title: Non-invasive imaging of cysteine cathepsin activity in solid tumors using a 64Cu-labeled activity-based probe.
abstract: The papain family of cysteine cathepsins are actively involved in multiple stages of tumorigenesis. Because elevated cathepsin activity can be found in many types of human cancers, they are promising biomarkers that can be used to target radiological contrast agents for tumor detection. However, currently there are no radiological imaging agents available for these important molecular targets. We report here the development of positron emission tomography (PET) radionuclide-labeled probes that target the cysteine cathepsins by formation of an enzyme activity-dependent bond with the active site cysteine. These probes contain an acyloxymethyl ketone (AOMK) functional group that irreversibly labels the active site cysteine of papain family proteases attached to a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) tag for labeling with (64)Cu for PET imaging studies. We performed biodistribution and microPET imaging studies in nude mice bearing subcutaneous tumors expressing various levels of cysteine cathepsin activity and found that the extent of probe uptake by tumors correlated with overall protease activity as measured by biochemical methods. Furthermore, probe signals could be reduced by pre-treatment with a general cathepsin inhibitor. We also found that inclusion of a Cy5 tag on the probe increased tumor uptake relative to probes lacking this fluorogenic dye. Overall, these results demonstrate that small molecule activity-based probes carrying radio-tracers can be used to image protease activity in living subjects.
authors: Molecular Imaging Program at Stanford, Stanford University, Stanford, California, United States of America.
authors: Gang
authors: G
authors: Ren
authors: Galia
authors: G
authors: Blum
authors: Martijn
authors: M
authors: Verdoes
authors: Hongguang
authors: H
authors: Liu
authors: Salahuddin
authors: S
authors: Syed
authors: Laura E
authors: LE
authors: Edgington
authors: Olivier
authors: O
authors: Gheysens
authors: Zheng
authors: Z
authors: Miao
authors: Han
authors: H
authors: Jiang
authors: Sanjiv Sam
authors: SS
authors: Gambhir
authors: Matthew
authors: M
authors: Bogyo
authors: Zhen
authors: Z
authors: Cheng
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes; D003545:Cysteine / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D015335:Molecular Probes / Q000737:chemistry / Q000378:metabolism*; D009369:Neoplasms / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography / Q000379:methods*; D013194:Staining and Labeling; D014018:Tissue Distribution
chemical_list: D003301:Copper Radioisotopes; D015335:Molecular Probes; D002403:Cathepsins; D003545:Cysteine