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Dysregulated activity of matrix metalloproteinases (MMPs) drives a variety of pathophysiological conditions. Non-invasive imaging of MMP activity  in vivo  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  in vivo . 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  in vivo . Methods Barbiturate-based MMP inhibitors with an identical targeting unit but varying hydrophilicity were synthesized, labeled with technetium-99m, and evaluated  in vitro  and  in vivo . 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.  In vivo  data were validated by scintillation counting, autoradiography, and MMP immunohistochemistry. Results We prepared three new  99m Tc‐labeled MMP inhibitors, bearing either a glycine ([ 99m Tc] MEA39 ), lysine ([ 99m Tc] MEA61 ), or the ligand HYNIC with the ionic co-ligand TPPTS ([ 99m Tc] MEA223 ) yielding gradually increasing hydrophilicity. [ 99m Tc] MEA39  and [ 99m Tc] MEA61  were rapidly eliminated via hepatobiliary pathways. In contrast, [ 99m Tc] MEA223  showed delayed  in vivo  clearance and primary renal elimination. In a thyroid tumor xenograft model, only [ 99m Tc] MEA223  exhibited a high tumor-to-blood ratio that could easily be delineated in SPECT images. Conclusion Introduction of HYNIC/TPPTS into the barbiturate lead structure ([ 99m Tc] MEA223 ) results in delayed renal elimination and allows non-invasive MMP imaging with high signal-to-noise ratios in a papillary thyroid tumor xenograft model.

Towards Optimized Bioavailability of 99mTc-Labeled Barbiturates for Non-invasive Imaging of Matrix Metalloproteinase Activity