Non-Invasive Imaging of Cysteine Cathepsin Activity in Solid Tumors Using a 64Cu-Labeled Activity-Based Probe

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 64Cu 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

Improved Approximation Guarantees for Minimum-Weight k-Trees And Prize-Collecting Salesmen

We consider a formalization of the following problem. A salesperson must sell some quota of brushes in order to win a trip to Hawaii. This salesperson has a map (a weighted graph) in which each city has an attached demand specifying the number of brushes that can be sold in that city. What is the best route to take to sell the quota while traveling the least distance possible? Notice that unlike the standard traveling salesman problem, not only do we need to figure out the order in which to visit the cities, but we must decide the more fundamental question: which cities do we want to visit? In this paper we give the first approximation algorithm having a poly-logarithmic performance guarantee for this problem, and approximate as well the slightly more general "Prize Collecting Traveling Salesman Problem" (PCTSP) of Balas, and a variation we call the "Bank-robber Problem" (also called the "Orienteering Problem" by Golden, Levi, and Vohra). We do this by providing an O(log² k) approxi..

A switchable two-photon membrane tracer capable of imaging membrane-associated protein tyrosine phosphatase activities

10.1002/anie.201205940Angewandte Chemie - International Edition521424-428ACIE