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Non-invasive imaging of MMP activity <jats:italic>in vivo<\/jats:italic> promises diagnostic and prognostic value. However, current targeting strategies by small molecules are typically limited with respect to the bioavailability of the labeled MMP binders <jats:italic>in vivo<\/jats:italic>. To this end, we here introduce and compare three chemical modifications of a recently developed barbiturate-based radiotracer with respect to bioavailability and potential to image MMP activity <jats:italic>in vivo<\/jats:italic>.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Barbiturate-based MMP inhibitors with an identical targeting unit but varying hydrophilicity were synthesized, labeled with technetium-99m, and evaluated <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Biodistribution and radiotracer elimination were determined in C57\/BL6 mice by serial SPECT imaging. MMP activity was imaged in a MMP-positive subcutaneous xenograft model of human K1 papillary thyroid tumors. <jats:italic>In vivo<\/jats:italic> data were validated by scintillation counting, autoradiography, and MMP immunohistochemistry.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We prepared three new <jats:sup>99m<\/jats:sup>Tc\u2010labeled MMP inhibitors, bearing either a glycine ([<jats:sup>99m<\/jats:sup>Tc]<jats:bold>MEA39<\/jats:bold>), lysine ([<jats:sup>99m<\/jats:sup>Tc]<jats:bold>MEA61<\/jats:bold>), or the ligand HYNIC with the ionic co-ligand TPPTS ([<jats:sup>99m<\/jats:sup>Tc]<jats:bold>MEA223<\/jats:bold>) yielding gradually increasing hydrophilicity. [<jats:sup>99m<\/jats:sup>Tc]<jats:bold>MEA39<\/jats:bold> and [<jats:sup>99m<\/jats:sup>Tc]<jats:bold>MEA61<\/jats:bold> were rapidly eliminated via hepatobiliary pathways. In contrast, [<jats:sup>99m<\/jats:sup>Tc]<jats:bold>MEA223<\/jats:bold> showed delayed <jats:italic>in vivo<\/jats:italic> clearance and primary renal elimination. In a thyroid tumor xenograft model, only [<jats:sup>99m<\/jats:sup>Tc]<jats:bold>MEA223<\/jats:bold> exhibited a high tumor-to-blood ratio that could easily be delineated in SPECT images.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Introduction of HYNIC\/TPPTS into the barbiturate lead structure ([<jats:sup>99m<\/jats:sup>Tc]<jats:bold>MEA223<\/jats:bold>) results in delayed renal elimination and allows non-invasive MMP imaging with high signal-to-noise ratios in a papillary thyroid tumor xenograft model.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s11307-021-01668-z","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T18:02:46Z","timestamp":1636394566000},"page":"434-443","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Towards Optimized Bioavailability of 99mTc-Labeled Barbiturates for Non-invasive Imaging of Matrix Metalloproteinase Activity"],"prefix":"10.1007","volume":"24","author":[{"given":"Lisa","family":"Honold","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"Austrup","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Faust","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian Paul","family":"Konken","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin","family":"Schwegmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bastian","family":"Zinnhardt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Constantin Gabriel","family":"Daniliuc","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00fcnter","family":"Haufe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Sch\u00e4fers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus","family":"Kopka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sven","family":"Hermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,11,8]]},"reference":[{"key":"1668_CR1","doi-asserted-by":"publisher","unstructured":"Gomis-R\u00fcth FX, Botelho TO, Bode W (2012) A standard orientation for metallopeptidases. 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