Development of Novel Hyperpolarized MR Molecular Imaging Probes Tested in Realistic Pre-Clinical Models and Correlative Science Studies

TRD 2项目总结/摘要 13个合作项目（CP 1- 10，13）中的11个是HMTRC更新背后的驱动力， 12个服务项目中有10个（SP 1-4、6和8-11）明确需要改进超极化（HP） 探针和方法，现实的临床前模型，相关的病理学和分子方法学，以及其他 TRD 2提供的协同成像研究。在过去十年的资助中，TRD 2有着出色的记录 生产力，支持了117篇同行评审的出版物和41项NIH赠款，并且在之前的资助期间， 在此期间，我们利用临床前进展获得了两种新HP探针的FDA IND批准- [2- 13 C]丙酮酸盐用于改善TCA循环的成像，以及在2021年共极化[13 C，15 N2]尿素和[1- 13 C]丙酮酸盐 用于同时进行代谢和灌注成像。 根据CP和SP的新需求，我们外部咨询委员会的建议，以及临床 咨询顾问，这个TRD 2更新项目将采取几个令人兴奋的创新方向，重点是增加HP 通过HP的开发/优化实现13 C探针灵敏度、体内性能和临床可翻译性 探针、探针配方和极化方法（目标1），优化更真实的临床前模型 目的2：探讨HP 13 C MR研究的方法，并获得相关的病理、分子和多模态 成像研究（目标3），以优化和验证HP 13 C MR生物标志物和临床转化方法。 这些研究目标将通过实施新的临床前9.4T与TRD 1协同实现 具有1H/13 C MRI冷冻探针功能的MR扫描仪，新一代更高场、更低温度的临床前 DNP偏振器和改进的射频线圈技术，可显著改善临床前HP 13 C MR研究。与 TRD 3，我们将实施更灵敏的动态HP 13 C MR脉冲序列（EPSI、EPI和bSSFP）， 专注于开发强大的，标准化的和定量的成像协议，以及新的在线临床前数据 分析和显示工具集成到免费的开源平台中。 尽管HP MR探头和技术将由CP专门驱动（推挽），并使用 在SP中，它们将大大扩展HP 13 C MR的科学范围和临床前适用性， 普遍并显著影响其临床翻译。该项目的主要成果是传播 优化的HP探针制备和方法，新的NMR兼容细胞和组织培养生物反应器 系统和临床前GEM和PDX模型，针对HP 13 C MR研究进行了优化，相关病理学，分子 和协同成像方法，以及相关的生物医学传播和培训， 社区

TRD2 PROJECT SUMMARY/ABSTRACT Eleven of the 13 Collaborative Projects (CPs 1-10,13) that are the driving force behind this HMTRC renewal and 10 of the 12 Service Projects (SPs 1-4, 6, and 8-11) demonstrate a clear need for improved hyperpolarized (HP) probes and methods, realistic preclinical models, correlative pathology and molecular methodologies, and other synergistic imaging studies provided by TRD2. Over the last decade of funding, TRD2 has an outstanding record of productivity, having supported 117 peer-reviewed publications and 41 NIH grants, and during the prior funding period, we have leveraged preclinical advances to obtain FDA IND approval for two new HP probes – [2- 13C]pyruvate for improved imaging of the TCA cycle and in 2021 co-polarized [13C,15N2]urea and [1-13C]pyruvate for simultaneous metabolic and perfusion imaging. Based on the new needs of the CPs and SPs, the advice of our External Advisory Committee, and clinical consultants, this TRD2 renewal project will take several exciting innovative directions focused on increasing HP 13C probe sensitivity, in vivo performance, and clinical translatability through the development/optimization of HP probes, probe formulations and polarization approaches (Aim 1), optimizing more realistic preclinical models and methods for HP 13C MR studies (Aim 2) and obtaining correlative pathologic, molecular and multimodal imaging studies (Aim 3) to optimize and validate HP 13C MR biomarkers and methods for clinical translation. These research goals will be accomplished in synergy with TRD1 through implementing a new preclinical 9.4T MR scanner with 1H/13C MRI cryoprobe capabilities, a next generation higher field, lower temperature preclinical DNP polarizer and improved rf coil technologies for significantly improved preclinical HP 13C MR studies. With TRD3, we will implement more sensitive dynamic HP 13C MR pulse sequences (EPSI, EPI and bSSFP), with a focus on developing robust, standardized, and quantitative imaging protocols, and new on-line preclinical data analysis and display tools integrated into the free, open-source platforms. Although the HP MR probes and techniques will be specifically driven (push-pull) by the CPs, and utilized (pushed) in the SPs, they will greatly expand the scientific scope and preclinical applicability of HP 13C MR in general and significantly impact its clinical translation. The main deliverables of this project are the dissemination of optimized HP probe preparations and methods, new NMR-compatible cell and tissue culture bioreactor systems and preclinical GEM and PDX models optimized for HP 13C MR studies, correlative pathology, molecular and synergistic imaging approaches, and the associated dissemination and training for the biomedical community.