title: A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals.
abstract: CatalyCEST MRI can detect enzyme activity by monitoring the change in chemical exchange with water after a contrast agent is cleaved by an enzyme. Often these molecules use paramagnetic metals and are delivered with an additional non-responsive reference molecule. To improve this approach for molecular imaging, a single diamagnetic agent with enzyme-responsive and enzyme-unresponsive CEST signals was synthesized and characterized. The CEST signal from the aryl amide disappeared after cleavage of a dipeptidyl ligand with cathepsin B, while a salicylic acid moiety was largely unresponsive to enzyme activity. The ratiometric comparison of the two CEST signals from the same agent allowed for concentration independent measurements of enzyme activity. The chemical exchange rate of the salicylic acid moiety was unchanged after enzyme catalysis, which further validated that this moiety was enzyme-unresponsive. The temperature dependence of the chemical exchange rate of the salicylic acid moiety was non-Arrhenius, suggesting a two-step chemical exchange mechanism for salicylic acid. The good detection sensitivity at low saturation power facilitates clinical translation, along with the potentially low toxicity of a non-metallic MRI contrast agent. The modular design of the agent constitutes a platform technology that expands the variety of agents that may be employed by catalyCEST MRI for molecular imaging.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.|Department of Surgery, University of California, San Diego, 9500 Gilman Dr, George Palade 310, La Jolla, CA, 92093-0647, USA.
authors.forename: Dina V
authors.initials: DV
authors.lastname: Hingorani
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Montano
authors.affiliation: Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Randtke
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.
authors.forename: Yeon Sun
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.
authors.forename: Julio
authors.initials: J
authors.lastname: Cárdenas-Rodríguez
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.|Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.|University of Arizona Cancer Center, 1515 N Campbell Ave., Tucson, AZ, 85724-5024, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pagel
mesh_terms: D000577:Amides / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D002384:Catalysis; D002401:Cathepsin B / Q000737:chemistry / Q000302:isolation & purification*; D003287:Contrast Media / Q000737:chemistry*; D008024:Ligands; D008279:Magnetic Resonance Imaging / Q000379:methods*; D057054:Molecular Imaging / Q000379:methods*; D014867:Water / Q000737:chemistry
chemical_list: D000577:Amides; D000588:Amines; D003287:Contrast Media; D008024:Ligands; D014867:Water; D002401:Cathepsin B
keywords: CEST MRI; cathepsin B; enzyme activity; ratiometric analysis