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

TRD2项目摘要/摘要 13个合作项目中的11个(合作项目1-10，13个)是推动香港地铁公司重建和 12个服务项目中的10个(SP 1-4、6和8-11)表明需要改进超极化(HP) 探索和方法、现实的临床前模型、相关的病理学和分子方法学等 由TRD2提供的协同成像研究。在过去十年的资助中，TRD2有着出色的记录 生产力，支持了117份同行评议的出版物和41份国家卫生研究院的赠款，并在之前的资助期间 在此期间，我们利用临床前的进展，获得了FDA IND对两个新的惠普探测器的批准-[2- 13C]丙酮酸用于改进TCA循环的成像，并在2021年共极化[13C，15N2]尿素和[1-13C]丙酮酸 用于同时进行新陈代谢和灌注成像。 基于CPS和SPS的新需求，我们外部咨询委员会的建议，以及临床 顾问们，这个TRD2续订项目将采取几个令人兴奋的创新方向，重点是增加惠普 通过HP的开发/优化实现13C探针的灵敏度、体内性能和临床可转译性 探头、探头配方和极化方法(目标1)，优化更现实的临床前模型 和Hp 13C磁共振研究方法(目标2)，并获得相关的病理、分子和多模式 影像研究(目标3)优化和验证惠普13C磁共振生物标志物和临床翻译方法。 这些研究目标将通过实施新的临床前9.4T与TRD1协同实现 具有1H/13C磁共振冷冻探头能力的磁共振扫描仪，新一代高场、低温临床前 DNP偏振器和改进的RF线圈技术显著改善了临床前HP 13C磁共振研究。使用 TRD3，我们将实现更敏感的动态HP 13C MR脉冲序列(EPSI、EPI和bSSFP)，具有 专注于开发强大、标准化和定量的成像方案，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CPS具体驱动(推拉)，并利用 在SPS中，他们将极大地扩展HP 13C磁共振的科学范围和临床前适用性 并对其临床翻译产生重大影响。该项目的主要交付成果是传播 优化的幽门螺杆菌探针制备和方法，新的核磁共振兼容细胞和组织培养生物反应器 针对Hp 13C磁共振研究优化的系统和临床前GEM和PDX模型，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.