes 1 and 2 were synthesized and characterized for their ability to react with 1O2 and for their relaxivity, r1, enhancement. We employed a chemical design based on capping the Gd-DOTA-chelate with two differently sized aromatic bridging moieties, benzene for 1 and naphthalene for 2, connected with secondary amine linkers. Upon exposure to 1O2, probes 1 and 2 underwent an uncapping transformation by oxidative cleavage of the benzyl/naphthylmethyl amine linker, resulting in an open form, probe 3, with r1 relaxivity changes corresponding to a 31% decrease or a 19% increase, respectively. To understand these r1 values, probes 1 and 2 were further characterized by relaxometric measurements at variable temperature and pH and 17O NMR, along with 1H NMR and luminescence of analogous Eu3+-complexes, suggesting that these relaxivity variations were the result of a complex interplay between several different factors, including the effect of second-sphere water. DFT calculations supported that probes 1–3 retain a single inner-sphere water molecule, indicating that the experimentally observed relaxivity differences did not arise from the change of coordination number but rather from steric shielding by the aromatic moiety which affects various interactions contributing to relaxivity. These results provide a mechanistic proof-of-concept and demonstrate that the oxidative cleavage of arylamines by 1O2 can promote relaxivity variations in Gd3+-complexes, representing a distinct strategy for the design of 1O2-responsive MRI contrast agents.

Source: Chemical & Biomedical Imaging

DOI: 10.1021/cbmi.6c00150