Novel Bisphosphonate PET Probes for Myeloma Bone Disease

项目摘要/摘要 多发性骨髓瘤(MM)是一种成熟浆细胞的恶性肿瘤，是第二常见的血液病 恶毒。骨髓瘤是多发性骨髓瘤的严重并发症，超过80%的多发性骨髓瘤患者 遭受破坏性的骨骼损伤，导致严重疼痛、病理性骨折、行动不便以及 神经缺陷。多发性肌萎缩侧索硬化症不仅是多发性骨髓瘤患者残疾和发病的主要原因，而且 增加了管理成本。虽然多发性骨髓瘤治疗的最新进展显著增加了 新诊断患者的中位存活率、溶骨性病变及其后遗症仍是主要来源 骨痛是多发性骨髓瘤患者最常见的症状。快速 成像技术的进步现在使医生能够识别出更小的溶骨性病变和骨骼 骨髓异常，然而，解剖学发现的临床价值并不总是明确的。因此，早些时候 迫切需要对治疗反应进行检测和更具体的非侵入性评估，以帮助 临床决策过程，并实现针对个别患者的治疗优化(个性化 医学“)。 在这一探索性的R21应用中，我们提出了新的18F-BP-PET成像探针，为MBD患者提供 一种对溶骨性损害更敏感的测量方法，促使他们利用新的治疗策略 已知可以提高这一群体的存活率。我们的目标是证明这些创新的BP-PET探测器可以克服 指出了目前多发性骨髓瘤影像检查的一些不足，并提供了对多发性骨髓瘤的早期诊断.我们的长- 学期目标是将这一新平台转化为临床上更有效的成像、检测和 正在上演MBD。我们创新的化学设计提供快速制备(在一个18F半衰期内) 宠物探头。冷化学将在南加州大学实验室由查尔斯·麦肯纳博士和他的 团队，然后在南加州大学HSC与陈凯博士的团队一起详细阐述了放射化学要求 实验室。所有放射化学，包括放射性同位素18F的原位回旋加速器产生，以及In 活体动物研究和PET成像将在南加州大学分子医院陈凯博士的指导下进行 影像中心。优化的放射合成程序将在自动合成模块中进行验证 未来的临床生产。为了证明新的18F-BP-PET探针的成像效率，我们将使用18F-FDG 和18F-NaF作为对照显像剂在MM啮齿动物模型中可靠地导致相关的骨损害 并将它们与我们最好的新型探针进行比较，以确定相对敏感度，检测早期骨骼损伤的能力， 监测治疗反应的特异性和适宜性。成功完成这些概念验证 研究将为下一阶段的翻译开发奠定坚实的基础。

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 is urgently needed, to assist in the clinical decision-making process and enable treatment optimization for the individual patient (“personalized medicine”). In this exploratory R21 application we propose novel 18F-BP-PET imaging probes to provide MBD patients a more sensitive measure of osteolytic lesions prompting them to take advantage of new treatment strategies known to improve survival in this group. It is our goal to show that these innovative BP-PET probes can overcome some of the disadvantages of current imaging strategies for MM and provide earlier diagnosis of MBD. Our long- term objective is to translate this new platform into the clinic as a more effective probe for imaging, detecting and staging MBD. Our innovative chemistry design offers rapid preparation (within one 18F half-life) of the proposed PET probes. Cold chemistry will be performed at the USC UPC laboratories by Dr. Charles McKenna and his team, and then elaborated for radiochemistry requirements with Dr. Kai Chen’s group at the USC HSC laboratories. All radiochemistry, including in situ cyclotron generation of the radioisotope 18F, as well as the in vivo animal studies and PET imaging will be performed under Dr. Kai Chen’s direction at the USC Molecular Imaging Center. The optimized radiosynthesis procedure will be validated in an automated synthesis module for future clinical production. To document the imaging efficacy of novel 18F-BP-PET probes, we will use 18F-FDG and 18F-NaF as control imaging agents in a rodent model of MM which reliably results in related bone lesions and compare them with our best novel probe to determine relative sensitivity, ability to detect early bone lesions, specificity and aptness to monitor treatment response. The successful completion of these proof-of-concept studies will serve as a solid foundation for next phase translational development.