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However, many existing CEST MRI agents exhibit a sensitivity limitation due to small chemical shifts between their exchangeable protons and water. We propose a new group of CEST MRI agents, free\u2010base porphyrins and chlorin, with large exchangeable proton chemical shifts from water for enhanced detection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To test these newly identified CEST agents, we acquired a series of Z\u2010spectra at multiple pH values and saturation field strengths to determine their CEST properties. The data were analyzed using the quantifying exchange using saturation power method to quantify exchange rates. After identifying several promising candidates, a porphyrin solution was injected into tumor\u2010bearing mice, and MR images were acquired to assess detection feasibility in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Based on the Z\u2010spectra, the inner nitrogen protons in free\u2010base porphyrins and chlorin resonate from \u22128 to \u221213.5 ppm from water, far shifted from the majority of endogenous metabolites (0\u20104 ppm) and Nuclear Overhauser enhancements (\u22121 to \u22123.5 ppm) and far removed from the salicylates, imidazoles, and anthranillates (5\u201012 ppm). The exchange rates are sufficiently slow to intermediate (500\u20109000 s<jats:sup>\u22121<\/jats:sup>) to allow robust detection and were sensitive to substituents on the porphyrin ring.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results highlight the capabilities of free\u2010base porphyrins and chlorin as highly upfield CEST MRI agents and provide a new scaffold that can be integrated into a variety of diagnostic or theranostic agents for biomedical applications.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mrm.27753","type":"journal-article","created":{"date-parts":[[2019,4,10]],"date-time":"2019-04-10T07:06:23Z","timestamp":1554879983000},"page":"577-585","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Free\u2010base porphyrins as CEST MRI contrast agents with highly upfield shifted labile 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