The U.S. Food and Drug Administration (FDA) has issued a boxed warning and mandated additional safety measures for all gadolinium-based contrast agents (GBCAs) used in clinical magnetic resonance imaging (MRI) due to their prolonged retention in the body and associated adverse health effects. This review explores recent advancements in CAs for MRI, highlighting four innovative probes: ORCAs, CEST CAs, F CAs, and HP C MRI. ORCAs offer a metal-free alternative that enhances imaging through nitroxides. CEST MRI facilitates the direct detection of specific molecules via proton exchange, aiding in disease diagnosis and metabolic assessment. F MRI CAs identify subtle biological changes, enabling earlier detection and tailored treatment approaches. HP C MRI improves visualization of metabolic processes, demonstrating potential in cancer diagnosis and monitoring. Finally, this review concludes by addressing the challenges facing the field and outlining future research directions, with a particular focus on leveraging artificial intelligence to enhance diagnostic capabilities and optimize both the performance and safety profiles of these innovative CAs. STATEMENT OF SIGNIFICANCE: The review addresses the urgent need for safer MRI contrast agents in light of FDA warnings about gadolinium-based agents. It highlights the key factors influencing the stability and functionality of nitroxide radicals (ORCA) and recent advancements in designing nitroxide-functionalized materials that enhance MRI contrast. It also explores the potential of these agents for multimodal imaging and targeted diagnostics while outlining future research directions and the integration of artificial intelligence to optimize their clinical application and safety.
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