PROJECT SUMMARY/ABSTRACT Multiple myeloma (MM), a malignancy of mature plasma cells, is the second most common hematologic malignancy. Myeloma bone disease (MBD) is a devastating complication of MM. More than 80% of MM patients suffer from destructive bone lesions, leading to severe pain, pathologic fractures, mobility issues, and neurological deficits. MBD is not only a main cause of disability and morbidity in MM patients but also dramatically increases the cost of management. While recent advances in MM therapy have significantly increased the median survival of newly diagnosed patients, osteolytic lesions and their sequelae continue to be a major source of patient morbidity and mortality, and bone pain is the most frequent presenting symptom of MM patients. Rapid improvements in imaging technology now allow physicians to identify ever-smaller osteolytic lesions and bone marrow abnormalities, however, the clinical value of anatomic findings is not always clear. Therefore, earlier detection and more specific non-invasive assessment of treatment response are urgently needed, to assist in the clinical decision-making process and enable treatment optimization for the individual patient (“personalized medicine”). The objective of this IMAT-ITCR collaborative project is to evaluate novel 18F-labeled bisphosphonate (BP) probes for PET imaging of MBD in preclinical models, with potentially significant advantages over existing imaging agents, such as 18F-NaF. In parallel, we will develop quantitative imaging strategies to enhance the accuracy of PET imaging of MBD. It is a highly interdisciplinary project, bridging BP chemistry, radiochemistry, and quantitative PET imaging to detect early osteolytic lesions in animal models of MM. Implementation of this proposal will be based on a collaboration led by the PIs, Drs. Chen and McKenna at the University of Southern California (USC) and Dr. Shoghi at the Washington University School of Medicine (WUSM) in St. Louis. Dr. McKenna will expand the new chemistry discovered in his laboratory to rapidly and efficiently introduce fluorine into the P-C-P backbone of BP and then will work with Dr. Chen's group to optimize the 18F radiolabeling procedure. Dr. Chen will validate the newly developed 18F-labeled BP probes for the detection of osteolytic lesions in rodent models of MM. To support quantitative imaging of bone lesions, Dr. Shoghi will develop quantitative imaging pipelines to enhance the accuracy of PET imaging data derived from the bone marrow. These pipelines will enhance the capabilities of the preclinical imaging informatics platform developed through the ITCR grant to enhance the imaging data analysis. Taken together, the results will establish a solid foundation for ultimate clinical translation.