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      A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals : A catalyCEST MRI contrast agent that detects cathepsin B activity

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          Substrate profiling of cysteine proteases using a combinatorial peptide library identifies functionally unique specificities.

          The substrate specificities of papain-like cysteine proteases (clan CA, family C1) papain, bromelain, and human cathepsins L, V, K, S, F, B, and five proteases of parasitic origin were studied using a completely diversified positional scanning synthetic combinatorial library. A bifunctional coumarin fluorophore was used that facilitated synthesis of the library and individual peptide substrates. The library has a total of 160,000 tetrapeptide substrate sequences completely randomizing each of the P1, P2, P3, and P4 positions with 20 amino acids. A microtiter plate assay format permitted a rapid determination of the specificity profile of each enzyme. Individual peptide substrates were then synthesized and tested for a quantitative determination of the specificity of the human cathepsins. Despite the conserved three-dimensional structure and similar substrate specificity of the enzymes studied, distinct amino acid preferences that differentiate each enzyme were identified. The specificities of cathepsins K and S partially match the cleavage site sequences in their physiological substrates. Capitalizing on its unique preference for proline and glycine at the P2 and P3 positions, respectively, selective substrates and a substrate-based inhibitor were developed for cathepsin K. A cluster analysis of the proteases based on the complete specificity profile provided a functional characterization distinct from standard sequence analysis. This approach provides useful information for developing selective chemical probes to study protease-related pathologies and physiologies.
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            Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis.

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              Numerical solution of the Bloch equations provides insights into the optimum design of PARACEST agents for MRI.

              Paramagnetic lanthanide complexes that display unusually slow water exchange between an inner sphere coordination site and bulk water may serve as a new class of MRI contrast agents with the use of chemical exchange saturation transfer (CEST) techniques. To aid in the design of paramagnetic CEST agents for reporting important biological indices in MRI measurements, we formulated a theoretical framework based on the modified Bloch equations that relates the chemical properties of a CEST agent (e.g., water exchange rates and bound water chemical shifts) and various NMR parameters (e.g., relaxation rates and applied B(1) field) to the measured CEST effect. Numerical solutions of this formulation for complex exchanging systems were readily obtained without algebraic manipulation or simplification. For paramagnetic CEST agents of the type used here, the CEST effect is relatively insensitive to the bound proton relaxation times, but requires a sufficiently large applied B(1) field to highly saturate the Ln(3+)-bound water protons. This in turn requires paramagnetic complexes with large Ln(3+)-bound water chemical shifts to avoid direct excitation of the exchanging bulk water protons. Although increasing the exchange rate of the bound protons enhances the CEST effect, this also causes exchange broadening and increases the B(1) required for saturation. For a given B(1), there is an optimal exchange rate that results in a maximal CEST effect. This numerical approach, which was formulated for a three-pool case, was incorporated into a MATLAB nonlinear least-square optimization routine, and the results were in excellent agreement with experimental Z-spectra obtained with an aqueous solution of a paramagnetic CEST agent containing two different types of bound protons (bound water and amide protons). Copyright 2005 Wiley-Liss, Inc.
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                Author and article information

                Journal
                Contrast Media & Molecular Imaging
                Contrast Media Mol. Imaging
                Wiley
                15554309
                March 2016
                March 2016
                December 03 2015
                : 11
                : 2
                : 130-138
                Affiliations
                [1 ]Department of Chemistry and Biochemistry; University of Arizona; Tucson AZ USA
                [2 ]Department of Surgery; University of California, San Diego; 9500 Gilman Dr, George Palade 310 La Jolla CA 92093-0647 USA
                [3 ]Department of Medical Imaging; University of Arizona; Tucson AZ USA
                [4 ]University of Arizona Cancer Center; 1515 N Campbell Ave. Tucson AZ 85724-5024 USA
                Article
                10.1002/cmmi.1672
                26633584
                db6cdf65-15a1-4a81-a2b4-479cb55381be
                © 2015

                http://doi.wiley.com/10.1002/tdm_license_1.1

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