Preclinical evaluation of [11C]L‐235 as a radioligand for Positron Emission Tomography cathepsin K imaging in bone. (2nd December 2020) - Bennacef, Idriss
Abstract : The cathepsin K (CatK) enzyme is abundantly expressed in osteoclasts, and CatK inhibitors have been developed for the treatment of osteoporosis. In our effort to support discovery and clinical evaluations of a CatK inhibitor, we sought to discover a radioligand to determine target engagement of the enzyme by therapeutic candidates using positron emission tomography (PET). L‐235, a potent and selective CatK inhibitor, was labeled with carbon‐11. PET imaging studies recording baseline distribution of [ 11 C]L‐235, and chase and blocking studies using the selective CatK inhibitor MK‐0674 were performed in juvenile and adult nonhuman primates (NHP) and ovariectomized rabbits. Retention of the PET tracer in regions expected to be osteoclast‐rich compared with osteoclast‐poor regions was examined. Increased retention of the radioligand was observed in osteoclast‐rich regions of juvenile rabbits and NHP but not in the adult monkey or adult ovariectomized rabbit. Target engagement of CatK was observed in blocking studies with MK‐0674, and the radioligand retention was shown to be sensitive to the level of MK‐0674 exposure. [ 11 C]L‐235 can assess target engagement of CatK in bone only in juvenile animals. [ 11 C]L‐235 may be a useful tool for guiding the discovery of CatK inhibitors. Abstract : L‐235, a potent and selective inhibitor of cathepsin K, was efficiently labeled with carbon‐11. A higher uptake in the tracer was observed in the extremities of long bones in juvenile rabbits and monkeys, and dose dependent displacement of the radioligand can be observed. However, no signal was observed in ovariectomized rabbit or elderly monkey which preclude its use in osteoporosis drug development.