Office of Technology Transfer – University of Michigan

Radiolabeled Cathepsin Inhibitors for In Vivo Imaging

Technology #5438

Positron Emission Tomography Radioligands for Osteoporosis Detection. Radiolabeled cathespin K Inhibitors can be used as biomarkers for osteoclast activation. Osteoclasts are cells that break down bone and release calcium into the bloodstream. This process is known as “resorption,” and specifically results in a decrease in trabecular Bone Mineral Density (BMD.) Osteoblasts, and the osteoclasts they affect, are found at the surface of bones (in trabecular bone); therefore, trabecular bone is more subject to bone turnover. The wrists, hips, and spine have a high trabecular bone to cortical bone ratio, and thus, are more prone to fractures. Chemical biomarkers of osteoporosis have been identified in osteoclasts, and detection of these markers, can be used as markers for bone degradation. Researchers at the University of Michigan have gone one step further and radiolabeled effectors that act on these biomarkers, in an effort to determine osteoclast activation and to use it as even earlier biomarker of osteoporosis, prior to actual bone degradation. These radiolabeled effectors can be used with imaging methods, including Positron Emission Tomography (PET), to produce a 3-dimentional image of the osteoclast bone activity. Determining osteoclast activity, prior to the breakdown of bone, wound make these radiolabeled effectors more sensitive markers than those we currently have. With these radiolabeled markers, images can then be obtained and used to diagnose bone activity that can lead to osteoporosis, prior to significant bone degradation, as well as developing osteoporosis, and other musculoskeletal diseases (osteoarthritis, rheumatoid arthritis, or osteoporosis) involving bone loss. If detected early, steps can be taken to prevent disease progression.

Cathespin K Radioligands Can Be Used to Determine Changes in Bone Mineral Density and Detect Early Stage Osteoporosis through PET/CT Technology.

Cathespin K radioligands can be used in conjunction with current imaging methods for osteoporosis detection. Osteoporosis is a disease in which the loss of BMD contributes to an increased probability of fracture(s), which can result from insufficient bone strength and growth during development, or a subsequent imbalance of either bone growth, bone resorption, or a combination of both. Osteoporosis affects 55% of Americans over the age of 50 and is responsible for millions of fractures annually. Fractures can lead to both disability and increased mortality. The 6-month mortality rate following hip fracture is 13.5% and almost 13% of people who have suffered a hip fracture need total assistance. Vertebral fractures have a smaller mortality rate but can lead to severe chronic pain and deformity.
Currently, there are several ways to detect osteoporosis and other musculoskeletal diseases. First, conventional radiography can be used to measure BMD alone, or in conjunction with either CT or MRI scanning, to detect small fractures and reduced bone mass. However, these tests are insensitive and can only detect bone loss once it has progressed to an advanced stages, or fractures once they have occurred. Therefore, these tests are helpful only to determining a diagnosis. Second, Dual Energy X-ray Absorptiometry (a.k.a. DXA, or DEXA) is the most common test to determine BMD. This test is more sensitive than conventional radiography and reports a BMD as a T-score, which is compared to the T-score of a young health adult, and can be used for early detection as well as diagnosis. However, this test has been questioned as it compares results with peak bone mass of young adults (T-score) rather than that of a same aged control (Z-score). Third, Quantitative Computed Tomography (QCT) gives a separate reading for both trabecular and cortical bone, and reports BMD in mg/cm3 rather than a relative Z-score. Therefore, it improves on some of the problems with DXA. However, this method requires a high dose of radiation, compared to methods such as DXA, and results can be operator-dependent. Four, Quantitative Ultrasound uses the heel bone as a common skeletal site as it has a high percentage of trabecular bone. This is inexpensive, quick, easy to use, and does not require radiation. However, it is tarsal- specific and far more sensitive imaging machinery are required for this to be effective.
There remains a need for a more sensitive and specific method to accurately detect changes in BMD, as well as to detect early stage osteoporosis, before significant bone degradation can occur.

Applications: •Measure osteoclast activity and BMD under varying biological conditions. •Diagnose osteoporosis and other bone loss diseases, such as osteoarthritis, and rheumatoid arthritis. • Monitor for the action of hormones and cytokines that have been shown to inhibit osteoclasts.

Advantages: •Designed for PET technology but compatible with other standard measures of bone density and structure. •Can be used in conjunction with standard measures of bone •Early indicator of osteoporosis for earlier preventive care.