TY - JOUR
TI - Synthesis and in Vitro and in Vivo Evaluation of MMP-12 Selective Optical Probes
AU - Bordenave, T.
AU - Helle, M.
AU - Beau, F.
AU - Georgiadis, D.
AU - Tepshi, L.
AU - Bernes, M.
AU - Ye, Y.
AU - Levenez, L.
AU - Poquet, E.
AU - Nozach, H.
AU - Razavian, M.
AU - Toczek, J.
AU - Stura, E.A.
AU - Dive, V.
AU - Sadeghi, M.M.
AU - Devel, L.
JO - Bioconjugate Chemistry
PY - 2016
VL - 27
TODO - 10
SP - 2407-2417
PB - American Chemical Society
SN - 1043-1802, 1520-4812
TODO - 10.1021/acs.bioconjchem.6b00377
TODO - Blood;  Crystal structure;  Fluorescence, Clearance rates;  Dye moieties;  Fluorescent tracers;  In-vitro;  In-vivo;  Optical probe;  Performance;  Structures and properties;  Vitro and in vivo;  Vivo evaluation, Probes, cyanine dye;  macrophage elastase;  tracer;  carbocyanine;  CY5.5 cyanine dye;  macrophage elastase;  peptide;  RXP470.1 peptide, animal experiment;  Article;  binding affinity;  chemical structure;  conjugate;  crystal structure;  crystallization;  HeLa cell line;  human;  human cell;  hydrophilicity;  in vitro study;  in vivo study;  molecular probe;  mouse;  nonhuman;  plasma clearance;  process optimization;  Suzuki reaction;  synthesis;  animal;  C57BL mouse;  chemistry;  metabolism;  molecular imaging;  molecular probe;  optics;  pharmacokinetics;  procedures;  synthesis;  tissue distribution;  X ray crystallography, Animals;  Carbocyanines;  Chemistry Techniques, Synthetic;  Crystallography, X-Ray;  HeLa Cells;  Humans;  Matrix Metalloproteinase 12;  Mice, Inbred C57BL;  Molecular Imaging;  Molecular Probes;  Optics and Photonics;  Peptides;  Tissue Distribution
TODO - In designing new tracers consisting of a small peptide conjugated to a reporter of comparable size, particular attention needs to be paid to the selection of the reporter group, which can dictate both the in vitro and the in vivo performances of the whole conjugate. In the case of fluorescent tracers, this is particularly true given the large numbers of available dye moieties differing in their structures and properties. Here, we have investigated the in vitro and in vivo properties of a novel series of MMP-12 selective probes composed of cyanine dyes varying in their structure, net charge, and hydrophilic character, tethered through a linker to a potent and specific MMP-12 phosphinic pseudopeptide inhibitor. The impact of linker length has been also explored. The crystallographic structure of one tracer in complex with MMP-12 has been obtained, providing the first crystal structure of a Cy5.5-derived probe and confirming that the binding of the targeting moiety is unaffected. MMP-12 remains the tracers' privileged target, as attested by their affinity selectivity profile evaluated in solution toward a panel of 12 metalloproteases. In vivo assessment of four selected probes has highlighted not only the impact of the dye structure but also that of the linker length on the probes' blood clearance rates and their biodistributions. These experiments have also provided valuable data on the stability of the dye moieties in vivo. This has permitted the identification of one probe, which combines favorable binding to MMP-12 in solution and on cells with optimized in vivo performance including blood clearance rate suitable for short-time imaging. Through this series of tracers, we have identified various critical factors modulating the tracers' in vivo behavior, which is both useful for the development and optimization of MMP-12 selective radiolabeled tracers and informative for the design of fluorescent probes in general. © 2016 American Chemical Society.
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