Novel Bisphosphonate PET Probes for Myeloma Bone Disease

项目总结/摘要 多发性骨髓瘤（MM）是一种成熟浆细胞的恶性肿瘤，是第二常见的血液系统疾病。 恶性肿瘤骨髓瘤骨病（MBD）是MM的一种毁灭性并发症。超过80%的MM患者 遭受破坏性骨损伤，导致严重疼痛、病理性骨折、活动性问题，以及 神经缺陷MBD不仅是MM患者残疾和发病的主要原因，而且还显著地影响了MM患者的生活质量。 增加了管理成本。虽然MM治疗的最新进展显著增加了 新诊断患者的中位生存期、溶骨性病变及其后遗症仍然是导致骨坏死的主要原因。 的患者发病率和死亡率，骨痛是最常见的表现症状的MM患者。快速 成像技术的改进现在允许医生识别更小的溶骨性病变和骨 骨髓异常，但解剖结果的临床价值并不总是明确的。因此，早些时候 检测和更具体的治疗反应的非侵入性评估是迫切需要的，以协助 并且能够针对个体患者进行治疗优化（“个性化 医学”）。 在这项探索性的R21应用中，我们提出了新型18F-BP-PET成像探头，为MBD患者提供 一种更敏感的溶骨性病变指标，促使他们利用新的治疗策略 可以提高这一群体的生存率我们的目标是证明这些创新的BP-PET探针可以克服 目前MM成像策略的一些缺点，并提供MBD的早期诊断。我们长久以来- 长期目标是将这一新平台转化为临床，作为更有效的成像、检测和 分期MBD。我们创新的化学设计提供了快速制备（在一个18F半衰期内）的建议 PET探头。冷化学将在南加州大学UPC实验室进行，由查尔斯·麦肯纳博士和他的 团队，然后与南加州大学HSC的Kai Chen博士团队详细说明放射化学要求 laboratories.所有放射化学，包括放射性同位素18F的原位回旋加速器生成，以及 体内动物研究和PET成像将在Kai Chen博士的指导下在USC Molecular 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记录新型18F-BP-PET探头的成像效果，我们将使用18F-FDG 和18F-NaF作为对照显像剂在啮齿类动物MM模型中，其可靠地导致相关骨病变 并与我们最好的新型探针进行比较，以确定相对灵敏度，检测早期骨病变的能力， 监测治疗反应的特异性和适用性。这些概念验证的成功完成 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.