Towards Metabolic Organic Radical Contrast Agents (mORCAs) for Magnetic Resonance Imaging
2025
Shuyang Zhang | Sabina Dhakal | Evan Curtis | Hunter Miller | Joseph T. Paletta | Connor Gee | Suchada Rajca | Forrest Kievit | Andrzej Rajca
We report two conjugates of gem-diethyl pyrroline nitroxide radicals with D-mannosamine as potential metabolic organic radical contrast agents, mORCAs, circumventing the need for biorthogonal reactions. In-cell EPR spectroscopy, using Jurkat cells and analogous conjugate, based on a pyrrolidine nitroxide radical, shows an efficient incorporation of highly immobilized nitroxides, with a correlation time of &tau:cor = 20 ns. In vivo MRI experiments in mice show that the paramagnetic nitroxide radical shortens the T1 and T2 relaxation times of protons in water located in the kidney and brain by only up to ~10% after 3 d. Ex vivo EPR spectroscopic analyses indicate that the contrast agents in mouse tissues are primarily localized in the kidney, lung, liver, heart, and blood, which primarily contain immobilized nitroxide radicals with &tau:cor = 4&ndash:9 ns. The spin concentrations in tissues remain low (1&ndash:3 nmol g⁻:1) at 24 h after the third mORCA injection, approximately one to two orders of magnitude lower than those of ORCAFluor and BASP-ORCA (measured at ~24 h post-injection). These low spin concentrations explain the small proton T1 and T2 relaxation changes observed in in vivo MRI.
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